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Progressive outer retinal necrosis caused by herpes simplex virus type 1 in a patient with acquired immunodeficiency syndrome
Progressive Outer Retinal Necrosis Caused by Herpes Simplex Virus Type 1 in a Patient with Acquired Immunodeficiency Syndrome Mitsutoshi Kashiwase, MD,1,3 Tetsutaro Sata, MD,2,3 Yasuyuki Yamauchi, MD,1 Hiroshi Minoda, MD,1 Norio Usui, MD,1 Takuya Iwasaki, MD,3 Takeshi Kurata, MD,3 Masahiko Usui, MD1 Objective/Background: To identify the etiologic agent of rapidly progressive outer retinal necrosis (PORN) in a 32-year-old man with acquired immunodeficiency syndrome (AIDS), who had retinitis developed from cytomegalovirus (CMV). Multiple yellowish spots appeared in the deep retina without evidence of intraocular inflammation or retinal vasculitis, diagnosed clinically as PORN. Death occurred after failure of multiple organs. Design: Case report. Methods: Both globes were taken at autopsy, fixed in formalin, and examined histopathologically and immunohistochemically to identify causative agents in the retinal lesions. Main Outcome Measure: Immunohistochemistry. Results: All layers of the retina were severely damaged and contained focal calcification. Cytomegalic inclusion bodies were found in cells in the damaged retina of the right eye. Immunohistochemical studies for herpesviruses revealed the presence of CMV antigens in the right retina at the posterior pole and herpes simplex virus type 1 (HSV-1)–specific antigen in the periphery of both retinas. No varicella-zoster virus (VZV) antigen was detected in either retina. Conclusions: PORN has been described as a variant of necrotizing herpetic retinopathy, occurring particularly in patients with AIDS. Although the etiologic agent has been reported to be VZV, HSV-1 can be an etiologic agent. Ophthalmology 2000;107:790 –794 © 2000 by the American Academy of Ophthalmology. Patients with acquired immunodeficiency syndrome (AIDS) are predisposed to several ophthalmic opportunistic infections with members of the herpesvirus family, Toxoplasma gondii, Cryptococcus neoformans, Pneumocystis carinii, Candida species, and bacteria.1 Necrotizing herpetic retinopathies have been considered to be a spectrum of disorders induced by herpesviruses including cytomegalovirus (CMV), whose clinical presentation depends on the immune status of the patients.2 Retinitis and acute retinal necrosis (ARN) can be caused by herpes simplex virus (HSV) or varicella-zoster virus (VZV).2– 4 In addition, as first reported by Forster et al5 in two patients with AIDS in 1990, rapidly progressive outer retinal necrosis (PORN) may occur. VZV Originally received: March 10, 1999. Accepted: November 12, 1999.
Manuscript no. 99124.
has been identified as an etiologic agent of PORN by various methods.6 –10 Immunocytochemical studies have detected VZV antigens in the outer nuclear layer of the retina.6 PORN is characterized clinically as showing minimal or no inflammation in the aqueous and vitreous humor, absence of retinal vasculitis, and patches of yellowish spots located deep in the retina. Most patients with PORN have a poor ophthalmologic prognosis because the retinal necrosis tends to be followed by rhegmatogenous retinal detachment, and antiviral therapy with acyclovir has not been effective because of the patients’ severely immunosuppressed state.11 We examined a patient with AIDS who developed the clinical picture of PORN after the occurrence of CMV retinitis. When both retinas were examined at autopsy, HSV type 1 (HSV-1) and CMV antigens, but not VZV were detected immunohistochemically. This is the first reported case of PORN caused by HSV-1 infection.
1
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan. 2 Laboratory of Pathology, AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Case Presentation
3
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. Supported by a grant-in-aid from Ministry of Health and Welfare, Japan (TS). Reprint requests to Tetsutaro Sata, MD, Laboratory of Pathology, AIDS Research Center, and Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
790
© 2000 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
A 32-year-old Japanese man, diagnosed with hemophilia B at the age of 3 years, had been treated with anticoagulant blood products. The patient was found to be infected with human immunodeficiency virus type 1 (HIV-1) at the age of 21. At the same time, he was diagnosed with AIDS at the C3 stage (CDC classification) because of the decreased CD4⫹ cell count, 98/l, and the presence ISSN 0161-6420/00/$–see front matter PII S0161-6420(99)00143-8
Kashiwase et al 䡠 Progressive Outer Retinal Necrosis and Herpes Simplex Virus-1
Figure 1. Ophthalmoscopic appearance of CMV retinitis in the right eye (first symptomatic day). Neuroepithelial necrosis with hemorrhage involves the optic disc and the macula. Figure 2. Subsequent fundus photographs of each eye. A, findings are consistent with CMV retinitis in the posterior pole of the right eye. Additionally, multifocal deep retinal opacities and diffuse retinal opacification involve all quadrants bilaterally. B, multifocal deep retinal lesions are seen with the central macula showing a cherry-red spot in the left eye.
of esophagitis caused by Candida. After the diagnosis, he was treated with zidovudine and either didanosine or stavudine. He had cutaneous herpes zoster eruptions extending from the left lumbar to femoral region at age 29. Ophthalmic examinations were performed every few months beginning in 1995. In the course of follow-up, HIV retinopathy with temporally located cotton-wool spots and hemorrhages had been observed, but this had improved without specific treatment. In July 1996, the patient complained of visual loss in the right eye. Visual acuity was 20/60 in the right eye and 20/20 in left eye. Slit-lamp examination disclosed a few inflammatory cells in the anterior chamber of the right eye. Ophthalmoscopic examination detected opacification caused by necrosis and hemorrhage in the right retina involving the optic disc and macula (Fig 1). The CD4⫹ cell count became 19/l and CMV antigenemia was present (5 of 26,000 cells).12–13 Intravitreous treatment with ganciclovir for presumed CMV retinitis was administered. At that time, the left eye remained normal in appearance. The patient then was admitted to the hospital for intravenous treatment with a regimen of 180 mg/kg/day of foscarnet. CMV retinitis was seen to gradually
improve according to ophthalmoscopic findings, and CMV antigenemia disappeared. However, the patient’s condition became worse because of renal failure and pharyngeal edema. Treatment with foscarnet was abandoned on day 39. Ulceration appearing similar to that from HSV infection developed on the left eyelid and was treated with acyclovir ointment. On day 46, edematous changes suddenly appeared at the posterior pole of both fundi, and a cherry-red spot appearance was appreciated, especially in the left eye. Later, patches of yellowish spots deep in the retina were observed at the posterior pole; these extended rapidly to the periphery. Within only 4 days, retinal necrosis extended to all retinal quadrants (Fig 2A,B). No inflammatory reaction was evident in the anterior chamber or vitreous, and no lesions of retinal vasculitis were found in either eye. The lesion was diagnosed as PORN on the basis of clinical appearance. Intravenous treatment with ganciclovir and high-titer ␥-globulin was started on hospital day 55. The patient died of multiple organ failure on hospital day 81. Retinal detachment did not occur at any time during the clinical course. Four days after the PORN-like retinitis appeared, the serum
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Figure 3. Histologic and immunohistochemical findings. A, cytomegalic cells (arrows) are present in outer retinal layer near thickened retinal vessels in the posterior retina of the right eye (stain, hematoxylin– eosin; original magnification, ⫻400); B, immunostaining for late CMV antigens showing cytomegalic cells (arrows) in the same field of the right eye (original magnification, ⫻400); C, degenerated herpes simplex virus (HSV)-1–infected cells are present in the peripheral retina of the left eye (stain, hematoxylin– eosin; original magnification, ⫻400); D, immunohistochemical detection of HSV-1 antigen by monoclonal antibody specific to HSV-1 in the same place of the left eye (original magnification, ⫻400).
complement fixation (CF) antibody titer to HSV was 1:16, and neutralizing (NT) antibody titer to HSV-1 and HSV type 2 (HSV-2) was 1:32 and 1:16, respectively. Three weeks later, the CF antibody titer remained 1:16, while NT antibody titer to HSV-1 and HSV-2 was 1:64 and 1:16, respectively. The increase in NT antibody to HSV-1 was not significant.
Histologic and Immunohistochemical Methods Both globes were obtained at autopsy and fixed in 10% formalin. The specimens first were cut horizontally to include the optic disc and then were cut perpendicular to the original plane. Tissue was processed routinely and embedded in paraffin. Some sections were stained with hematoxylin and eosin and others were stained by the periodic-acid–Schiff (PAS) method. Additionally, sections were examined by immunohistochemistry with a labeled streptavidinbiotin method (Dako, Kyoto, Japan) to detect VZV, HSV-1, HSV-2, human herpesvirus 6 (HHV6), and CMV antigens. The antibodies used were rabbit polyclonal antibodies to HSV,14 and CMV,15 and monoclonal antibodies to VZV,16 HSV-1, HSV-2,14
792
HHV6 (P101, Chemicon, CA), and the immediate early protein 2 of CMV (E5).15 All antibodies except E5 recognize viral structural proteins that corresponded to late antigens of the herpesviruses. For positive controls, we used the skin and liver tissues infected with HSV-1, HSV-2, and VZV, and eye tissues of CMV retinitis. For negative controls, we used a series of retinal tissues collected from AIDS patients without any lesions.
Microscopic Findings Including Immunohistochemistry Most retinal structures from the posterior pole to the periphery of both eyes were destroyed. In the periphery both eyes showed accompanying calcification. Retinal alterations were much more severe in the right eye than in the left. The outer retinal layer, however, remained in place at the posterior pole of the right eye, where retinal pigment epithelial cells (RPE) and Bruch’s membrane showed degeneration and lymphoid cells infiltrating into the choroid. Characteristic cytomegalic cells were observed in the outer retinal layer and the RPE of the right eye (Fig 3A). Most of the cornea, iris, corpus ciliare, vitreous, choroid, sclera, and optic
Kashiwase et al 䡠 Progressive Outer Retinal Necrosis and Herpes Simplex Virus-1 disc were devoid of abnormalities. No vasculitis was found in the choroidal or retinal regions of either eye. No microorganisms were found on PAS staining. In the right retina, both the cytomegalic cells and other cells lacking characteristic features were stained immunohistochemically by anti-cytomegalovirus immediate early antigen (E5) and by anti-late antigen antibodies (Fig 3B). No cytomegalovirus antigen, however, was detected in the left eye. In the peripheries of each eye where calcification was seen, HSV antigen was detected by the rabbit anti-HSV antibody. HSV-1 antigen-positive cells showed degeneration and were difficult to identify by cell type (Fig 3C). With monoclonal antibodies specific for HSV-1 or HSV-2, staining was seen only with anti-HSV-1 monoclonal antibodies (Fig 3D). Neither VZV nor HHV6 antigens were detected in either eye. Extraocular autopsy findings included cerebral toxoplasmosis involving the frontal lobe. No cytomegalic cells or nuclear inclusion body-bearing cells suggestive of HSV-1 infection were observed in systemic organs.
Discussion PORN has been reported as a distinct form of ARN differing from acute necrotizing retinopathy caused by VZV in patients with AIDS.5 VZV antigen has been detected immunohistochemically in the outer retina in eyes showing PORN, and VZV is considered the usual etiologic agent.6 Engstrom et al11 have retrospectively studied 65 involved eyes from 38 patients and defined clinical criteria for PORN: multifocal lesions characterized by deep retinal opacification without granular borders, sometimes including areas of confluent opacification; lesion location in the peripheral retina, with or without macular involvement; extremely rapid progression; absence of vascular inflammation; and minimal or no intraocular inflammation. PORN is further characterized by an extremely poor prognosis, manifesting poor responses to antiviral treatment related to an immunodeficient state. Progression to loss of light perception occurs in two thirds of patients because of photoreceptor necrosis involving the atrophic retina. Clinically, our patient first manifested CMV retinitis and then multiple discrete areas of retinal opacification developed in the deep layers of each eye after anti-CMV therapy was abandoned. Ophthalmic findings were characterized by absence of intraocular inflammation and lack of retinal vasculitis and by rapid progression of confluent yellow-white patches corresponding to full-thickness retinal necrosis from the posterior pole to the periphery. Our patient’s findings met at least four of Engstrom’s criteria, with the only point of difference being that the lesion initially occurred at the posterior pole of the retina. However, Margolis et al6 have reported four of five cases of PORN to show retinitis extending peripherally from the posterior pole. Several reports have identified VZV as a causative agent of PORN. Electron microscopically, herpesvirus particles were demonstrated in a retinal biopsy specimen from a case of PORN.5 VZV has been isolated from chorioretinal specimens in PORN cases,6,7 and immunohistochemical examination has demonstrated VZV antigen in the outer retina.6 Polymerase chain reaction (PCR) has detected VZV DNA in specimens of vitreous aspirate,8 surgically enucleated eye specimens,9 and necropsy spec-
imens of the eye.10 HSV, however, has not been documented in previous reports. At autopsy our case showed HSV-1 antigen in the peripheral retina of both eyes and cytomegalic cells with positive CMV antigens in the posterior retina of the right eye. Regretfully, PCR for herpesviruses, together with -globin genes, failed to amplify, seemingly because of an inadequate specimen for PCR. The major differences in clinical findings of ARN from those of PORN involved the depth of retinal lesions, the presence of retinal vasculitis, and intraocular inflammation.17 Our case did not show the clinical findings of ARN described in previous reports.18 –22 Histopathologic findings in ARN included inflammatory infiltrates in the anterior segment of the eye involving the iris and ciliary body and in the choroid and optic nerve.23, 24 In the retina, completely necrotic areas were admixed with areas showing partial preservation of retinal structure. The necrotic areas showed only a residual skeletal framework of blood vessels. The RPE degenerated and disappeared, accompanied by formation of a fibrous layer with neovascularization. Superficial layers of the retina were infiltrated with plasma cells and polymorphonuclear leukocytes, and arteries were surrounded by inflammatory cell infiltrates.23 In contrast, the histopathology of PORN included locally deep necrosis with destruction of retinal architecture and sometimes retinal detachment, but except for macrophages inflammatory cells were scarce.9 Retinal necrosis was particularly marked in the outer nuclear layer.6 In some areas, choriocapillaris had intense lymphocytic infiltrates, whereas in other areas all layers of the choroid might be involved by such infiltrates.6 In our case, histologic changes of the RPE, Bruch’s membrane, and the choroid in the periphery of the retina were less severe where HSV-1 antigen was identified; marked inflammatory cell infiltrates, a fibrous layer, and neovascularization were not observed. Considering the features of the case in the aggregate, we were convinced that the findings were consistent with PORN and differ from ARN both clinically and histopathologically. Two cases of PORN in which HSV infection was suspected as a cause have been reported.25,26 These two patients with AIDS showed acute necrotizing retinitis similar to PORN with deep retinal lesions and absence of both intraocular inflammation and retinal vasculitis. Both authors suspected HSV as a causative agent because the patients had histories of cutaneous or genital HSV infection. However, both authors failed to identify HSV in ocular tissues. This patient had a history of herpes zoster and showed an ulcer suggestive of HSV infection on his left upper eyelid, although no confirmatory test such as antigen detection was performed. Keratitis and iridocyclitis pose comparable problems because ocular manifestations caused by HSV or VZV are clinically similar. Although VZV has been considered the causative agent of PORN, we concluded that in our case HSV-1 caused an identical retinitis. Acknowledgments. The authors thank Ms. Yuko Sato and Ms. Noriko Sakurai for excellent technical assistance.
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References 1. Cunningham ET Jr, Margolis TP. Ocular manifestations of HIV infection. N Engl J Med 1998;339:236 – 44. 2. Guex-Crosier Y, Rochat C, Herbort CP. Necrotizing herpetic retinopathies. A spectrum of herpes virus-induced diseases determined by the immune state of the host. Ocul Immunol Inflamm 1997;5:259 – 65. 3. Batisse D, Eliaszewicz M, Zazoun L, et al. Acute retinal necrosis in the course of AIDS: study of 26 cases. AIDS 1996;10:55– 60. 4. Garweg J, Bo¨hnke M. Varicella-zoster virus is strongly associated with atypical necrotizing herpetic retinopathies. Clin Infect Dis 1997;24:603– 8. 5. Forster DJ, Dugel PU, Frangieh GT, et al. Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol 1990;110:341– 8. 6. Margolis TP, Lowder CY, Holland GN, et al. Varicella-zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1991;112:119 –31. 7. Galindez OA, Sabates NR, Whitacre MM, Sabates FN. Rapidly progressive outer retinal necrosis caused by varicella zoster virus in a patient infected with human immunodeficiency virus. Clin Infect Dis 1996;22:149 –51. 8. Pavesio CE, Mitchell SM, Barton K, et al. Progressive outer retinal necrosis (PORN) in AIDS patients: a different appearance of varicella-zoster retinitits. Eye 1995;9:271– 6. 9. Greven CM, Ford J, Stanton C, et al. Progressive outer retinal necrosis secondary to varicella zoster virus in acquired immune deficiency syndrome. Retina 1995;15:14 –20. 10. van den Horn GJ, Meenken C, Troost D. Association of progressive outer retinal necrosis and varicella zoster encephalitis in a patient with AIDS. Br J Ophthalmol 1996;80:982–5. 11. Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology 1994;101:1488 –502. 12. van der Bij W, Schirm J, Torensma R, et al. Comparison between viremia and antigenemia for detection of cytomegalovirus in blood. J Clin Microbiol 1988;26:2531–5. 13. Pannuti CS, Kalla´s EG, Muccioli C, et al. Cytomegalovirus antigenemia in acquired immunodeficiency syndrome patients with untreated cytomegalovirus retinitis. Am J Ophthalmol 1996;122:847–52. 14. Takebe N, Yokoyama A, Akasaka Y, et al. Fatal herpes
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simplex hepatitis type 2 in a post-thymectomized adult. Gastroenterologia Japonica 1993;28:304 –11. Maeda A, Sata T, Sato Y, Kurata T. A comparative study of congenital and postnatally acquired human cytomegalovirus infection in infants: lack of expression of viral immediate early protein in congenital cases. Virchows Arch A Pathol Anat Histopathol. 1994;424:121– 8. Okuno T, Yamanishi K, Shiraki K, Takahashi M. Synthesis and processing of glycoproteins of varicella-zoster virus (VZV) as studied with monoclonal antibodies to VZV antigens. Virology 1983;129:357– 68. 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. Pepose JS, Hilborne LH, Cancilla PA, Foos RY. Concurrent herpes simplex and cytomegalovirus retinitis and encephalitis in the acquired immune deficiency syndrome (AIDS). Ophthalmology 1984;91:1669 –77. Lewis ML, Culbertson WW, Post MJD, et al. Herpes simplex virus type 1. A cause of the acute retinal necrosis syndrome. Ophthalmology 1989;96:875– 8. Duker JS, Nielsen JC, Eagle RC Jr, et al. Rapidly progressive acute retinal necrosis secondary to herpes simplex virus, type 1. Ophthalmology 1990;97:1638 – 43. Cunningham ET Jr, Short GA, Irvine AR, et al. Acquired immunodeficiency syndrome–associated herpes simplex virus retinitis: clinical description and use of a polymerase chain reaction– based assay as a diagnostic tool. Arch Ophthalmol 1996;114:834 – 40. Rahhal FM, Siegel LM, Russak V, et al. Clinicopathologic correlations in acute retinal necrosis caused by herpes simplex virus type 2. Arch Ophthalmol 1996;114:1416 –19. Culbertson WW, Blumenkranz MS, Haines H, et al. The acute retinal necrosis syndrome. Part 2: Histopathology and etiology. Ophthalmology 1982;89:1317–25. Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25:607–19. Sidikaro Y, Silver L, Holland GN, Kreiger AE. Rhegmatogenous retinal detachments in patients with AIDS and necrotizing retinal infections. Ophthalmology 1991;98:129 –35. Ormerod LD, Larkin JA, Margo CA, et al. Rapidly progressive herpetic retinal necrosis: a blinding disease characteristic of advanced AIDS. Clin lnfect Dis 1998;26:34 – 45.
Manuscript no. 99124.
has been identified as an etiologic agent of PORN by various methods.6 –10 Immunocytochemical studies have detected VZV antigens in the outer nuclear layer of the retina.6 PORN is characterized clinically as showing minimal or no inflammation in the aqueous and vitreous humor, absence of retinal vasculitis, and patches of yellowish spots located deep in the retina. Most patients with PORN have a poor ophthalmologic prognosis because the retinal necrosis tends to be followed by rhegmatogenous retinal detachment, and antiviral therapy with acyclovir has not been effective because of the patients’ severely immunosuppressed state.11 We examined a patient with AIDS who developed the clinical picture of PORN after the occurrence of CMV retinitis. When both retinas were examined at autopsy, HSV type 1 (HSV-1) and CMV antigens, but not VZV were detected immunohistochemically. This is the first reported case of PORN caused by HSV-1 infection.
1
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan. 2 Laboratory of Pathology, AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Case Presentation
3
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. Supported by a grant-in-aid from Ministry of Health and Welfare, Japan (TS). Reprint requests to Tetsutaro Sata, MD, Laboratory of Pathology, AIDS Research Center, and Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
790
© 2000 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
A 32-year-old Japanese man, diagnosed with hemophilia B at the age of 3 years, had been treated with anticoagulant blood products. The patient was found to be infected with human immunodeficiency virus type 1 (HIV-1) at the age of 21. At the same time, he was diagnosed with AIDS at the C3 stage (CDC classification) because of the decreased CD4⫹ cell count, 98/l, and the presence ISSN 0161-6420/00/$–see front matter PII S0161-6420(99)00143-8
Kashiwase et al 䡠 Progressive Outer Retinal Necrosis and Herpes Simplex Virus-1
Figure 1. Ophthalmoscopic appearance of CMV retinitis in the right eye (first symptomatic day). Neuroepithelial necrosis with hemorrhage involves the optic disc and the macula. Figure 2. Subsequent fundus photographs of each eye. A, findings are consistent with CMV retinitis in the posterior pole of the right eye. Additionally, multifocal deep retinal opacities and diffuse retinal opacification involve all quadrants bilaterally. B, multifocal deep retinal lesions are seen with the central macula showing a cherry-red spot in the left eye.
of esophagitis caused by Candida. After the diagnosis, he was treated with zidovudine and either didanosine or stavudine. He had cutaneous herpes zoster eruptions extending from the left lumbar to femoral region at age 29. Ophthalmic examinations were performed every few months beginning in 1995. In the course of follow-up, HIV retinopathy with temporally located cotton-wool spots and hemorrhages had been observed, but this had improved without specific treatment. In July 1996, the patient complained of visual loss in the right eye. Visual acuity was 20/60 in the right eye and 20/20 in left eye. Slit-lamp examination disclosed a few inflammatory cells in the anterior chamber of the right eye. Ophthalmoscopic examination detected opacification caused by necrosis and hemorrhage in the right retina involving the optic disc and macula (Fig 1). The CD4⫹ cell count became 19/l and CMV antigenemia was present (5 of 26,000 cells).12–13 Intravitreous treatment with ganciclovir for presumed CMV retinitis was administered. At that time, the left eye remained normal in appearance. The patient then was admitted to the hospital for intravenous treatment with a regimen of 180 mg/kg/day of foscarnet. CMV retinitis was seen to gradually
improve according to ophthalmoscopic findings, and CMV antigenemia disappeared. However, the patient’s condition became worse because of renal failure and pharyngeal edema. Treatment with foscarnet was abandoned on day 39. Ulceration appearing similar to that from HSV infection developed on the left eyelid and was treated with acyclovir ointment. On day 46, edematous changes suddenly appeared at the posterior pole of both fundi, and a cherry-red spot appearance was appreciated, especially in the left eye. Later, patches of yellowish spots deep in the retina were observed at the posterior pole; these extended rapidly to the periphery. Within only 4 days, retinal necrosis extended to all retinal quadrants (Fig 2A,B). No inflammatory reaction was evident in the anterior chamber or vitreous, and no lesions of retinal vasculitis were found in either eye. The lesion was diagnosed as PORN on the basis of clinical appearance. Intravenous treatment with ganciclovir and high-titer ␥-globulin was started on hospital day 55. The patient died of multiple organ failure on hospital day 81. Retinal detachment did not occur at any time during the clinical course. Four days after the PORN-like retinitis appeared, the serum
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Ophthalmology Volume 107, Number 4, April 2000
Figure 3. Histologic and immunohistochemical findings. A, cytomegalic cells (arrows) are present in outer retinal layer near thickened retinal vessels in the posterior retina of the right eye (stain, hematoxylin– eosin; original magnification, ⫻400); B, immunostaining for late CMV antigens showing cytomegalic cells (arrows) in the same field of the right eye (original magnification, ⫻400); C, degenerated herpes simplex virus (HSV)-1–infected cells are present in the peripheral retina of the left eye (stain, hematoxylin– eosin; original magnification, ⫻400); D, immunohistochemical detection of HSV-1 antigen by monoclonal antibody specific to HSV-1 in the same place of the left eye (original magnification, ⫻400).
complement fixation (CF) antibody titer to HSV was 1:16, and neutralizing (NT) antibody titer to HSV-1 and HSV type 2 (HSV-2) was 1:32 and 1:16, respectively. Three weeks later, the CF antibody titer remained 1:16, while NT antibody titer to HSV-1 and HSV-2 was 1:64 and 1:16, respectively. The increase in NT antibody to HSV-1 was not significant.
Histologic and Immunohistochemical Methods Both globes were obtained at autopsy and fixed in 10% formalin. The specimens first were cut horizontally to include the optic disc and then were cut perpendicular to the original plane. Tissue was processed routinely and embedded in paraffin. Some sections were stained with hematoxylin and eosin and others were stained by the periodic-acid–Schiff (PAS) method. Additionally, sections were examined by immunohistochemistry with a labeled streptavidinbiotin method (Dako, Kyoto, Japan) to detect VZV, HSV-1, HSV-2, human herpesvirus 6 (HHV6), and CMV antigens. The antibodies used were rabbit polyclonal antibodies to HSV,14 and CMV,15 and monoclonal antibodies to VZV,16 HSV-1, HSV-2,14
792
HHV6 (P101, Chemicon, CA), and the immediate early protein 2 of CMV (E5).15 All antibodies except E5 recognize viral structural proteins that corresponded to late antigens of the herpesviruses. For positive controls, we used the skin and liver tissues infected with HSV-1, HSV-2, and VZV, and eye tissues of CMV retinitis. For negative controls, we used a series of retinal tissues collected from AIDS patients without any lesions.
Microscopic Findings Including Immunohistochemistry Most retinal structures from the posterior pole to the periphery of both eyes were destroyed. In the periphery both eyes showed accompanying calcification. Retinal alterations were much more severe in the right eye than in the left. The outer retinal layer, however, remained in place at the posterior pole of the right eye, where retinal pigment epithelial cells (RPE) and Bruch’s membrane showed degeneration and lymphoid cells infiltrating into the choroid. Characteristic cytomegalic cells were observed in the outer retinal layer and the RPE of the right eye (Fig 3A). Most of the cornea, iris, corpus ciliare, vitreous, choroid, sclera, and optic
Kashiwase et al 䡠 Progressive Outer Retinal Necrosis and Herpes Simplex Virus-1 disc were devoid of abnormalities. No vasculitis was found in the choroidal or retinal regions of either eye. No microorganisms were found on PAS staining. In the right retina, both the cytomegalic cells and other cells lacking characteristic features were stained immunohistochemically by anti-cytomegalovirus immediate early antigen (E5) and by anti-late antigen antibodies (Fig 3B). No cytomegalovirus antigen, however, was detected in the left eye. In the peripheries of each eye where calcification was seen, HSV antigen was detected by the rabbit anti-HSV antibody. HSV-1 antigen-positive cells showed degeneration and were difficult to identify by cell type (Fig 3C). With monoclonal antibodies specific for HSV-1 or HSV-2, staining was seen only with anti-HSV-1 monoclonal antibodies (Fig 3D). Neither VZV nor HHV6 antigens were detected in either eye. Extraocular autopsy findings included cerebral toxoplasmosis involving the frontal lobe. No cytomegalic cells or nuclear inclusion body-bearing cells suggestive of HSV-1 infection were observed in systemic organs.
Discussion PORN has been reported as a distinct form of ARN differing from acute necrotizing retinopathy caused by VZV in patients with AIDS.5 VZV antigen has been detected immunohistochemically in the outer retina in eyes showing PORN, and VZV is considered the usual etiologic agent.6 Engstrom et al11 have retrospectively studied 65 involved eyes from 38 patients and defined clinical criteria for PORN: multifocal lesions characterized by deep retinal opacification without granular borders, sometimes including areas of confluent opacification; lesion location in the peripheral retina, with or without macular involvement; extremely rapid progression; absence of vascular inflammation; and minimal or no intraocular inflammation. PORN is further characterized by an extremely poor prognosis, manifesting poor responses to antiviral treatment related to an immunodeficient state. Progression to loss of light perception occurs in two thirds of patients because of photoreceptor necrosis involving the atrophic retina. Clinically, our patient first manifested CMV retinitis and then multiple discrete areas of retinal opacification developed in the deep layers of each eye after anti-CMV therapy was abandoned. Ophthalmic findings were characterized by absence of intraocular inflammation and lack of retinal vasculitis and by rapid progression of confluent yellow-white patches corresponding to full-thickness retinal necrosis from the posterior pole to the periphery. Our patient’s findings met at least four of Engstrom’s criteria, with the only point of difference being that the lesion initially occurred at the posterior pole of the retina. However, Margolis et al6 have reported four of five cases of PORN to show retinitis extending peripherally from the posterior pole. Several reports have identified VZV as a causative agent of PORN. Electron microscopically, herpesvirus particles were demonstrated in a retinal biopsy specimen from a case of PORN.5 VZV has been isolated from chorioretinal specimens in PORN cases,6,7 and immunohistochemical examination has demonstrated VZV antigen in the outer retina.6 Polymerase chain reaction (PCR) has detected VZV DNA in specimens of vitreous aspirate,8 surgically enucleated eye specimens,9 and necropsy spec-
imens of the eye.10 HSV, however, has not been documented in previous reports. At autopsy our case showed HSV-1 antigen in the peripheral retina of both eyes and cytomegalic cells with positive CMV antigens in the posterior retina of the right eye. Regretfully, PCR for herpesviruses, together with -globin genes, failed to amplify, seemingly because of an inadequate specimen for PCR. The major differences in clinical findings of ARN from those of PORN involved the depth of retinal lesions, the presence of retinal vasculitis, and intraocular inflammation.17 Our case did not show the clinical findings of ARN described in previous reports.18 –22 Histopathologic findings in ARN included inflammatory infiltrates in the anterior segment of the eye involving the iris and ciliary body and in the choroid and optic nerve.23, 24 In the retina, completely necrotic areas were admixed with areas showing partial preservation of retinal structure. The necrotic areas showed only a residual skeletal framework of blood vessels. The RPE degenerated and disappeared, accompanied by formation of a fibrous layer with neovascularization. Superficial layers of the retina were infiltrated with plasma cells and polymorphonuclear leukocytes, and arteries were surrounded by inflammatory cell infiltrates.23 In contrast, the histopathology of PORN included locally deep necrosis with destruction of retinal architecture and sometimes retinal detachment, but except for macrophages inflammatory cells were scarce.9 Retinal necrosis was particularly marked in the outer nuclear layer.6 In some areas, choriocapillaris had intense lymphocytic infiltrates, whereas in other areas all layers of the choroid might be involved by such infiltrates.6 In our case, histologic changes of the RPE, Bruch’s membrane, and the choroid in the periphery of the retina were less severe where HSV-1 antigen was identified; marked inflammatory cell infiltrates, a fibrous layer, and neovascularization were not observed. Considering the features of the case in the aggregate, we were convinced that the findings were consistent with PORN and differ from ARN both clinically and histopathologically. Two cases of PORN in which HSV infection was suspected as a cause have been reported.25,26 These two patients with AIDS showed acute necrotizing retinitis similar to PORN with deep retinal lesions and absence of both intraocular inflammation and retinal vasculitis. Both authors suspected HSV as a causative agent because the patients had histories of cutaneous or genital HSV infection. However, both authors failed to identify HSV in ocular tissues. This patient had a history of herpes zoster and showed an ulcer suggestive of HSV infection on his left upper eyelid, although no confirmatory test such as antigen detection was performed. Keratitis and iridocyclitis pose comparable problems because ocular manifestations caused by HSV or VZV are clinically similar. Although VZV has been considered the causative agent of PORN, we concluded that in our case HSV-1 caused an identical retinitis. Acknowledgments. The authors thank Ms. Yuko Sato and Ms. Noriko Sakurai for excellent technical assistance.
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