Herpes Zoster: A Brief Definitive Review.

ABSTRACT: This brief definitive review of herpes zoster (HZ) will cover the current state of knowledge and questions that remain to be answered regarding HZ in general and HZ ophthalmicus in particular. A question-and-answer format will be used to address various important topics related to this common and serious disease. Questions to be addressed relate to common misconceptions, contagiousness of infection, unknowns regarding pathogenesis, rising incidence, risk factors and complications, relationship with temporal arteritis, vaccination, and current and future antiviral treatment. In addition, the importance of the Zoster Eye Disease Study to determine the efficacy of suppressive valacyclovir treatment in preventing complications of HZ ophthalmicus and the need to support enrollment will be discussed.

Classification Criteria for Herpes Simplex Virus Anterior Uveitis.

PURPOSE: The purpose of this study was to determine classification criteria for herpes simplex virus (HSV) anterior uveitis DESIGN: Machine learning of cases with HSV anterior uveitis and 8 other anterior uveitides. METHODS: Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used in the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated in the validation set. RESULTS: A total of 1,083 cases of anterior uveitides, including 101 cases of HSV anterior uveitis, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval: 92.4-98.6). Key criteria for HSV anterior uveitis included unilateral anterior uveitis with either 1) positive aqueous humor polymerase chain reaction assay for HSV; 2) sectoral iris atrophy in a patient ≤50 years old; or 3) HSV keratitis. The misclassification rates for HSV anterior uveitis were 8.3% in the training set and 17% in the validation set. CONCLUSIONS: The criteria for HSV anterior uveitis had a reasonably low misclassification rate and appeared to perform well enough for use in clinical and translational research.

Classification Criteria for Varicella Zoster Virus Anterior Uveitis.

PURPOSE: To determine classification criteria for varicella zoster virus (VZV) anterior uveitis. DESIGN: Machine learning of cases with VZV anterior uveitis and 8 other anterior uveitides. METHODS: Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the anterior uveitides. The resulting criteria were evaluated on the validation set. RESULTS: One thousand eighty-three cases of anterior uveitides, including 123 cases of VZV anterior uveitis, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for VZV anterior uveitis included unilateral anterior uveitis with either (1) positive aqueous humor polymerase chain reaction assay for VZV; (2) sectoral iris atrophy in a patient ≥60 years of age; or (3) concurrent or recent dermatomal herpes zoster. The misclassification rates for VZV anterior uveitis were 0.9% in the training set and 0% in the validation set, respectively. CONCLUSIONS: The criteria for VZV anterior uveitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

Distinguishing Features of Anterior Uveitis Caused by Herpes Simplex Virus, Varicella-Zoster Virus, and Cytomegalovirus.

PURPOSE: To determine distinguishing features of the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV). DESIGN: Retrospective, multicenter case series. METHODS: Consecutive patients with herpetic AU examined at 11 tertiary centers in Japan between January 2012 and December 2017 and who were followed for ≥3 months were evaluated. Diagnosis was made by polymerase chain reaction (PCR) for HSV, VZV, or CMV in the aqueous humor, or classical signs of herpes zoster ophthalmicus. RESULTS: This study enrolled 259 herpetic AU patients, including PCR-proven HSV-AU (30 patients), VZV-AU (50), and CMV-AU (147), and herpes zoster ophthalmicus (32). All HSV-AU and VZV-AU patients were unilateral, while 3% of CMV-AU patients were bilateral. Most HSV-AU and VZV-AU patients were sudden onset with an acute clinical course, while CMV-AU had a more insidious onset and chronic course. There were no significant differences for all surveyed symptoms, signs, and complications between HSV-AU and VZV-AU. However, significant differences were detected for many items between CMV-AU and the other two herpetic AU types. Ocular hyperemia and pain, blurring of vision, ciliary injection, medium-to-large keratic precipitates (KPs), cells and flare in the anterior chamber, and posterior synechia significantly more often occurred in HSV-AU and VZV-AU vs CMV-AU. In contrast, small KPs, coin-shaped KPs, diffuse iris atrophy, elevated intraocular pressure, and glaucoma surgery were significantly more frequent in CMV-AU vs HSV-AU and VZV-AU. CONCLUSION: This multicenter, retrospective study identified distinguishing features of HSV-AU, VZV-AU, and CMV-AU.

ACUTE RETINAL NECROSIS ASSOCIATED WITH HERPES ZOSTER VACCINATION.

PURPOSE: To report a case of Zostavax-associated acute retinal necrosis in a patient with chronic lymphocytic leukemia. METHODS: Case report. PATIENTS: A 76-year-old white man. RESULTS: Unilateral acute retinal necrosis with obliterative angiopathy developed in close proximity of a Zostavax vaccine. Treatment with valacyclovir hydrochloride (1 g orally three times a day) and intravitreal ganciclovir (4 mg/0.1 mL) was initiated on presentation. Because of continuous increase of the retinal necrosis, patient was switched to intravenous acyclovir (7.5 mg/kg body weight, adapted to reduced glomerular filtration rate) and given intravitreal foscarnet (2.4 mg/0.1 mL). Despite being on maximal antiviral therapy, the patient suffered a central retinal artery occlusion. DISCUSSION: Acute retinal necrosis is a severe complication and potentially blinding disease of herpes zoster, and can occur in association with herpes zoster immunization, in particular, in immune suppressed patients.

Ophthalmic Shingles with Simultaneous Acute Retinal Necrosis in the Opposite Eye.

Purpose: To report a case of acute retinal necrosis (ARN) occurring in the opposite eye to the ophthalmic shingles eruption.Design: Case report.Methods: Clinical examination and multimodal imaging review, including ultra-widefield photography and fluorescein angiography (FA).Results: A 49-years-old man attended the Uveitis Service for concurrent acute visual loss in the right eye and ophthalmic shingles skin eruption of the left ophthalmic trigeminal branch. Fundus examination of the right eye revealed multiple yellowish patchy areas of retinitis in the peripheral retina consistent with ARN. Multimodal imaging and laboratory tests confirmed the diagnosis.Discussion: Herpes Zoster Ophtalmicus (HZO) represents the 10-20% of Herpes Zoster (HZ) cases and ARN is a rare but sight-threatening complication due to the viral widespread along the retina. By definition, the reactivation of Varicella Zoster virus (VZV) has a unilateral clinical expression, due to the centrifugal neural pathway followed by the virus from the neural ganglia, and HZO, as well, results located on the same side of the skin affection. The case presented contradicted this postulate.Conclusion: prompt diagnosis, through fundus examination and FA, and proper antiviral therapy were the mainstays to counteract the posterior uveitis. Nowadays, vaccination is a safe weapon to efficaciously reduce the ZVZ incidence among general population.

Immune Cell Status and Cytokines Profiles in Patients with Acute Retinal Necrosis.

Purpose: To assess the immune status of acute retinal necrosis (ARN) patients and to investigate the immune cell types involved in the immunopathogenesis.Methods: Peripheral blood and intraocular fluid were collected from 17 ARN patients and 9 control subjects. The Percentage of immune cells was measured using flow cytometry, levels of complement and antibodies were determined by rate nephelometry, and cytokine levels in the serum and aqueous humor (AH) were detected using cytokine quantitative chips. Data were analyzed using SPSS 23.0. p < .05 was considered statistically significant.Results: Proportion of T-helper 17 cells (p = .034) in serum and concentrations of multiple cytokines associated with Th17 cells (IL-6, IL-17, IL-17 F, IL-21, IL-22) in AH and serum were elevated of ARN patients.Conclusion: Th17 cells appeared to participate in the development of ARN. We found inflammatory cytokines and cells were elevated in the serum and AH of ARN patients.

Viral Kerato-Uveitis with Choroidal Vitiligo.

Purpose: To describe unusual fundus findings in typical varicella zoster (VZV) kerato-uveitis.Methods: Observational, retrospective case study of five patients diagnosed with VZV kerato-uveitis.Results: Four out of five cases had a history of typical herpes zoster ophthalmicus skin rash over the forehead. All five patients had stromal keratitis, granulomatous keratic precipitates, and mild-moderate anterior chamber reaction, and two cases had typical VZV-iris atrophic changes. All cases demonstrated clear vitreous and multiple hypopigmented choroidal lesions (MHCL) with indistinct borders only in the affected eyes. Imaging studies failed to demonstrate evidence of active or resolved choroiditis. MHCL remained status quo in all including two cases who had recurrences of kerato-uveitis.Conclusion: We describe previously unreported novel fundus finding, MHCL in typical VZV-kerato-uveitis cases. We presume MHCL are due to loss of melanin from choroidal melanocytes secondary to the VZV infection and propose a term "choroidal vitiligo" to describe these novel fundus findings.

Transitory outward pupillary curling in a case of HSV associated acute anterior uveitis: a hitherto unreported sign.

We report a case of herpes simplex virus (HSV) associated acute anterior uveitis in otherwise healthy 38-year-old man with an unusual finding of outward pupillary margin curling. At presentation visual acuity was 20/60 in right eye (OD) and 20/20 in left eye (OS). Intraocular pressure was 44 and 18 mm Hg in OD and OS respectively. OD revealed diffuse conjunctival congestion, stromal oedema, pigmented keratic precipitates, cells grade 3+ and flare 2+ on slit-lamp examination and diminished corneal sensations. OS was unremarkable. There was a history of three similar episodes in last 1 year. Aetiology of this recurrent acute anterior uveitis was confirmed to be HSV via DNA-PCR assay of aqueous fluid. This hitherto unreported sign associated with viral hypertensive uveitis was transitory in nature and reversible with control of anterior chamber inflammation, without leaving any permanent damage. Topical steroids and antiglaucoma were stopped, while antiviral therapy was continued for 3 months.

Herpetic Anterior Uveitis in a Chinese Referral Center: Clinical Manifestations and Laboratory Test Results.

PURPOSE: To describe and to compare the clinical manifestation and laboratory test results of herpetic anterior uveitis (HAU) caused by Herpes simplex virus (HSV) and varicella-zoster virus (VZV). METHODS: A retrospective, observational study on patients diagnosed with HAU. Etiology, clinical features, ocular complications, and recurrences of the infection were evaluated as main clinical parameters. The aqueous Interleukin-8 (IL-8) level was also measured to assess the intraocular inflammation. RESULTS: Thirty-two eyes (32 patients) were involved. Among all involved cases, 24 had VZV-AU and 8 had HSV-AU. Common clinical features of HAU included the presence of KPs (90.6%), distorted pupil (83.3%), Iris atrophy (71.9%) and corneal edema (50%). The intraocular fluid analysis showed higher viral load and IL-8 level in VZV-AU. CONCLUSIONS: Compared with HSV-AU, the intraocular inflammation was more severe in VZV-AU. The intraocular fluid analysis was valuable for the etiological diagnosis and the evaluation of disease severity.

BILATERAL ACUTE RETINAL NECROSIS: A Case Series.

PURPOSE: To investigate the clinical characteristics and visual outcome of bilateral acute retinal necrosis. METHODS: The study included 30 patients (60 eyes) who were diagnosed with bilateral acute retinal necrosis. The medical records were reviewed. RESULTS: Twenty-five patients developed the disease in the contralateral eye within 5 months and 5 patients at >2 years after the initial onset. At presentation, 14 of 21 eyes suffered from retinal necrosis of more than 180° in the initially affected eye, whereas 3 of 22 eyes suffered it in the later-affected eye. Retinal detachment occurred in 23 of the 27 initially affected eyes and in 5 of the 27 later-affected eyes. The mean logarithm of the minimum angle of resolution best-corrected visual acuity decreased from 2.0 ± 1.1 (Snellen equivalent counting fingers) to 2.2 ± 1.0 (Snellen equivalent counting fingers) in the initially affected eyes after a follow-up of 34.1 ± 48.2 months (P = 0.529), and improved from 0.5 ± 0.4 (Snellen equivalent 20/66) to 0.3 ± 0.4 (Snellen equivalent 20/40) in the later-affected eyes after a follow-up of 21.2 ± 23.3 months (P = 0.005). CONCLUSION: Bilateral acute retinal necrosis usually occurs in the contralateral eye within a few months, but sometimes after several years. Inflammation and retinal necrosis are less severe in the later-affected eye, with less retinal detachment and a better visual outcome.

Recurrent Herpes Zoster Ophthalmicus in a Patient With a Novel Toll-Like Receptor 3 Variant Linked to Compromised Activation Capacity in Fibroblasts.

BACKGROUND: Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus. METHODS: Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed. RESULTS: Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised. CONCLUSIONS: We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.

Comparison of visual field defect progression in secondary Glaucoma due to anterior uveitis caused by three types of herpes viruses.

PURPOSE: To clarify the prevalence of secondary glaucoma (SG) and its speed of progression in patients with herpes simplex virus (HSV)-anterior uveitis (AU), varicella zoster virus (VZV)-AU, and cytomegalovirus (CMV)-AU. METHODS: In total, 170 patients with herpetic AU were enrolled in this retrospective observational case series. Patients with visual field (VF) defects and glaucomatous disc abnormalities were diagnosed with SG. Moreover, the speed of SG progression was defined as decreasing mean deviation (MD) values per year. SG prevalence and annual MD-value decrease were compared among the three types of herpetic AU. RESULTS: SG prevalence was 16%, 9%, and 72% in patients with HSV-AU, VZV-AU, and CMV-AU, respectively. Patients with CMV-AU had the highest SG prevalence (odds ratio = 3.15; 95% confidence interval = 1.15-8.65; P < 0.05). Furthermore, the annual MD-value change was significantly higher in SG caused by CMV-AU than in that caused by HSV/VZV-AU (-2.6 ± 2.4 dB/year and -0.45 ± 0.54 dB/year, respectively; P < 0.05). CONCLUSIONS: Our results demonstrated that patients with CMV-AU may have a higher risk and faster speed of progression of SG than patients with HSV/VZV-AU. Therefore, clinicians should monitor glaucoma onset and VF-defect progression in patients with CMV-AU.

Development of Acute Retinal Necrosis in a Patient with Ocular Sarcoidosis: A Case Report.

Purpose: To report a case of acute retinal necrosis (ARN) caused by varicella-zoster virus (VZV) in an elderly patient with ocular sarcoidosis after oral corticosteroid indication. Methods: Retrospective case report. Results: A 75-year-old male with a past history of ocular sarcoidosis came with blurred left vision. Ocular findings in the left eye were consistent with ocular sarcoidosis, while no inflammation in the right eye. On day 14, intraocular inflammation in the left eye resolved by topical corticosteroid, but inflammatory cells were found in the right eye. Suspecting recurrence of ocular sarcoidosis, systemic corticosteroid was initiated. On day 21, inflammation worsened, and the presence of extended yellowish white peripheral retinal lesion in the right eye suggested ARN. Polymerase chain reaction (PCR) testing using ocular fluid detected 3.0 × 107 copies/ml of VZV DNA. Conclusions: In the case of poor response to immunosuppressive therapy in elderly uveitis, infection including ARN should be considered. Immediate PCR testing for pathogen screening is required.

Acute Retinal Necrosis: Virological Features Using Quantitative Polymerase Chain Reaction, Therapeutic Management, and Clinical Outcomes.

PURPOSE: To evaluate outcomes of patients treated with intensive intravitreal therapy and to describe the evolution of quantitative real-time polymerase chain reaction (qPCR) in patients treated for acute retinal necrosis (ARN) syndrome. DESIGN: Retrospective observational case series. METHODS: This study included 25 eyes of 24 patients with ARN who were treated and followed up in 2 departments of ophthalmology in Lyon, France. Assessed outcomes included qPCR viral load profile during treatment, number of antiviral intravitreal injections (IVT), retinal detachment rate, and best-corrected visual acuity. RESULTS: Final visual acuity was 20/200 or less in 20% of cases; the rate of retinal detachment was 16%. Viral load kinetics changed in 3 phases: a first plateau period that was not consistent, a logarithmic decrease phase, and a negativation phase. Mean decay of the logarithm of the viral load was estimated at 0.076 per day; mean time of negativation was 56.1 days. Median IVT number was 9 (range, 0-28). Ten patients were treated with injections until the viral load was undetectable. Resistance to acyclovir was observed in a patient with a prolonged initial plateau of the viral load. CONCLUSIONS: Numerous and prolonged IVTs, used as adjunctive therapy, could improve the prognosis of treated patients by decreasing the risk of retinal detachment and improving visual acuity. QPCR enables monitoring of the response to treatment and can provide evidence for resistance to antiviral treatment by enabling the detection of cases with a prolonged initial plateau of viral load.

Headache and vision changes in an elderly man with rheumatoid arthritis.

We present a case of an elderly, immunosuppressed patient with rheumatoid arthritis who was not appropriately vaccinated, and subsequently developed herpes zoster ophthalmicus, which initially presented similar to giant cell arteritis. Evidence-based vaccinations are integral in decreasing the incidence of preventable diseases and promoting optimal health at the individual and population level. Although the patient ultimately did not suffer any long-term adverse sequelae, this case highlights the importance of vaccination in the rheumatology setting, and to consider both inflammatory and infectious causes of headache and vision changes in the elderly.