Flow cytometric analysis of T lymphocytes and cytokines in aqueous humor of patients with varicella zoster virus-mediated acute retinal necrosis.

BACKGROUND: The purpose of this study is to investigate the aqueous humor (AH) T lymphocyte subsets and cytokines of acute retinal necrosis (ARN) to elucidate the immunologic inflammatory features of this disorder. METHODS: Three patients with ARN infected with varicella zoster virus (VZV) who underwent multiple intravitreal injections of ganciclovir were enrolled in this study. The control group consisted of four non-infectious patients with acute anterior uveitis (AAU). Flow cytometric analysis was performed on the lymphocyte subsets from the AH and peripheral blood (PB) samples during the active phase of intraocular inflammation. Five inflammatory cytokines were measured in each AH sample and various clinical characteristics were also assessed. RESULTS: VZV deoxyribonucleic acid (DNA) was detected by real-time polymerase chain reaction (PCR) in AH from all the ARN patients, who showed higher CD8+ T lymphocytes population in AH than the AAU patients (p = 0.006). CD4/CD8 ratios of T lymphocytes and the percentage of CD8 + CD25+ T lymphocytes in AH were significantly lower in ARN than in AAU (p = 0.006; p = 0.012). In the ARN patients, the percentages of CD4+ and CD8+ T lymphocytes in AH were higher than those found in PB. The percentage of CD4 + CD25+ T lymphocytes in AH was significantly higher than the proportion in PB in the AAU patients (p = 0.001). Immunoregulatory cytokine Interleukin-10 in AH was significantly elevated in the ARN patients in comparison with the case of the AAU patients (p = 0.036). In ARN, the copy number of VZV DNA in AH positively correlated with the percentage of CD8+ T lymphocytes in AH and negatively correlated with the CD4/CD8 ratio in AH during the course of disease treatment (p = 0.009, r = 0.92; p = 0.039, r = - 0.834). CONCLUSION: The ARN patients caused by VZV had different intraocular T lymphocyte subsets and cytokines profile than those of the non-infectious patients. High percentages of CD8+ T lymphocytes and low CD4/CD8 T cell ratios may be a potential biomarker for diagnosis of viral-infectious uveitis. T lymphocytes examination at the inflammatory sites has the potential to become a useful research tool for differentiating viral and non-viral uveitis.

Visual outcome and poor prognostic factors in acute retinal necrosis syndrome.

OBJECTIVE: To evaluate the impact of selected clinical parameters on the mid-/long-term visual outcome of patients with acute retinal necrosis (ARN) DESIGN: A retrospective cohort study SETTING: Two University Hospitals (Parma, Italy; Lausanne, Switzerland). PARTICIPANTS: Thirty-nine non-HIV patients (39 eyes) with ARN, as confirmed by polymerase chain reaction on intraocular samples. The following potential predictors were tested using linear regression models: age, sex, etiology, best-corrected visual acuity (BCVA) on admission, delay between ARN symptom onset and treatment initiation, and surgery (performed or not). MAIN OUTCOME: BCVA at the final follow up RESULTS: Thirty-nine of 39 non-HIV patients (22 men and 17 women; mean age, 50 years) diagnosed with ARN were enrolled in the study. Etiologies were: varicella-zoster virus in 25 eyes (64%), herpes simplex viruses in the remaining 14 eyes. The average follow-up duration was 19 ± 13 months. All patients had undergone systemic antivirals; surgery was performed in 16 eyes. The mean delay between onset of visual symptoms and antiviral treatment initiation was 15 ± 31 days (range, 1-180 days). The mean BCVA at baseline was 0.83 ± 0.75 logMAR, while the mean final BCVA was 0.75 ± 0.81 logMAR. Both initial BCVA and treatment delay (TD) were significantly correlated with the final BCVA (p < 0.05). CONCLUSIONS: Initial BCVA and TD seem to be significant predictors of mid-/long-term visual outcome in non-HIV patients affected by ARN.

Tocilizumab and Aflibercept as a Treatment Option for Refractory Macular Edema after Acute Retinal Necrosis.

Introduction: The inflammatory milieu after acute retinal necrosis (ARN) may lead to a breakdown of the inner and outer blood-retinal barrier and consequently to a cystoid macular edema (CME) with accumulation of intra- and subretinal fluid. Up to now, there is no established therapeutic approach for CME in ARN patients.Case report: We report a case of an immunocompetent 14-year-old female with chronic ARN-related CME, which was unresponsive to valacyclovir, prednisone and intravitreal ranibizumab injections. A combination treatment of tocilizumab, an interleukin-6 receptor inhibitor, and intravitreal aflibercept was successful to control the CME.Conclusion: In selected patients with treatment-refractory CME following ARN a therapy with tocilizumab and intravitreal aflibercept might be considered.

Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants.

Purpose: Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases. Methods: We collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance. Results: We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients. Discussion: We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.

Acute Retinal Necrosis: Clinical Features, Diagnostic Pitfalls, Treatment, and Outcome of an Insidious Disease in Children. Case Report and Review of the Literature.

Objective: This study aims to explore clinical features, diagnostic work-up, treatment, and outcomes of pediatric patients with acute retinal necrosis (ARN), and to propose a standardized management of this condition in childhood. Methods: Clinical manifestations, diagnostic work-up, and treatment of three pediatric cases with ARN were analyzed. Furthermore, a review of the literature was performed from January 1990 to November 2021, focused on 1) clinical presentation; 2) differential diagnosis, including both infectious and non-infectious conditions; 3) key role of diagnostic techniques; and 4) currently available treatments. Results: Data from 72 children with ARN (69 from literature and 3 from our center) were analyzed. The most frequent presenting symptoms were red eye resistant to topical treatment (57%) and altered vision (58%), 25 patients had bilateral involvement. In 30% a known history of herpetic infection was reported. PCR testing on anterior chamber and/or vitreous sampling was performed in 46 cases (64%) and was diagnostic in 88% of them, with herpes simplex virus (HSV) 2 being the most frequently identified pathogen (57%). All patients underwent systemic antiviral therapy (16% only oral); adjunctive intravitreal injections were performed in 21% of them. Conclusions: ARN is a rare but severe ocular infection presenting as a panuveitis with occlusive retinal vasculitis and peripheral retinal necrosis. Varicella-zoster virus and HSV 1-2 are most frequently implicated. Due to a high incidence of rhegmatogenous retinal detachment and optic atrophy, ARN has a poor prognosis with a potentially severe impact on visual function. Although a prompt recognition is crucial to prevent complications, ARN diagnosis in children is still challenging.

Acute retinal necrosis: A mini review.

Acute retinal necrosis is a rare but potentially devastating disease. Even in the era of modern medicine, retinal detachment is a frequent complication leading to vison loss, as well as phthisis bulbi. Whereas IV acyclovir still remains the standard of care, high doses of valacyclovir with/without additional intravitreal injections of foscarnet have been used. In an attempt to reduce the retinal detachment rate, prophylactic laser treatment and early vitrectomy have been proposed. In this article, we aim to review current diagnostic and treatment modalities.

Clinically applicable artificial intelligence algorithm for the diagnosis, evaluation, and monitoring of acute retinal necrosis.

The prompt detection and proper evaluation of necrotic retinal region are especially important for the diagnosis and treatment of acute retinal necrosis (ARN). The potential application of artificial intelligence (AI) algorithms in these areas of clinical research has not been reported previously. The present study aims to create a computational algorithm for the automated detection and evaluation of retinal necrosis from retinal fundus photographs. A total of 149 wide-angle fundus photographs from 40 eyes of 32 ARN patients were collected, and the U-Net method was used to construct the AI algorithm. Thereby, a novel algorithm based on deep machine learning in detection and evaluation of retinal necrosis was constructed for the first time. This algorithm had an area under the receiver operating curve of 0.92, with 86% sensitivity and 88% specificity in the detection of retinal necrosis. For the purpose of retinal necrosis evaluation, necrotic areas calculated by the AI algorithm were significantly positively correlated with viral load in aqueous humor samples (R2=0.7444, P<0.0001) and therapeutic response of ARN (R2=0.999, P<0.0001). Therefore, our AI algorithm has a potential application in the clinical aided diagnosis of ARN, evaluation of ARN severity, and treatment response monitoring.

Acute Retinal Necrosis as a presenting ophthalmic manifestation in COVID 19 recovered patients.

Purpose: Infection by the SARS-CoV2 virus results in an immune dysregulated state which can predispose to reactivation of Herpes viruses. This report describes the development of Acute Retinal Necrosis (ARN) in two patients who had recovered from SARS-CoV2 infection.Methods: Observational report of two consecutive patients who presented with ARN after having recovered from SARS-CoV-2 infection.Results: Case 1 was a 5-year-old child with extensive peripheral necrotizing retinitis. Case 2 was a 61-year-old gentlemen with bilateral retinal detachment with sieve-like breaks and optic atrophy. Both patients had recovered from SARS- Cov-2 infection 1 month ago. PCR from vitreous sample of both patients was positive for Herpes simplex virus. Case 1 was treated with oral valacyclovir. Case 2 underwent surgery in both eyes for retinal detachmentConclusion: Immune dysregulation after COVID-19 infection can result in reactivation of herpesvirus and may lead to development of ARN.

Case series: Two cases of herpetic retinitis presenting as progressive outer retinal necrosis in immunocompetent individuals.

PURPOSE: To raise awareness of ophthalmologists that Varicella Zoster Virus (VZV) retinitis should be considered in the differential diagnosis of retinitis that presents with features of progressive outer retinal necrosis (PORN) in healthy immunocompetent patients. OBSERVATIONS: Case 1 is a 39-year-old healthy Caucasian male who presented after one week of decreased vision in the left eye. Patient was found to have optic disc edema and multifocal retinitis primarily localized to the posterior pole with only a few lesions in the periphery and minimal vitritis. Viral PCR of a vitreous tap was positive for 1 million copies of VZV. Patient ultimately progressed to no light perception vision despite multiple intravitreal injections of foscarnet and several days of intravenous acyclovir therapy. Case 2 is another 39-year-old healthy Caucasian male that presented after 2 weeks of decreased vision in the left eye. On initial exam by his primary ophthalmologist, patient was found to have optic disc edema and multifocal retinitis primarily localized to the posterior pole with no peripheral lesions and no vitritis. The patient then presented to our clinic with extensive retinitis throughout the posterior pole and periphery, and he underwent a vitreous tap with viral PCR positive for 3160 copies of VZV. He was treated with intravitreal injections of foscarnet and intravenous acyclovir therapy with subtle progression to the right eye and only minimal improvement of left eye vision to 20/200. CONCLUSIONS AND IMPORTANCE: Progressive outer retinal necrosis (PORN) is a herpetic retinopathy characterized by rapidly progressive necrosis of the outer retina in severely immunocompromised subjects. As demonstrated in this case series, VZV retinitis should be considered as a differential diagnosis in patients with hallmark features of PORN, even in the absence of obvious systemic immunosuppression.

Concurrent acute retinal necrosis and orbital inflammation: Report of 2 cases.

PURPOSE: To describe the rare entity of concurrent herpetic acute retinal necrosis (ARN) and orbital inflammation. OBSERVATIONS: Two cases of ARN with simultaneous orbital inflammation are described. A 40-year old male presented with a painful left eye and hand motion visual acuity (VA). Both panuveitis and orbital inflammation with involvement of the sclera and optic nerve were observed. He was initially treated with oral steroid therapy, after which the orbital inflammation improved but the panuveitis remained. A diagnostic anterior chamber paracentesis was positive for HSV-2 by PCR. He was started on systemic antivirals, but ultimately developed a retinal detachment. The second patient was an 18-year old female with hand motion VA in the left eye. Panuveitis and severe conjunctival chemosis were observed. MRI demonstrated dacryoadenitis with preseptal inflammation. The patient was initially started on oral steroid therapy, which alleviated the orbital inflammation but not the intraocular inflammation. An anterior chamber diagnostic paracentesis was positive for HSV-1, after which the patient underwent vitrectomy for a retinal detachment. The patient was started on systemic antiviral therapy. CONCLUSIONS AND IMPORTANCE: Herpetic disease should remain on the differential for cases of concurrent intraocular and orbital inflammation. Early recognition of this process may help prevent severe vision loss. It is important to recognize that orbital inflammation secondary to herpetic disease may be diverse in its presentation.

Delayed recurrence of acute retinal necrosis (ARN): A case series.

PURPOSE: To report five cases of acute retinal necrosis (ARN) that reactivated in the same eye or presented in the contralateral eye between two and nineteen years after the initial episode of acute retinal necrosis. CASES: Five patients with a previous history of ARN developed recurrent ARN infection following a lengthy latency period. In all five patients who initially presented with unilateral disease, four developed infection in the contralateral eye and one developed recurrent infection in the ipsilateral eye. Latency periods ranged from two to nineteen years, and final visual acuity in the affected eyes ranged from 20/30 to no light perception. Each patient was treated with antiviral medication for both the initial infection and for subsequent reactivations, but was not on long-term prophylaxis at the time of recurrent disease. CONCLUSION: Although rare, delayed onset reactivation of ARN can occur in either the same eye or contralateral eye despite adequate treatment. While contralateral spread of initial infection is fairly common, these reactivations rarely occur more than six weeks after initial infection. Currently there are no guidelines for use of prophylactic antiviral medication to prevent late recurrence of ARN.