Research
Brief Report
Acute Retinal Necrosis Associated With Epstein-Barr Virus Immunohistopathologic Confirmation Shlomit Schaal, MD, PhD; Aleksandr Kagan, MD; Yujuan Wang, MD; Chi-Chao Chan, MD; Henry J. Kaplan, MD
IMPORTANCE Acute retinal necrosis (ARN) is an infectious retinitis primarily caused by the
herpesviruses. Although the Epstein-Barr virus (EBV) has been implicated as a cause of ARN, to our knowledge, there has been no histopathologic documentation. We report the clinical history and histopathologic confirmation that EBV can cause ARN. OBSERVATIONS Clinical course and histopathology of a patient diagnosed with ARN caused by infection with EBV confirmed by molecular pathology. CONCLUSIONS AND RELEVANCE Epstein-Barr virus is a recognized cause of intraocular inflammation and has been implicated as a possible cause of ARN. However, to our knowledge, tissue demonstration of EBV in a patient with ARN has not previously been reported. We identified the organism in the necrotic retina of a patient receiving immunosuppression because of idiopathic pulmonary fibrosis. JAMA Ophthalmol. 2014;132(7):881-882. doi:10.1001/jamaophthalmol.2014.266 Published online April 17, 2014.
A
cute retinal necrosis (ARN) is a syndrome characterized by progressive intraretinal inflammation and necrosis. The clinical diagnosis is frequently supported by the identification of the causative infectious agent, most commonly varicella-zoster virus (VZV), though herpes simplex virus (HSV) types 1 and 2, cytomegalovirus, and EpsteinBarr virus (EBV) have also been implicated.1,2 Epstein-Barr virus, a double-stranded DNA virus transmitted by oral secretions, infects more than 90% of humans.3 Primary infection is characterized most commonly by the clinical syndrome of infectious mononucleosis, which is characterized by fever, pharyngitis, lymphadenopathy, palatal petechiae, hepatomegaly, and splenomegaly. The virus remains latent within memory B cells where it may reactivate, yielding virus capable of infecting new B cells and epithelial cells.4 There are only a few reported cases of EBV-associated ARN1,2,5 and all lack definitive demonstration of the virus. Epstein-Barr virus DNA has been previously detected by polymerase chain reaction (PCR) in vitreous samples of patients with ARN, but only in conjunction with VZV DNA.1,2 Herein, we describe a case of ARN in which EBV was the sole virus detected both by vitreous PCR and, most importantly, by molecular pathology (microdissection and PCR) confirming the virus within the retina of the enucleated globe.
Report of a Case A 55-year-old woman with rheumatoid arthritis, chronic renal failure of unknown etiology, and idiopathic pulmonary fibro-
Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky (Schaal, Kagan, Kaplan); Laboratory of Immunology, Immunopathology Section, National Eye Institute, Bethesda, Maryland (Wang, Chan). Corresponding Author: Shlomit Schaal, MD, PhD, Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E Muhammad Ali Blvd, Louisville, KY 40202 ([email protected]).
sis was receiving an immunosuppressive regimen consisting of methylprednisolone (alternating 40 mg/32 mg, orally, daily) and infliximab (Remicade; 9 mg/kg every 4 weeks). She presented with decreased vision in her left eye of 3 weeks’ duration. Her visual acuity was 20/20 OD and 20/100 OS. Clinical examination of the right eye was normal; however, in her left eye, she presented with ciliary flush, nongranulomatous endothelial keratic precipitates, 2+ cell and 2+ flare within the anterior chamber, 3+ vitreous cells, extensive peripheral retinal necrosis for 270°, with periarteritis, but sparing of the macula and the optic nerve (Figure, A). She was diagnosed with ARN in her left eye and started treatment with oral valacyclovir hydrochloride (1 g, twice daily) and topical corticosteroids. Serum EBV viral capsid antigen IgG was elevated (>75 000 AU/mL) with no detectable EBV viral capsid antigen IgM. The EBV nuclear antigen titer was mildly elevated at 29 (normal, 0-21.9) and EBV early antigen titer was 10.3 (normal, 0-10.9). The HSV-1 IgG titer was elevated with an undetectable HSV-1 IgM titer. The VZV IgG titer was elevated with a nondetectable VZV IgM titer. Titers for HSV-2 IgG and IgM were undetectable. During the course of the disease, the left eye did not demonstrate any signs of clinical improvement, despite the addition of intravitreal ganciclovir (2 mg) over the next 2 weeks. A 25-gauge diagnostic pars plana vitrectomy was performed with endolaser photocoagulation to healthy retina walling off atrophic areas. Vitreous fluid PCR was positive for EBV DNA (2421 copies) and negative for cytomegalovirus, VZV, and HSV-1 and 2 DNA. The patient’s visual acuity deteriorated to no light perception over the course of 1 week after surgery. Follow-up exami-
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JAMA Ophthalmology July 2014 Volume 132, Number 7
Copyright 2014 American Medical Association. All rights reserved.
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881
Research Brief Report
Epstein-Barr Virus and Acute Retinal Necrosis
Figure. Clinical Histopathologic Analysis of Acute Retinal Necrosis Caused by Epstein-Barr Virus (EBV) A
B
C
EBV HSV VZV 16S
00 ive ive -4 at sit 11 Neg Po
A, Confluent areas of peripheral retinal necrosis, though the optic nerve and macula are uninvolved. Periarteritis extending peripherally can be seen in the left eye. B, Postoperative fundus photograph showing progression of the retinal necrosis to involve the macula in the left eye. C, Histologic examination confirmed retinal necrosis with complete loss of the normal lamellar
architecture of the retina as well as moderate monocytic cellular infiltration in the retina. Polymerase chain reaction detected positive EBV DNA and negative 16S ribosomal RNA in the microdissected necrotic retinal cells (hematoxylin-eosin, original magnification ×200). HSV indicates herpes simplex virus, and VZV, varicella-zoster virus.
nation showed rapid progression of the retinal necrosis to involve the optic nerve and macula (Figure, B). An enucleation of the left eye was performed to confirm the infectious diagnosis in the event that a similar clinical presentation affected the fellow eye. Polymerase chain reaction of the microdissected, affected retinal cells detected EBV DNA using EBVspecific primer pair and universal HSV primer. No bacterial DNA was detected using 16S ribosomal RNA gene primer pair. Histologic analysis showed extensive necrosis of the retina and retinal pigment epithelium, with moderate mononuclear inflammatory cellular infiltration composed of lymphocytes (T cells>B cells) and macrophages (Figure, C).
thermore, to our knowledge, this is the first case in which EBV was detected by molecular pathology within retinal cells, eliminating the possibility that infiltrating lymphocytes were responsible for the positive data. This is an important distinction, since EBV-infected lymphocytes may be detected within the retina without the virus being the cause of the retinal infection. Traditionally, ARN has been diagnosed clinically in immunocompetent patients and treated with intravenous acyclovir.5 More recently, clinicians have used oral and/or intravitreal antiviral agents, early prophylactic laser retinopexy, and/or early vitrectomy for treatment. Because EBV is relatively resistant to antiviral medication,3 early sampling of the aqueous and/or vitreous with PCR for herpesviruses should be considered to determine the precise etiologic pathogen. In cases where EBV is confirmed to be responsible for the infection, we suggest that early vitrectomy with intravitreal injection of multiple antiviral drugs be considered, especially in immunosuppressed patients. To the best of our knowledge, this is the first case of ARN in which EBV was identified in ocular tissue and confirmed as the sole causative agent.
Discussion The role of EBV in ARN is unclear because its seroprevalence in the United States is greater than 90% and PCR detects EBV in 20% of normal cadaveric eyes,1 yet reports of EBV-related ARN have been described with variable levels of causative evidence. Our case yielded positive vitreous PCR results for EBV without detection of DNA from other herpesviruses. Fur-
ARTICLE INFORMATION Submitted for Publication: August 29, 2013; final revision received December 16, 2013; accepted December 19, 2013. Published Online: April 17, 2014. doi:10.1001/jamaophthalmol.2014.266. Author Contributions: Dr Schaal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schaal, Kaplan. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Schaal, Kagan. Critical revision of the manuscript for important intellectual content: Schaal, Wang, Chan, Kaplan. Statistical analysis: Schaal. Obtained funding: Schaal.
882
Administrative, technical, and material support: Schaal, Kagan, Wang. Study supervision: Schaal, Chan, Kaplan. Conflict of Interest Disclosures: None reported. Funding/Support: The work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc and Kentucky Research Challenge Trust Fund (Dr Kaplan). Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES
clinical features, early vitrectomy, and outcomes. Ophthalmology. 2009;116(10):1971-1975, e2. 2. Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology. 2007;114(4):756-762. 3. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-492. 4. Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011;24(1):193-209. 5. Hershberger VS, Hutchins RK, Witte DP, Schneider S, Harris RE, McGonegle SJ. Epstein-Barr virus-related bilateral acute retinal necrosis in a patient with X-linked lymphoproliferative disorder. Arch Ophthalmol. 2003;121(7):1047-1049.
1. Hillenkamp J, Nölle B, Bruns C, Rautenberg P, Fickenscher H, Roider J. Acute retinal necrosis:
JAMA Ophthalmology July 2014 Volume 132, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a J H Quillen College User on 05/27/2015
jamaophthalmology.com
Brief Report
Acute Retinal Necrosis Associated With Epstein-Barr Virus Immunohistopathologic Confirmation Shlomit Schaal, MD, PhD; Aleksandr Kagan, MD; Yujuan Wang, MD; Chi-Chao Chan, MD; Henry J. Kaplan, MD
IMPORTANCE Acute retinal necrosis (ARN) is an infectious retinitis primarily caused by the
herpesviruses. Although the Epstein-Barr virus (EBV) has been implicated as a cause of ARN, to our knowledge, there has been no histopathologic documentation. We report the clinical history and histopathologic confirmation that EBV can cause ARN. OBSERVATIONS Clinical course and histopathology of a patient diagnosed with ARN caused by infection with EBV confirmed by molecular pathology. CONCLUSIONS AND RELEVANCE Epstein-Barr virus is a recognized cause of intraocular inflammation and has been implicated as a possible cause of ARN. However, to our knowledge, tissue demonstration of EBV in a patient with ARN has not previously been reported. We identified the organism in the necrotic retina of a patient receiving immunosuppression because of idiopathic pulmonary fibrosis. JAMA Ophthalmol. 2014;132(7):881-882. doi:10.1001/jamaophthalmol.2014.266 Published online April 17, 2014.
A
cute retinal necrosis (ARN) is a syndrome characterized by progressive intraretinal inflammation and necrosis. The clinical diagnosis is frequently supported by the identification of the causative infectious agent, most commonly varicella-zoster virus (VZV), though herpes simplex virus (HSV) types 1 and 2, cytomegalovirus, and EpsteinBarr virus (EBV) have also been implicated.1,2 Epstein-Barr virus, a double-stranded DNA virus transmitted by oral secretions, infects more than 90% of humans.3 Primary infection is characterized most commonly by the clinical syndrome of infectious mononucleosis, which is characterized by fever, pharyngitis, lymphadenopathy, palatal petechiae, hepatomegaly, and splenomegaly. The virus remains latent within memory B cells where it may reactivate, yielding virus capable of infecting new B cells and epithelial cells.4 There are only a few reported cases of EBV-associated ARN1,2,5 and all lack definitive demonstration of the virus. Epstein-Barr virus DNA has been previously detected by polymerase chain reaction (PCR) in vitreous samples of patients with ARN, but only in conjunction with VZV DNA.1,2 Herein, we describe a case of ARN in which EBV was the sole virus detected both by vitreous PCR and, most importantly, by molecular pathology (microdissection and PCR) confirming the virus within the retina of the enucleated globe.
Report of a Case A 55-year-old woman with rheumatoid arthritis, chronic renal failure of unknown etiology, and idiopathic pulmonary fibro-
Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky (Schaal, Kagan, Kaplan); Laboratory of Immunology, Immunopathology Section, National Eye Institute, Bethesda, Maryland (Wang, Chan). Corresponding Author: Shlomit Schaal, MD, PhD, Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E Muhammad Ali Blvd, Louisville, KY 40202 ([email protected]).
sis was receiving an immunosuppressive regimen consisting of methylprednisolone (alternating 40 mg/32 mg, orally, daily) and infliximab (Remicade; 9 mg/kg every 4 weeks). She presented with decreased vision in her left eye of 3 weeks’ duration. Her visual acuity was 20/20 OD and 20/100 OS. Clinical examination of the right eye was normal; however, in her left eye, she presented with ciliary flush, nongranulomatous endothelial keratic precipitates, 2+ cell and 2+ flare within the anterior chamber, 3+ vitreous cells, extensive peripheral retinal necrosis for 270°, with periarteritis, but sparing of the macula and the optic nerve (Figure, A). She was diagnosed with ARN in her left eye and started treatment with oral valacyclovir hydrochloride (1 g, twice daily) and topical corticosteroids. Serum EBV viral capsid antigen IgG was elevated (>75 000 AU/mL) with no detectable EBV viral capsid antigen IgM. The EBV nuclear antigen titer was mildly elevated at 29 (normal, 0-21.9) and EBV early antigen titer was 10.3 (normal, 0-10.9). The HSV-1 IgG titer was elevated with an undetectable HSV-1 IgM titer. The VZV IgG titer was elevated with a nondetectable VZV IgM titer. Titers for HSV-2 IgG and IgM were undetectable. During the course of the disease, the left eye did not demonstrate any signs of clinical improvement, despite the addition of intravitreal ganciclovir (2 mg) over the next 2 weeks. A 25-gauge diagnostic pars plana vitrectomy was performed with endolaser photocoagulation to healthy retina walling off atrophic areas. Vitreous fluid PCR was positive for EBV DNA (2421 copies) and negative for cytomegalovirus, VZV, and HSV-1 and 2 DNA. The patient’s visual acuity deteriorated to no light perception over the course of 1 week after surgery. Follow-up exami-
jamaophthalmology.com
JAMA Ophthalmology July 2014 Volume 132, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a J H Quillen College User on 05/27/2015
881
Research Brief Report
Epstein-Barr Virus and Acute Retinal Necrosis
Figure. Clinical Histopathologic Analysis of Acute Retinal Necrosis Caused by Epstein-Barr Virus (EBV) A
B
C
EBV HSV VZV 16S
00 ive ive -4 at sit 11 Neg Po
A, Confluent areas of peripheral retinal necrosis, though the optic nerve and macula are uninvolved. Periarteritis extending peripherally can be seen in the left eye. B, Postoperative fundus photograph showing progression of the retinal necrosis to involve the macula in the left eye. C, Histologic examination confirmed retinal necrosis with complete loss of the normal lamellar
architecture of the retina as well as moderate monocytic cellular infiltration in the retina. Polymerase chain reaction detected positive EBV DNA and negative 16S ribosomal RNA in the microdissected necrotic retinal cells (hematoxylin-eosin, original magnification ×200). HSV indicates herpes simplex virus, and VZV, varicella-zoster virus.
nation showed rapid progression of the retinal necrosis to involve the optic nerve and macula (Figure, B). An enucleation of the left eye was performed to confirm the infectious diagnosis in the event that a similar clinical presentation affected the fellow eye. Polymerase chain reaction of the microdissected, affected retinal cells detected EBV DNA using EBVspecific primer pair and universal HSV primer. No bacterial DNA was detected using 16S ribosomal RNA gene primer pair. Histologic analysis showed extensive necrosis of the retina and retinal pigment epithelium, with moderate mononuclear inflammatory cellular infiltration composed of lymphocytes (T cells>B cells) and macrophages (Figure, C).
thermore, to our knowledge, this is the first case in which EBV was detected by molecular pathology within retinal cells, eliminating the possibility that infiltrating lymphocytes were responsible for the positive data. This is an important distinction, since EBV-infected lymphocytes may be detected within the retina without the virus being the cause of the retinal infection. Traditionally, ARN has been diagnosed clinically in immunocompetent patients and treated with intravenous acyclovir.5 More recently, clinicians have used oral and/or intravitreal antiviral agents, early prophylactic laser retinopexy, and/or early vitrectomy for treatment. Because EBV is relatively resistant to antiviral medication,3 early sampling of the aqueous and/or vitreous with PCR for herpesviruses should be considered to determine the precise etiologic pathogen. In cases where EBV is confirmed to be responsible for the infection, we suggest that early vitrectomy with intravitreal injection of multiple antiviral drugs be considered, especially in immunosuppressed patients. To the best of our knowledge, this is the first case of ARN in which EBV was identified in ocular tissue and confirmed as the sole causative agent.
Discussion The role of EBV in ARN is unclear because its seroprevalence in the United States is greater than 90% and PCR detects EBV in 20% of normal cadaveric eyes,1 yet reports of EBV-related ARN have been described with variable levels of causative evidence. Our case yielded positive vitreous PCR results for EBV without detection of DNA from other herpesviruses. Fur-
ARTICLE INFORMATION Submitted for Publication: August 29, 2013; final revision received December 16, 2013; accepted December 19, 2013. Published Online: April 17, 2014. doi:10.1001/jamaophthalmol.2014.266. Author Contributions: Dr Schaal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schaal, Kaplan. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Schaal, Kagan. Critical revision of the manuscript for important intellectual content: Schaal, Wang, Chan, Kaplan. Statistical analysis: Schaal. Obtained funding: Schaal.
882
Administrative, technical, and material support: Schaal, Kagan, Wang. Study supervision: Schaal, Chan, Kaplan. Conflict of Interest Disclosures: None reported. Funding/Support: The work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc and Kentucky Research Challenge Trust Fund (Dr Kaplan). Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES
clinical features, early vitrectomy, and outcomes. Ophthalmology. 2009;116(10):1971-1975, e2. 2. Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology. 2007;114(4):756-762. 3. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-492. 4. Odumade OA, Hogquist KA, Balfour HH Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011;24(1):193-209. 5. Hershberger VS, Hutchins RK, Witte DP, Schneider S, Harris RE, McGonegle SJ. Epstein-Barr virus-related bilateral acute retinal necrosis in a patient with X-linked lymphoproliferative disorder. Arch Ophthalmol. 2003;121(7):1047-1049.
1. Hillenkamp J, Nölle B, Bruns C, Rautenberg P, Fickenscher H, Roider J. Acute retinal necrosis:
JAMA Ophthalmology July 2014 Volume 132, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a J H Quillen College User on 05/27/2015
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