Original Article Seasonality of Acute Retinal Necrosis Alireza Hedayatfar1, 2, MD; Maryam Ashraf Khorasani1, MD; Mehdi Behnia2, MD; Ahad Sedaghat1, MD 1Eye Research Center, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran 2Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran ORCID: Alireza Hedayatfar: https://orcid.org/0000-0002-5667-5379 Abstract Purpose: To study the seasonal variability in the occurrence of acute retinal necrosis (ARN) in a series of polymerase chain reaction (PCR)-positive patients. Methods: Consecutive patients clinically diagnosed with ARN and a positive PCR result of aqueous humor during a seven-year period were studied retrospectively. Patients’ demographics, causative viral agent(s), and the date of disease onset were extracted from medical records. Results: Twenty eyes of 20 patients were enrolled; the mean age at presentation was 39.6 ± 14.4 (range, 6–62) years. Nine patients were female. The most common causative agent was varicella-zoster virus in 16 patients (80%), followed by herpes simplex virus in two patients (10%). The disease onset was in winter in 10 patients (50%), and the highest incidence was in February (five patients, 25%). The cumulative occurrence of ARN was significantly higher in the first half of the year (winter and spring) compared to the second half of the year (summer and fall) (P = 0.030). In general, seasons with a high incidence of ARN were preceded by cold seasons. Conclusion: In our series, we observed seasonal variability in the incidence of ARN, with the highest incidence during winter and spring. However, further epidemiologic studies in different geographical areas are required to elucidate the true seasonal nature of ARN. Keywords: Acute Retinal Necrosis; Herpetic Viral Retinitis; Polymerase Chain Reaction; Seasonal Variation; Varicella-Zoster Virus J Ophthalmic Vis Res 2020; 15 (1): 53–58 Correspondence to: Alireza Hedayatfar, MD. Ocular Inflammation and Uveitis Clinic, Noor Eye Hospital, No. 96 Esfandiar Blvd., Vali’asr Ave., Tehran 19686, Iran. E-mail:alireza.hedayatfar@gmail.com Received: 03-12-2018 Accepted: 17-07-2019 Access this article online Website: https://knepublishing.com/index.php/JOVR DOI: 10.18502/jovr.v15i1.5944 INTRODUCTION Acute retinal necrosis (ARN) was first described in 1971 by Urayama et al as a syndrome of acute panuveitis with retinal periarteritis progressing to diffuse necrotizing retinitis and retinal detachment (RD).[1] This uncommon but potentially blinding This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. How to cite this article: Hedayatfar A, Ashraf Khorasani M, Behnia M, Sedaghat A. Seasonality of Acute Retinal Necrosis. J Ophthalmic Vis Res 2020;15:53–58. © 2020 JOURNAL OF OPHTHALMIC AND VISION RESEARCH | PUBLISHED BY KNOWLEDGE E 53 http://crossmark.crossref.org/dialog/?doi=10.18502/jovr.v15i1.5944&domain=pdf&date_stamp=2019-07-17 https://knepublishing.com/index.php/JOVR Seasonality of ARN; Hedayatfar et al condition is usually noticed in immunocompetent hosts but occasionally among immunocompro- mised patients.[2, 3] In a nationwide survey in the UK, the estimated incidence of ARN was one case per 2 million people per year, which had been stable over one decade.[4, 5] ARN is caused by members of the Herpesviridae family, most commonly varicella-zoster virus (VZV) and herpes simplex virus (HSV), and occasion- ally Epstein–Barr virus (EBV) and cytomegalovirus (CMV).[6–8] Although ARN is essentially a clinical diagnosis, ocular fluid polymerase chain reaction (PCR) testing has been widely used as an aid to the diagnosis and identification of the causative virus.[9–12] ARN is a rapidly destructive disease. Systemic antiviral therapy is the mainstay of treatment. Corticosteroids are usually used along with antiviral agents to reduce the ocular inflammation. Antivirals hasten the remission of retinitis in the affected eye and have a protective effect on the fel- low eye.[13] Moreover, early laser retinopexy can reduce the risk of RD,[14, 15] which is a complication that is considered a major cause of poor visual outcome in ARN.[16, 17] Therefore, early diagnosis and prompt management are important for reduc- ing ocular morbidity, and can potentially save a significant number of eyes from severe vision loss. In this retrospective chart review, we observed a clustering tendency in the occurrence of ARN in specific months of the year; this observation could highlight important aspects of the epidemiology of the disease. METHODS We retrospectively reviewed the medical records of patients diagnosed with ARN at two referral centers in Tehran from January 2011 to Decem- ber 2017. Only eyes with positive aqueous PCR were included. The study protocol was approved by the Institutional Review Boards, and informed consent was obtained from the participants at the time of anterior chamber paracentesis. Data on the demographics, causative viral agent(s), and date of the start of the ocular symptoms (consid- ered as disease onset) were extracted. ARN was clinically diagnosed based on the characteristic clinical features consisting of the presence of one or multiple peripheral foci of retinitis with rapid circumferential progression, occlusive retinal vasculitis (mainly arteritis), and prominent vitreous inflammation. Wide-field fluorescein angiography was used to confirm the occlusive nature of vas- culitis and extent of retinal ischemia. A tailored laboratory work-up was performed to assess the immune status of the patients and rule-out other causes of uveitis. The average temperatures in each month from January 2011 to December 2017 were extracted based on the data provided by the WorldWeatherOnline.com in Tehran, Mehrabad Airport. Technique of anterior chamber paracentesis and PCR For aqueous sampling, anterior chamber paracentesis was performed using a 30-gauge needle attached to an insulin syringe, and 0.1– 0.2 cc of aqueous humor was aspirated. The procedure was generally performed in the clinic after the examination. For patients who received an intravitreal injection of ganciclovir, both sampling and injection were performed in the operating room. The samples were kept at 2–8∘C and delivered to the laboratory within 1 h and were stored at –20∘C. DNA extraction was performed within one week using High Pure Viral Nucleic Acid Kit (Roche Diagnostics GmbH, Mannheim, Germany) following the manufacturer’s instructions.[18] Qualitative PCR was performed using the flash method by the DNA Technology Kit (DNA-Technology, Moscow, Russia).[19] The results are expressed as mean ± standard error. Due to the limited number of cases, Fisher’s exact test was used to compare the cumulative occurrence of ARN between the first and second halves of the year. A p-value < 0.05 was considered statistically significant. RESULTS Twenty eyes of 20 patients were included in this study. The mean age at presentation was 39.6 ± 14.4 (range: 6–62) years. Nine patients were female. None of the patients were HIV-positive. ARN was unilateral in all patients except one [Table 1]. The patient with bilateral ARN did not consent for bilateral sampling, therefore, only the eye with more extensive involvement was sampled (positive 54 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 15, ISSUE 1, JANUARY-MARCH 2020 WorldWeatherOnline.com Seasonality of ARN; Hedayatfar et al Table 1. Demographics, causative viral agent(s), and date of disease onset in ARN cases Patient # PCR result Gender Age at onset (years) Laterality ARN onset (month) ARN onset (year) 1 VZV M 41 OD 6 2013 2 VZV M 30 OS 5 2014 3 VZV F 56 OD 1 2016 4 VZV F 28 OS 4 2013 5 VZV M 58 OD 10 2015 6 VZV M 53 OS 2 2011 7 VZV M 45 OD 5 2012 8 VZV F 44 OU 8 2013 9 VZV F 45 OD 6 2017 10 VZV M 40 OD 1 2015 11 VZV M 21 OS 2 2017 12 VZV F 35 OS 2 2016 13 VZV M 48 OS 1 2017 14 VZV M 56 OS 3 2015 15 VZV F 29 OD 3 2015 16 VZV, EBV F 62 OS 4 2016 17 HSV M 6 OS 2 2017 18 HSV M 25 OD 2 2014 19 EBV F 26 OD 3 2017 20 CMV M 43 OD 5 2014 ARN, acute retinal necrosis; CMV, cytomegalovirus; EBV, Epstein–Barr virus; F, female; HSV, Herpes Simplex virus; m, male; OD, right eye; OS, left eye; OU, bilateral; PCR, polymerase chain reaction; VZV, Varicella-Zoster Virus for VZV) while the other eye was excluded from the study. Based on the PCR results, the most common causative agent was VZV detected in 16 patients (80%), followed by HSV in 2 patients (10%; HSV-1 and HSV-2 each in one patient). CMV was detected in one patient (5%) and EBV in one eye (5%). In one VZV-positive patient, a simultaneous co-infection by EBV was present [Table 1]. In most patients (85%, 17 patients), the dis- ease onset was in winter (ten patients, 50%) or spring (seven patients, 35%). Summer (two patients, 10%) and autumn (one patient, 5%) were the seasons with the lowest incidence [Figure 1(a)]. February was the month with the highest incidence of ARN (five patients, 25%), and July, September, November, and December were the months with the lowest incidence (no cases) [Figure 1(b)]. The cumulative occurrence of ARN was significantly higher in the first half of the year (winter and spring) compared to the sec- ond half of the year (summer and fall) (P = 0.030). Figure 2 shows the average temperature in each month during the study period. The cold- est month in the study period was January (mean temperature, 5.1∘C), followed by Febru- ary (mean temperature, 6.5∘C) and December (mean temperature, 7.0∘C). July (mean tempera- ture, 34.0∘C), August (mean temperature, 32.9∘C), and June (mean temperature, 31.7∘C) were the warmest months. The coldest season that was winter (average temperature, 7.7∘C) had the high- est incidence of ARN (50%). Autumn, which was the second coldest season (average temperature, 12.9∘C), had the lowest incidence of ARN (5%). The high incidence rate of ARN (35%) in spring suggests a time lag between the beginning of cold seasons and an increase in the incidence of ARN. JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 15, ISSUE 1, JANUARY-MARCH 2020 55 Seasonality of ARN; Hedayatfar et al Figure 1. Cumulative number of cases of acute retinal necrosis in each season (a) and month (b). DISCUSSION In this series, there was a tendency for the occur- rence of ARN during winter and spring. The sea- sons with a high incidence of ARN were preceded by cold seasons. While the temperature began dropping mid-autumn, the peak of ARN occurred during winter, and once the temperature started rising mid-spring, the incidence of ARN declined in summer. Previous studies have shown patterns of sea- sonal variability in the incidence of infections associated with the Herpesviridae family. Varicella shows pronounced seasonality in temperate cli- mates and most tropical climates, with a peak incidence in the cooler, drier months during winter or spring.[20–23] In a study using the Connecticut statewide hospital discharge database in the pre- vaccine era, 73.2% of the varicella hospitalizations occurred during winter and spring.[24] In contrast, zoster does not show any seasonal pattern in the UK, Canada,[25] or Western Australia.[26] Seasonal variations in the occurrence of herpetic kerati- tis were reported as well. In a study in Japan, a negative correlation was observed between the incidence of dendritic keratitis recurrences 56 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 15, ISSUE 1, JANUARY-MARCH 2020 Seasonality of ARN; Hedayatfar et al Figure 2. Average temperature in each month in the study period. and temperature and 42.2% of the recurrences occurred during winter.[27] Gamus found the high- est rate of herpetic eye attacks during January,[28] and others reported the highest incidence of her- petic keratitis in late autumn and winter.[29] Seasonal cycles in infectious diseases are gen- erally attributed to seasonal differences in weather conditions, seasonal rhythmicity in host susceptibil- ity to infectious agents, and the virulence or preva- lence of causal pathogens.[30, 31] The explanation of the seasonal variability in the incidence of ARN in this series would be undoubtedly complex and multifactorial. Tehran has a four-season climate. The weather is usually mild and rainy in spring, hot and dry in summer, mild to cold in autumn, but chilly and occasionally snowy in winters. Records of the average monthly temperature also showed that winter and autumn were the coldest seasons. The higher incidence rate of ARN in winter and spring suggests a temporal pattern in which the cold seasons preceded seasons with a high inci- dence of ARN. However, this is an assumption and cannot be confirmed using statistical methods. Administering the time series analysis, which is often used to extract possible correlations in similar situations, needs a large sample size far exceeding the number of cases included in the current study. To the best of our knowledge, this is the first report on the concept of seasonality in ARN. We included a homogenous group of patients with PCR-proven ARN and set Tehran, a four-season city, as the reference to evaluate the probable climatological association. A limi- tation of the current study is the small sample size, which is due to the rarity of ARN. The second limitation is that the temperature data were collected based on records provided from a single station in Tehran (Mehrabad Airport). Considering the area of the Tehran metropoli- tan, a single station may not comprehensively reflect the whole climate of the source popula- tion. The knowledge of the seasonal variability in the incidence of ARN could potentially be beneficial to ophthalmologists to expect new cases during specific months of the year and be prompt in diagnosis and treatment. However, further epi- demiologic studies in different geographical areas are required to elucidate the true seasonal nature of ARN. Financial Support and Sponsorship Nil. Conflicts of Interest There are no conflicts of interest. JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 15, ISSUE 1, JANUARY-MARCH 2020 57 Seasonality of ARN; Hedayatfar et al REFERENCES 1. Urayama A, Yamada N, Sasaki T. Unilateral acute uveitis with periarteritis and detachment. J Clin Ophthalmol 1971;25:607–619. 2. Freeman WR, Lerner CW, Mines JA, Lash RS, Nadel AJ, Starr MB, et al. 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