Development and validation of new diagnostic criteria for acute retinal necrosis

Jpn J Ophthalmol DOI 10.1007/s10384-014-0362-0 CLINICAL INVESTIGATION Development and validation of new diagnostic criteria for acute retinal necrosis Hiroshi Takase Annabelle A. Okada Hiroshi Goto Nobuhisa Mizuki Kenichi Namba Nobuyuki Ohguro Koh-Hei Sonoda Makoto Tomita Hiroshi Keino Takeshi Kezuka Reo Kubono Kazuomi Mizuuchi Etsuko Shibuya Hiroyuki Takahashi Ryoji Yanai Manabu Mochizuki Received: 28 August 2014 / Accepted: 24 September 2014 Ó Japanese Ophthalmological Society 2014 Abstract Purpose The purposes of this study are to develop and validate new diagnostic criteria for acute retinal necrosis (ARN) based on the ocular findings, clinical course, and virologic testing of intraocular fluids. Subjects and methods The Japanese ARN Study Group, comprising 8 uveitis specialists and 1 statistician, was formed to develop new diagnostic criteria for ARN. The criteria used a combination of clinical features consistent with ARN including 6 early-stage ocular findings ([1a] anterior chamber cells or mutton-fat keratic precipitates; [1b] yellow-white lesion(s) in the peripheral retina [granular or patchy in the early stage, then gradually merging]; [1c] retinal arteritis; [1d] hyperemia of the optic disc; [1e] inflammatory vitreous opacities; and [1f] elevated intraocular pressure), 5 clinical courses ([2a] rapid expansion of the retinal lesion(s) circumferentially, [2b] development of retinal breaks or retinal detachment, [2c] retinal vascular occlusion, [2d] optic atrophy, and [2e] response to antiviral agents), and the results of virologic testing of intraocular fluids by means of either polymerase chain reaction or the Goldmann-Witmer coefficient for herpes simplex virus or varicella zoster virus. Various combinations of findings were analyzed to maximize the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The criteria were then used to retrospectively analyze patients who had been diagnosed as having ARN or control uveitis. Patients were followed at 1 of 7 tertiary uveitis clinics between 2009 and 2011. Results Analysis of the data allowed delineation of 2 levels of diagnosis: virus-confirmed ARN (defined as the presence of both early-stage ocular findings 1a and 1b, the presence of any 1 of the 5 clinical courses, and a positive virologic test result) and virus-unconfirmed ARN (defined H. Takase R. Kubono H. Takahashi M. Mochizuki (&) Department of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan e-mail: m.manabu.oph@tmd.ac.jp H. Takase A. A. Okada H. Goto N. Mizuki K. Namba N. Ohguro K.-H. Sonoda M. Tomita H. Keino T. Kezuka R. Kubono K. Mizuuchi E. Shibuya H. Takahashi R. Yanai M. Mochizuki Japanese Acute Retinal Necrosis Study Group, Tokyo, Japan A. A. Okada H. Keino Department of Ophthalmology, School of Medicine, Kyorin University, Mitaka, Tokyo, Japan H. Goto T. Kezuka Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan N. Mizuki E. Shibuya Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan K. Namba K. Mizuuchi Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan N. Ohguro Department of Ophthalmology, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan K.-H. Sonoda R. Yanai Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan M. Tomita Tokyo Medical and Dental University Hospital of Medicine, Clinical Research Center, Tokyo, Japan

H. Takase et al. as the presence of 4 of 6 early-stage ocular findings including 1a and 1b, presence of any 2 of the 5 clinical courses, and a negative virologic test result, or when virologic testing had not been performed). The new diagnostic criteria were applied to 45 patients with ARN and 409 patients with control uveitis, resulting in a sensitivity of 0.89, a specificity of 1.00, a PPV of 1.00, and an NPV of 0.99. Conclusions New diagnostic criteria for ARN were developed and found to achieve high statistical values. Keywords Acute retinal necrosis Infectious uveitis Diagnostic criteria Polymerase chain reaction Goldmann-Witmer coefficient Introduction Acute retinal necrosis (ARN) is a sight-threatening disease caused by herpes viruses such as herpes simplex virus (HSV) type 1 (HSV-1), HSV-2, or varicella zoster virus (VZV). ARN was originally reported in 1971 by Urayama and colleagues [1] as a unilateral acute uveitis accompanied by retinal arteritis and white retinal lesions in the peripheral retina followed by retinal detachment. Diagnostic criteria for ARN were described by the American Uveitis Society (AUS) [2]. These diagnostic criteria are based on the clinical findings and do not incorporate the results of microbiologic testing of the ocular tissues or fluids, although the involvement of the herpes viruses was implicated. At that time, the pathogenesis of ARN was not well clarified, and molecular methods such as the polymerase chain reaction (PCR) were not available. Since then, advances in molecular technologies have made PCR more available for clinical use, and data regarding the pathogenic etiology of ARN have accumulated over the past 2 decades [3, 4]. Moreover, a multiplex PCR system enabling detection of the genome of multiple pathogens using a small volume of intraocular fluid from patients with uveitis has been shown by us to be useful in diagnosing a variety of diseases [5, 6]. Using this system, we have confirmed that ARN in Japan occurs in eyes infected with HSV-1, HSV-2, or VZV, but not with other types of human herpes viruses or other pathogens such as Toxoplasma gondii [5 9]. Because the causative viruses of ARN have been identified and PCR has become more widely accessible, we believed that it was time to update the diagnostic criteria for ARN by taking into account the results of virologic testing of intraocular fluids. The current multicenter study was initiated to develop and validate new diagnostic criteria for ARN based on the ocular findings, clinical course, and virologic testing of intraocular fluids. Subjects and methods This study was approved by the ethics committees of Tokyo Medical and Dental University Hospital, Tokyo Medical University Hospital, Yokohama City University Hospital, Hokkaido University Hospital, Japan Community Health Care Organization Osaka Hospital, Kyorin University Hospital, and Yamaguchi University Hospital. The procedures used conformed to the tenets of the Declaration of Helsinki, and informed consent was obtained from each patient for the procedures performed and for the review of his or her records. The Japanese Acute Retinal Necrosis Study Group was formed; it comprises 8 uveitis specialists and 1 statistician. In study group meetings, new diagnostic criteria for ARN were developed on the basis of the members clinical experience. To evaluate the diagnostic utility of the new diagnostic criteria, i.e., the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), a retrospective study was performed on patients who had been diagnosed by their treating physicians as having ARN. For the control, patients who had been diagnosed as having cytomegalovirus (CMV) retinitis, ocular toxoplasmosis, sarcoidosis, Behçet disease, ocular tuberculosis, syphilitic uveitis, or intraocular lymphoma were enrolled. These control diseases, all posterior uveitis or panuveitis, were selected for their potential to mimic the signs commonly observed in ARN, such as the presence of retinal white lesions, in all of the diseases or the presence of retinal arteritis in CMV retinitis, toxoplasmosis, and syphilitic uveitis. Only patients who were definitely diagnosed as having such control diseases were used in this study. All enrolled patients were examined for the first time at one of the 7 participating tertiary uveitis clinics between January 1, 2009 and December 31, 2011. Data regarding the patients demographics, ocular signs, clinical courses as proposed by the study group, and the results of virologic testing of intraocular fluids were collected from the medical records. Using those data, various combinations of the ocular findings, clinical courses, and intraocular fluid test results were analyzed to maximize the diagnostic parameters of the new diagnostic criteria. Statistical analyses were performed using the Fisher exact test and the Mann Whitney test. Probability values \0.05 were considered significant. Results Development of new diagnostic criteria for ARN New diagnostic criteria were proposed in the study group meetings on the basis of a combination of various clinical

New diagnostic criteria for ARN a retinal lesion(s) circumferentially, (2b) development of retinal breaks or retinal detachment, (2c) retinal vascular occlusion, (2d) optic atrophy, and (2e) response to antiviral agents. Virologic testing of intraocular fluids consisted of analysis by either PCR or the Goldmann-Witmer coefficient for HSV-1, HSV-2, or VZV. Ocular findings in the early stage of ARN versus control uveitis b Fig. 1 Left eye of a 21-year-old man with acute retinal necrosis. Color fundus pictures at the initial presentation (a) and 2 days after the initial presentation and initiation of systemic antiviral therapy (b) show yellow-white granular (white arrows), patchy (black arrows), or merged (white arrow heads) lesions in the peripheral retina. Within 2 days, the retinal lesions had merged and expanded circumferentially. The optic disc was swollen. Retinal vasculitis including peripheral arteritis (black arrow heads) is seen, in particular, in the earlier color picture (a) features consistent with ARN including 6 ocular findings in the early stage of the disease, 5 clinical courses, and the virologic test results of intraocular fluids. The 6 ocular findings in the early stage of the disease consisted of (1a) anterior chamber cells or mutton-fat keratic precipitates; (1b) yellow-white lesion(s) in the peripheral retina (granular or patchy in the early stage, then gradually merging; Fig. 1); (1c) retinal arteritis; (1d) hyperemia of the optic disc; (1e) inflammatory vitreous opacities; and (1f) elevated intraocular pressure (IOP). The 5 clinical courses consisted of (2a) rapid expansion of the To validate the diagnostic criteria, we retrospectively analyzed data from 45 patients with ARN and 409 patients as controls for uveitis, as listed in Table 1. The diagnosis of ARN had been made by treating physicians according to their own diagnostic standards based on the clinical findings such as yellow-white lesions in the peripheral retina that showed rapid progression circumferentially, development of retinal breaks or retinal detachment, response to antiviral therapy, and the virologic test results of the intraocular fluids. The control uveitis patients comprised 32 patients with CMV retinitis, 135 patients with biopsyproven sarcoidosis, 48 patients with ocular toxoplasmosis, 111 patients with Behçet disease, 30 patients with ocular tuberculosis, 5 patients with syphilitic uveitis, and 48 patients with intraocular lymphoma. The rates of the various ocular findings and the sensitivity, specificity, PPV, and NPV of the findings are summarized in Table 2. The ocular finding of anterior chamber cells or mutton-fat keratic precipitates was present in 44 of 45 patients with ARN (98 %), as opposed to only 248 of the 409 patients with control uveitis (61 %). The difference in these rates was significant (P \ 0.0001). The sensitivity of the finding was calculated to be 0.98, and the specificity, 0.39. The PPV was 0.15 and the NPV 0.99. This ocular finding had the highest sensitivity among the 6 ocular findings. Yellow-white lesion(s) in the peripheral retina (granular or patchy in the early stage, then gradually merging) was present in 41 of the 45 ARN patients (91 %), but in only 18 of the 403 control uveitis patients (4 %); this difference was significant (P \ 0.0001). The diagnostic parameters of this ocular finding were 0.91 for sensitivity, 0.96 for specificity, 0.69 for PPV, and 0.99 for NPV. This ocular finding showed the highest specificity among the 6 ocular findings. The other ocular findings, with the exception of elevated IOP, also showed high diagnostic parameters. Although the rate of elevated IOP in the ARN patients (11 %) was not significantly greater than that in the control uveitis patients (9 %), the specificity and NPV were high (0.91 and 0.90, respectively), suggesting the usefulness of this ocular finding when used in a combination with the other ocular findings in the diagnostic criteria.

H. Takase et al. Clinical courses and results of virologic testing of intraocular fluids in ARN versus control uveitis Table 3 summarizes the rates and diagnostic parameters for the 5 clinical courses in patients with ARN or control uveitis. The rate of each clinical course was significantly higher in patients with ARN than in patients with control uveitis. The 5 clinical courses had similarly high NPV (0.81 0.96). The specificities were also high for the clinical courses (0.89 0.98), with the exception of response to antiviral therapy, which had a low specificity of 0.52. However, the number of patients who underwent antiviral therapy was small among the control uveitis patients. Antiviral agents were found to have been administered to 44 of the 45 patients with ARN (98 %), 32 of the 32 patients with CMV retinitis (100 %), and 1 of the 135 patients with sarcoidosis (0.7 %). Table 1 Patient demographics Diagnosis Number of patients Male:female Mean age (range) Acute retinal necrosis 45 25:20 52 (21 83) Control uveitis (total) 409 221:188 50 (8 88) CMV retinitis 32 26:6 57 (19 79) Sarcoidosis 135 38:97 55 (20 83) Ocular toxoplasmosis 48 31:17 43 (8 69) Behçet disease 111 81:30 40 (14 70) Ocular tuberculosis 30 19:11 46 (19 78) Syphilitic uveitis 5 5:0 44 (30 60) Intraocular lymphoma 48 31:17 70 (32 88) Total 454 246:208 51 (8 88) CMV cytomegalovirus Virologic testing of intraocular fluids by PCR was performed for 44 patients with ARN (96 %) and 48 patients with control uveitis (11 %). The overall rate of positive results for HSV-1, HSV-2, or VZV was 95 % for ARN and 8 % for control uveitis, a difference that was significant (P \ 0.0001). The Goldmann-Witmer coefficient was calculated in 8 patients with ARN and 4 patients with control uveitis. The results were considered positive ([6.0) in 2 of the 8 patients with ARN (25 %) and in none of the patients with control uveitis. The diagnostic parameters for the virologic test results were 0.95 for sensitivity, 0.92 for specificity, 0.91 for PPV, and 0.96 for NPV (Table 4). Diagnostic parameters of the diagnostic criteria for ARN By analyzing all diagnostic parameters, the diagnostic criteria were defined as shown in Table 5. Part I of the diagnostic criteria consists of a description of the basic concepts for using the criteria. In these basic concepts, the presence of 2 of the early-stage ocular findings, 1a and 1b, are defined as important signs for suspecting ARN. When the diagnostic parameters for presence of both 1a and 1b were calculated, the sensitivity was found to be 0.89; the specificity 0.97, the PPV 0.74, and the NPV 0.99. We then defined 2 levels of certainty in diagnosing ARN using combinations of the early-stage ocular findings, clinical courses, and virologic test results of the intraocular fluids. A virus-confirmed ARN diagnosis was defined as the presence of both early-stage ocular findings 1a and 1b, the presence of any 1 of the 5 clinical courses, and a positive virologic test result. Using this definition, 37 of the 45 patients with ARN (82 %), but none of the 409 patients Table 2 Diagnostic parameters of early-stage ocular findings in acute retinal necrosis versus control uveitis Ocular findings in the early stage Acute retinal necrosis Control uveitis P value a Sensitivity Specificity PPV NPV 1a. Anterior chamber cells or mutton-fat keratic precipitates 1b. Yellow-white lesion(s) in the peripheral retina (granular or patchy in the early stage, then gradually merging) 44 1 98 248 161 61 \0.0001 0.98 0.39 0.15 0.99 41 4 91 18 385 4 \0.0001 0.91 0.96 0.69 0.99 1c. Retinal arteritis 35 8 81 29 359 7 \0.0001 0.81 0.93 0.55 0.98 1d. Hyperemia of the optic disc 31 11 74 105 294 26 \0.0001 0.74 0.74 0.23 0.96 1e. Inflammatory vitreous opacities 40 5 89 249 156 61 0.0001 0.89 0.39 0.14 0.97 1f. Elevated intraocular pressure 5 40 11 37 372 9 0.4229 0.11 0.91 0.12 0.90 PPV positive predictive value, NPV negative predictive value

New diagnostic criteria for ARN Table 3 Diagnostic parameters of clinical courses in acute retinal necrosis versus control uveitis Clinical courses Acute retinal necrosis Control uveitis P value a Sensitivity Specificity PPV NPV 2a. Rapid expansion of retinal lesion(s) circumferentially 2b. Development of retinal break or retinal detachment 2c. Development of retinal vascular occlusion 27 18 60 6 339 2 \0.0001 0.60 0.98 0.82 0.95 26 19 58 11 390 3 \0.0001 0.58 0.97 0.70 0.95 26 14 65 45 354 11 \0.0001 0.65 0.89 0.37 0.96 2d. Development of optic atrophy 16 27 37 16 384 4 \0.0001 0.37 0.96 0.50 0.93 2e. Good response to antiviral agents 40 4 91 16 17 48 0.0001 0.91 0.52 0.71 0.81 PPV positive predictive value, NPV negative predictive value Table 4 Diagnostic parameters of virologic testing results in acute retinal necrosis versus control uveitis Virologic testing of intraocular fluids Acute retinal necrosis Control uveitis P value a Sensitivity Specificity PPV NPV Positive by either PCR or Goldmann- Witmer coefficient for HSV-1, HSV-2, or VZV Positive by PCR for HSV-1, HSV-2, or VZV Positive by Goldmann-Witmer coefficient for HSV-1, HSV-2, or VZV 41 2 95 4 44 8 \0.0001 0.95 0.92 0.91 0.96 41 2 95 4 44 8 \0.0001 0.95 0.92 0.91 0.96 2 4 33 0 4 0 0.3333 0.33 1.00 1.00 0.50 PPV positive predictive value, NPV negative predictive value, PCR polymerase chain reaction with control uveitis were classified as having virus-confirmed ARN. A virus-unconfirmed ARN diagnosis was defined as the presence of 4 of 6 early stage ocular findings including 1a and 1b, presence of any 2 of the 5 clinical courses, a negative virologic test result, or when virologic testing had not been performed. Using this definition, 4 of the 45 patients with ARN (9 %), but none of the 409 patients with control uveitis were classified as having virus-unconfirmed ARN. Taken together, these new diagnostic criteria for ARN classified 41 of 45 patients with ARN (91 %) as having virus-confirmed or unconfirmed ARN. The sensitivity of these criteria was found to be 0.91, the specificity 1.00, the PPV 1.00, and the NPV 0.99 (Table 6). Discussion In this study, we developed new diagnostic criteria for ARN. We then validated the criteria using patients who had been diagnosed with ARN according to the internal diagnostic standards of each participating clinic. Control uveitis patients were selected on the basis of having been diagnosed with a disease that may resemble ARN [10]. The visual prognosis of ARN is quite poor [11], and one of the factors that affect the prognosis of ARN is the advanced state of the disease at the time of initiation of antiviral therapy [11 13]. Although the ideal treatment protocol for ARN is still controversial, there is no doubt that early diagnosis and early initiation of antiviral therapy are related to improved prognosis. For this reason, diagnostic criteria for ARN that can easily be used by primary ophthalmologists would be useful for making an early diagnosis. Previously, diagnostic criteria for ARN were published in 1994 by the AUS [2]. These diagnostic criteria were relatively strict in that, to make a diagnosis of acute retinal necrosis, all 5 clinical characteristics had to be present, i.e., 1 or more foci of retinal necrosis, rapid progression of the disease if antiviral therapy has not been given, circumferential spread of disease, occlusive

H. Takase et al. Table 5 Diagnostic criteria for acute retinal necrosis I. Basic concepts 1. Diagnosis is made on the basis of the combination of the ocular findings in the early stage, clinical courses, and virologic testing of intraocular fluids 2. When early-stage ocular findings 1a and 1b are positive, acute retinal necrosis is strongly suspected, and virologic testing of the intraocular fluids and antiviral therapy are highly recommended 3. The final diagnosis is determined on the basis of the subsequent clinical course and the virologic test results 4. Acute retinal necrosis usually occurs in immunocompetent individuals. In immunodeficient patients, it should be noted that in addition to the ocular symptoms or clinical courses described below, the ocular symptoms vary II. Diagnostic criteria 1. Ocular findings in the early stage 1a. Anterior chamber cells or mutton-fat keratic precipitates 1b. Yellow-white lesion(s) in the peripheral retina (granular or patchy in the early stage, then gradually merging) 1c. Retinal arteritis 1d. Hyperemia of the optic disc 1e. Inflammatory vitreous opacities 1f. Elevated intraocular pressure 2. Clinical courses 2a. Rapid expansion of retinal lesion(s) circumferentially 2b. Development of retinal break or retinal detachment 2c. Retinal vascular occlusion 2d. Optic atrophy 2e. Response to antiviral agents 3. Virologic testing of intraocular fluids Positive by either PCR or Goldmann-Witmer coefficient for HSV-1, HSV-2, or VZV III. Classification 1. Virus-confirmed acute retinal necrosis Presence of ocular findings 1a and 1b, presence of any 1 of the 5 clinical courses, and a positive virologic test result 2. Virus-unconfirmed acute retinal necrosis Presence of 4 of the 6 ocular findings including 1a and 1b, presence of any 2 of the 5 clinical courses, and a negative virologic test result or when virologic testing has not been performed vasculopathy with arteriolar involvement, and a prominent inflammatory reaction in the vitreous and anterior chambers. If the characteristics of the disease did not meet the criteria, then the term necrotizing herpetic retinopathy was used. Because of the reliance on the late ocular findings and clinical course, diagnosing ARN in the early stage of the disease using the AUS diagnostic criteria is difficult. We had 2 reasons for developing new diagnostic criteria for ARN. The first was that we believed the diagnosis of ARN should incorporate the results of virologic testing of the intraocular fluids because it was well established that the causative pathogens of ARN are HSV-1, HSV-2, and VZV. In addition, PCR analysis of the intraocular fluids has become more widely available to clinicians. The second reason was that, to improve the prognosis of ARN, we believed that any diagnostic criteria should be capable of identifying ARN in the early stage of the disease. The diagnostic parameters of the new diagnostic criteria we created were 0.89 for sensitivity, 1.00 for specificity, 1.00 for PPV, and 0.99 for NPV. The concept of the new diagnostic criteria for ARN reported here is based on the notion that the causative pathogens for ARN are HSV-1, HSV-2, and VZV. However, the argument exists that CMV or other pathogens could cause retinal necrosis that resembles ARN [4, 10]. We, therefore, included the diagnoses of CMV retinitis and toxoplasmosis among the control uveitis patients used in the validation study. As our results showed, no patient who was positive for CMV or toxoplasma by intraocular fluid analysis met either our new diagnostic criteria or the AUS diagnostic criteria. Our data suggest that, at least in the patients we analyzed, ARN is caused by HSV or VZV, but not by other pathogens. Although the current study provided important information regarding the development and validation of new diagnostic criteria for ARN, it has several limitations. First, these new diagnostic criteria were developed by a small number of study group members and may not reflect the opinions of other uveitis specialists. Second, the validation study was performed at just 7 tertiary institutions and only Table 6 Predictive values of diagnostic criteria for acute retinal necrosis (ARN) Diagnostic criteria ARN Control uveitis P value a Sensitivity Specificity PPV NPV Virus-confirmed ARN 37 8 82 0 409 0 \0.0001 0.82 1.00 1.00 0.98 Virus-unconfirmed ARN 33 12 73 0 409 0 \0.0001 0.73 1.00 1.00 0.97 Total 40 5 89 0 409 0 \0.0001 0.89 1.00 1.00 0.99 PPV positive predictive value, NPV negative predictive value

New diagnostic criteria for ARN in Japan. These diagnostic criteria were designed to be used not only by uveitis specialists but also by general practitioners. Therefore, to completely validate the new diagnostic criteria, a nationwide validation study should be performed in Japan. Moreover, an international validation study should also be performed because the composition of control uveitis possibly resembling ARN differs depending on the country or region of the world. The third limitation of our study is that, because uveitis patients often do not require virologic testing of the intraocular fluids or administration of antiviral agents, such data were available for only a small number of the control cases. In a future study, therefore, the calculations of the diagnostic parameters for virologic test results should be reconsidered using control patients who have undergone virologic testing of the intraocular fluids. In conclusion, we developed new diagnostic criteria for ARN that achieved high statistical values. Further validation is necessary to assist in refining these diagnostic criteria. Acknowledgments We thank Dr. Norio Usui for his thoughtful comments and discussions. This study was supported by a Health and Labour Sciences Research Grant for research on rare and intractable diseases from the Ministry of Health, Labour and Welfare of Japan. Conflicts of interest H. Takase, None; A. A. Okada, None; H. Goto, None; N. Mizuki, None; K. Namba, None; N. Ohguro, None; K.-H. Sonoda, None; M. Tomita, None; H. Keino, None; T. Kezuka, None; R. Kubono, None; K. Mizuuchi, None; E. Shibuya, None; H. Takahashi, None; R. Yanai, None; M. Mochizuki, None. References 2. Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol. 1994;117:663 7. 3. Usui Y, Goto H. Overview and diagnosis of acute retinal necrosis syndrome. Semin Ophthalmol. 2008;23:275 83. 4. Wong RW, Jumper JM, McDonald HR, Johnson RN, Fu A, Lujan BJ, et al. Emerging concepts in the management of acute retinal necrosis. Br J Ophthalmol. 2013;97:545 52. 5. Sugita S, Ogawa M, Shimizu N, Morio T, Ohguro N, Nakai K, et al. Use of a comprehensive polymerase chain reaction system for diagnosis of ocular infectious diseases. Ophthalmology. 2013;120:1761 8. 6. Sugita S, Shimizu N, Watanabe K, Mizukami M, Morio T, Sugamoto Y, et al. Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis. Br J Ophthalmol. 2008;92:928 32. 7. Sugita S, Ogawa M, Inoue S, Shimizu N, Mochizuki M. Diagnosis of ocular toxoplasmosis by two polymerase chain reaction (PCR) examinations: qualitative multiplex and quantitative realtime. Jpn J Ophthalmol. 2011;55:495 501. 8. Sugita S, Shimizu N, Kawaguchi T, Akao N, Morio T, Mochizuki M. Identification of human herpesvirus 6 in a patient with severe unilateral panuveitis. Arch Ophthalmol. 2007;125:1426 7. 9. Sugita S, Shimizu N, Watanabe K, Ogawa M, Maruyama K, Usui N, et al. Virological analysis in patients with human herpes virus 6-associated ocular inflammatory disorders. Invest Ophthalmol Vis Sci. 2012;53:4692 8. 10. Balansard B, Bodaghi B, Cassoux N, Fardeau C, Romand S, Rozenberg F, et al. Necrotising retinopathies simulating acute retinal necrosis syndrome. Br J Ophthalmol. 2005;89:96 101. 11. Iwahashi-Shima C, Azumi A, Ohguro N, Okada AA, Kaburaki T, Goto H, et al. Acute retinal necrosis: factors associated with anatomic and visual outcomes. Jpn J Ophthalmol. 2013;57:98 103. 12. Ishida T, Sugamoto Y, Sugita S, Mochizuki M. Prophylactic vitrectomy for acute retinal necrosis. Jpn J Ophthalmol. 2009;53:486 9. 13. Watanabe T, Miki D, Okada AA, Hirakata A. Treatment results for acute retinal necrosis. Nihon Ganka Gakkai Zasshi. 2011;115:7 12. 1. Urayama A, Yamada N, Sasaki T. Unilateral acute uveitis with retinal periarteritis and detachment [in Japanese]. Rinsho Ganka. 1971;25:607 19.