ACUTE RETINAL NECROSIS AND CYSTIC ENCEPHALOMALACIA IN A PREMATURE NEONATE Ryan K. Wong, BA,* Aziz A. Khanifar, MD,* Grace Sun, MD,* Linda A. Heier, MD,† Norman Saffra, MD, FACS,‡ R. V. Paul Chan, MD, MS*
Purpose: To report a case of an infant born at 30 weeks gestational age (GA) who, at 37 weeks GA, presented with bilateral acute retinal necrosis (ARN) syndrome and herpes simplex virus (HSV) encephalomalacia. Methods: Observational case report. Results: A premature infant was found to have ARN based on dilated funduscopic examination and positive HSV serologies. Herpes simplex virus encephalomalacia was diagnosed base on magnetic resonance imaging (MRI). Conclusion: To our knowledge, this is the youngest reported patient with ARN. This case demonstrates that neonatal ARN may present with posterior chorioretinal lesions and highlights the importance of considering HSV infection of the central nervous system with MRI findings of cystic encephalomalacia. RETINAL CASES & BRIEF REPORTS 4:202–205, 2010
From the Departments of *Ophthalmology and †Radiology, Weill Cornell Medical College, New York, New York; and ‡Division of Ophthalmology, Maimonides Medical Center, Brooklyn, New York.
Case Report A female infant born at 30 weeks GA was transferred from an outside hospital at 37 weeks GA to the neonatal intensive care unit of New York Presbyterian Hospital, Weill Cornell Medical Center for evaluation of panuveitis and chorioretinitis of both eyes for 1 week. Before transfer, she had been admitted for prematurity and respiratory distress and was being treated with ganciclovir for suspected cytomegalovirus retinitis. Her medical history was significant for a birth weight of 1,380 g, resolved retinopathy of prematurity, and being born to a 17-year-old mother through normal spontaneous vaginal delivery. Maternal testing was negative for syphilis, hepatitis B virus, and human immunodeficiency virus infection. Anterior segment examination was benign. A dilated funduscopic examination demonstrated marked vitritis, peripheral chorioretinal scarring, and areas of active chorioretinitis in both eyes (Figures 1 and 2). Active chorioretinitis was peripheral in the right eye and in three discrete areas in the left eye (two areas nasal to the optic nerve and one area inferotemporal). Vascular sheathing was apparent in both eyes. There was no evidence of retinopathy of prematurity, retinal detachment, retinal holes, tears, or traction. Congenital infectious etiologies such as toxoplasmosis, syphilis, rubella, cytomegalovirus, HSV, and varicella zoster virus were considered at this point. While awaiting results of serologic testing, the patient was treated empirically with pyrimethamine, sulfadiazine, and prednisone because toxoplasmosis was considered a likely cause of the condition. The ganciclovir that the patient had received at the outside hospital was discontinued.
A
cute retinal necrosis syndrome is a rapidly progressing retinitis, which was first described in 1971 by Urayama et al.1 It is classically characterized by peripheral necrotizing retinitis, occlusive vasculopathy, and vitritis. Usual etiologic agents are HSV -1 and HSV-2, varicella zoster virus, cytomegalovirus, and, more rarely, EpsteinBarr virus.2,3 Typically, adults are affected, although cases involving children have been documented.4,5 We report a case of an infant born at 30 weeks GA who, at 37 weeks GA, presented with bilateral ARN and HSV encephalomalacia. To our knowledge, this patient is the youngest reported case of ARN.
Supported by the St. Giles Foundation (RVPC). None of the authors has any conflicts of interest to disclose. Reprint requests: R.V. Paul Chan, MD, MS, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, Room Y 11.34, New York, NY 10021; e-mail: [email protected]
202
203
NEONATAL ARN AND CYSTIC ENCEPHALOMALACIA
Fig. 1. RetCam (RetCam 2, Clarity Medical Systems, Pleasanton, CA) color fundus photograph of the right eye. Poor fundus view resulting from vitritis. Posterior nasal area of chorioretinal scarring (arrow).
Serial ophthalmologic examinations showed improvement with decreased vitritis and chorioretinitis in both eyes. Accordingly, the presumptive diagnosis remained toxoplasmosis, and the patient continued treatment with the addition of topical steroids and a cycloplegic agent. Furthermore, the MRI of the brain showed multiple scattered areas of cystic encephalomalacia in the subcortical white matter, which was initially interpreted as consistent with the entire spectrum of TORCH infections. By hospital day 10, tests revealed that toxoplasmosis IgA, IgM, and IgG were negative. Cytomegalovirus IgM and cytomegalovirus polymerase chain reaction of serum and urine were negative as well. On hospital day 11, the patient developed grouped vesicles on her lower lip, at which point toxoplasmosis treatment was discontinued. In addition, prednisone was continued and intravenous acyclovir was initiated for what was now suspected ARN secondary to HSV infection. Herpes simplex virus infection was later confirmed when tests showed that HSV 1/2 IgM and direct fluorescent antibody testing of the vesicular lesions were positive. The varicella zoster virus IgM was negative. Furthermore, extensive review of the patient’s previous MRI with a neuroradiologist
Fig. 2. RetCam (RetCam 2, Clarity Medical Systems) photograph of the inferotemporal left eye. Poor fundus view resulting from marked vitritis. There is active chorioretinitis peripherally (arrows).
Fig. 3. The MRI of the head/brain. Evidence of cystic encephalomalacia (arrows).
revealed that the patient’s brain lesions were highly indicative of HSV infection (Figure 3). Even with the eruption of the skin lesions and modifications in treatment, the infant’s vitritis and areas of chorioretinitis continued to resolve (Figures 4 and 5). The patient was transferred back to the referring hospital after 10 days of treatment with acyclovir (hospital day 20).
Discussion Acute retinal necrosis is a well-described entity that occurs mostly in adults and occasionally in children.4,5 The syndrome occurs equally in both sexes, and patients often present with changes in vision, periorbital pain, red eye, floaters, or more vague symptoms such
Fig. 4. RetCam (RetCam 2, Clarity Medical Systems) color fundus photograph of the right eye. Improved fundus view resulting from decreased vitritis. Posterior nasal chorioretinal lesion remains stable (arrow).
204
RETINAL CASES & BRIEF REPORTSℜ
Fig. 5. RetCam (RetCam 2, Clarity Medical Systems) color fundus photograph of inferotemporal left eye. Improved fundus view resulting from decreased vitritis. There is decreased chorioretinitis (arrow) and subsequent chorioretinal scarring (arrowhead).
as fever, headache, or neck stiffness. Potential complications of the disease include ischemic optic neuropathy and rhegmatogenous and exudative retinal detachment that can lead to severe vision loss. For patients who cannot communicate their symptoms such as infants, vigilance in the assessment for ARN is suggested. Rarely, the syndrome can even manifest in neonates. Kychenthal et al4 reported a case of a 25day-old infant, with an unknown GA, who developed bilateral ARN and HSV-2 encephalitis. This neonate’s hospital course was complicated by bilateral retinal detachments requiring extensive laser photocoagulation in the right eye and pars plana vitrectomy, hyaloid peel, endolaser, and silicone oil tamponade in the left eye. We believe our patient was even younger, born prematurely at 30 weeks, and presented with bilateral ARN and HSV encephalomalacia at 50 days of life. The differential diagnosis of chorioretinal scarring in a neonate includes prior toxoplasmosis infection. Failure to consider other etiologies, infectious and noninfectious, can delay the diagnosis of ARN. Moesen et al5 reported a 12-year-old boy who presented with blurred vision, pain, and redness of the eye. His history was significant for a chorioretinal lesion attributed to inactive toxoplasmosis infection. He was initially treated with antiparasite therapy and steroids, but his condition worsened and further evaluation revealed ARN. Tran et al6 reported 3 cases of previous, inactive chorioretinal scars in patients with HSV-2 ARN. In these patients, toxoplasmosis was considered until negative polymerase chain reaction tests returned. Similarly in our case, toxoplasmosis was initially high on the differential diagnosis until serologic testing ruled it out. Acute retinal necrosis has been associated with HSV encephalitis and meningitis.4,7 In our case, there was
●
2010
●
VOLUME 4
●
NUMBER 2
obvious evidence of central nervous system involvement through an MRI showing multiple areas of cystic encephalomalacia. Thus, when considering a diagnosis of ARN, the presence or absence of a history of central nervous system disease should be verified. The mechanism of ARN may involve reactivated herpes viruses. Herpes simplex virus ARN has been demonstrated in children with documented neonatal herpes infections.6,7 Furthermore, some authors suggest that cases of HSV ARN occurring in individuals without a history of neonatal herpes actually represent reactivation of subclinical congenital or neonatal HSV infection.2 However, our case, along with the case involving the 25-day-old infant, may suggest that HSV can cause primary necrotizing retinitis. The ages of these patients would seem to indicate cases of active neonatal herpes infections, because they would not have been able to build immunity to HSV yet. The visual outcomes of children afflicted with ARN varies widely with some authors reporting visual acuities of 20/20 and 20/40, whereas others show outcomes with vision limited to counting fingers and light perception.2,8,9 Nonetheless, the standard treatment of ARN is with intravenous acyclovir, but advanced cases may require laser treatment or vitrectomy. The role of steroids, on the other hand, is controversial. Some authors believe that steroid-induced immunosuppression may exacerbate the progression of ARN,5 whereas others believe steroids play an important role in reducing inflammation and may prevent complications such as retinal detachment.10 In our patient, treatment with systemic steroids, even with a temporary absence of antiviral therapy, resulted in reduction of vitritis and chorioretinitis. In conclusion, we report a case of an infant born at 30 weeks GA who developed ARN and HSV encephalomalacia. To our knowledge, this case represents the youngest patient with ARN reported and the first instance involving an infant born before term. We believe the case highlights the following: 1) the need to consider ARN in prematurely born infants; 2) the importance of considering HSV infection of the central nervous system with the MRI findings of cystic encephalomalacia; and 3) the possibility of posterior lesions appearing in cases of neonatal ARN. Key words: acute retinal necrosis syndrome, cystic encephalomalacia, premature infant. References 1.
2.
Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25:607– 619. Tan JCH, Byles D, Stanford MR, Frith PA, Graham EM.
205
NEONATAL ARN AND CYSTIC ENCEPHALOMALACIA
3. 4.
5.
6.
Acute retinal necrosis in children caused by herpes simplex virus. Retina 2001;21:344 –347. Kramer S, Brummer C, Zierhut M. Epstein-Barr virus associated acute retinal necrosis. Br J Ophthalmol 2001;85:114. Kychenthal A, Coombes A, Greenwood J, et al. Bilateral acute retinal necrosis and herpes simplex type 2 encephalitis in a neonate. Br J Ophthalmol 2001;85:629 – 630. Moesen I, Khemka S, Ayliffe W. Acute retinal necrosis secondary to herpes simplex virus type 2 with preexisting chorioretinal scarring. J Pediatr Ophthalmol Strabismus 2008;45:59 – 61. Tran TH, Stanescu D, Caspers-Velu L, et al. Clinical characteristics of acute HSV-2 retinal necrosis. Am J Ophthalmol 2004;137:872– 879.
7.
8. 9.
10.
Thompson WS, Culbertson WW, Smiddy WE, Robertson JE, Rosenbaum JT. Acute retinal necrosis caused by reactivation of herpes simplex virus type 2. Am J Ophthalmol 1994;118: 205–211. Iino Y, Tanaka M, Hatano N, et al. A case of a five-year-old boy with acute retinal necrosis. Retina 2002;22:225–228. Tran TH, Rozenberg F, Fillet AM, Bodaghi B. Diagnostic and therapeutic management of a severe acyclovir-resistant acute retinal necrosis in a young child. Graefes Arch Clin Exp Ophthalmol 2005;243:266 –268. Davis JL, Fox GM, Blumenkranz MS. Acute Retinal Necrosis. Albert and Jakobiec’s Principles and Practice of Ophthalmology. 3rd ed. Vol. 2. Philadelphia: Saunders Elsevier; 2008:2107–2124.
Purpose: To report a case of an infant born at 30 weeks gestational age (GA) who, at 37 weeks GA, presented with bilateral acute retinal necrosis (ARN) syndrome and herpes simplex virus (HSV) encephalomalacia. Methods: Observational case report. Results: A premature infant was found to have ARN based on dilated funduscopic examination and positive HSV serologies. Herpes simplex virus encephalomalacia was diagnosed base on magnetic resonance imaging (MRI). Conclusion: To our knowledge, this is the youngest reported patient with ARN. This case demonstrates that neonatal ARN may present with posterior chorioretinal lesions and highlights the importance of considering HSV infection of the central nervous system with MRI findings of cystic encephalomalacia. RETINAL CASES & BRIEF REPORTS 4:202–205, 2010
From the Departments of *Ophthalmology and †Radiology, Weill Cornell Medical College, New York, New York; and ‡Division of Ophthalmology, Maimonides Medical Center, Brooklyn, New York.
Case Report A female infant born at 30 weeks GA was transferred from an outside hospital at 37 weeks GA to the neonatal intensive care unit of New York Presbyterian Hospital, Weill Cornell Medical Center for evaluation of panuveitis and chorioretinitis of both eyes for 1 week. Before transfer, she had been admitted for prematurity and respiratory distress and was being treated with ganciclovir for suspected cytomegalovirus retinitis. Her medical history was significant for a birth weight of 1,380 g, resolved retinopathy of prematurity, and being born to a 17-year-old mother through normal spontaneous vaginal delivery. Maternal testing was negative for syphilis, hepatitis B virus, and human immunodeficiency virus infection. Anterior segment examination was benign. A dilated funduscopic examination demonstrated marked vitritis, peripheral chorioretinal scarring, and areas of active chorioretinitis in both eyes (Figures 1 and 2). Active chorioretinitis was peripheral in the right eye and in three discrete areas in the left eye (two areas nasal to the optic nerve and one area inferotemporal). Vascular sheathing was apparent in both eyes. There was no evidence of retinopathy of prematurity, retinal detachment, retinal holes, tears, or traction. Congenital infectious etiologies such as toxoplasmosis, syphilis, rubella, cytomegalovirus, HSV, and varicella zoster virus were considered at this point. While awaiting results of serologic testing, the patient was treated empirically with pyrimethamine, sulfadiazine, and prednisone because toxoplasmosis was considered a likely cause of the condition. The ganciclovir that the patient had received at the outside hospital was discontinued.
A
cute retinal necrosis syndrome is a rapidly progressing retinitis, which was first described in 1971 by Urayama et al.1 It is classically characterized by peripheral necrotizing retinitis, occlusive vasculopathy, and vitritis. Usual etiologic agents are HSV -1 and HSV-2, varicella zoster virus, cytomegalovirus, and, more rarely, EpsteinBarr virus.2,3 Typically, adults are affected, although cases involving children have been documented.4,5 We report a case of an infant born at 30 weeks GA who, at 37 weeks GA, presented with bilateral ARN and HSV encephalomalacia. To our knowledge, this patient is the youngest reported case of ARN.
Supported by the St. Giles Foundation (RVPC). None of the authors has any conflicts of interest to disclose. Reprint requests: R.V. Paul Chan, MD, MS, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, Room Y 11.34, New York, NY 10021; e-mail: [email protected]
202
203
NEONATAL ARN AND CYSTIC ENCEPHALOMALACIA
Fig. 1. RetCam (RetCam 2, Clarity Medical Systems, Pleasanton, CA) color fundus photograph of the right eye. Poor fundus view resulting from vitritis. Posterior nasal area of chorioretinal scarring (arrow).
Serial ophthalmologic examinations showed improvement with decreased vitritis and chorioretinitis in both eyes. Accordingly, the presumptive diagnosis remained toxoplasmosis, and the patient continued treatment with the addition of topical steroids and a cycloplegic agent. Furthermore, the MRI of the brain showed multiple scattered areas of cystic encephalomalacia in the subcortical white matter, which was initially interpreted as consistent with the entire spectrum of TORCH infections. By hospital day 10, tests revealed that toxoplasmosis IgA, IgM, and IgG were negative. Cytomegalovirus IgM and cytomegalovirus polymerase chain reaction of serum and urine were negative as well. On hospital day 11, the patient developed grouped vesicles on her lower lip, at which point toxoplasmosis treatment was discontinued. In addition, prednisone was continued and intravenous acyclovir was initiated for what was now suspected ARN secondary to HSV infection. Herpes simplex virus infection was later confirmed when tests showed that HSV 1/2 IgM and direct fluorescent antibody testing of the vesicular lesions were positive. The varicella zoster virus IgM was negative. Furthermore, extensive review of the patient’s previous MRI with a neuroradiologist
Fig. 2. RetCam (RetCam 2, Clarity Medical Systems) photograph of the inferotemporal left eye. Poor fundus view resulting from marked vitritis. There is active chorioretinitis peripherally (arrows).
Fig. 3. The MRI of the head/brain. Evidence of cystic encephalomalacia (arrows).
revealed that the patient’s brain lesions were highly indicative of HSV infection (Figure 3). Even with the eruption of the skin lesions and modifications in treatment, the infant’s vitritis and areas of chorioretinitis continued to resolve (Figures 4 and 5). The patient was transferred back to the referring hospital after 10 days of treatment with acyclovir (hospital day 20).
Discussion Acute retinal necrosis is a well-described entity that occurs mostly in adults and occasionally in children.4,5 The syndrome occurs equally in both sexes, and patients often present with changes in vision, periorbital pain, red eye, floaters, or more vague symptoms such
Fig. 4. RetCam (RetCam 2, Clarity Medical Systems) color fundus photograph of the right eye. Improved fundus view resulting from decreased vitritis. Posterior nasal chorioretinal lesion remains stable (arrow).
204
RETINAL CASES & BRIEF REPORTSℜ
Fig. 5. RetCam (RetCam 2, Clarity Medical Systems) color fundus photograph of inferotemporal left eye. Improved fundus view resulting from decreased vitritis. There is decreased chorioretinitis (arrow) and subsequent chorioretinal scarring (arrowhead).
as fever, headache, or neck stiffness. Potential complications of the disease include ischemic optic neuropathy and rhegmatogenous and exudative retinal detachment that can lead to severe vision loss. For patients who cannot communicate their symptoms such as infants, vigilance in the assessment for ARN is suggested. Rarely, the syndrome can even manifest in neonates. Kychenthal et al4 reported a case of a 25day-old infant, with an unknown GA, who developed bilateral ARN and HSV-2 encephalitis. This neonate’s hospital course was complicated by bilateral retinal detachments requiring extensive laser photocoagulation in the right eye and pars plana vitrectomy, hyaloid peel, endolaser, and silicone oil tamponade in the left eye. We believe our patient was even younger, born prematurely at 30 weeks, and presented with bilateral ARN and HSV encephalomalacia at 50 days of life. The differential diagnosis of chorioretinal scarring in a neonate includes prior toxoplasmosis infection. Failure to consider other etiologies, infectious and noninfectious, can delay the diagnosis of ARN. Moesen et al5 reported a 12-year-old boy who presented with blurred vision, pain, and redness of the eye. His history was significant for a chorioretinal lesion attributed to inactive toxoplasmosis infection. He was initially treated with antiparasite therapy and steroids, but his condition worsened and further evaluation revealed ARN. Tran et al6 reported 3 cases of previous, inactive chorioretinal scars in patients with HSV-2 ARN. In these patients, toxoplasmosis was considered until negative polymerase chain reaction tests returned. Similarly in our case, toxoplasmosis was initially high on the differential diagnosis until serologic testing ruled it out. Acute retinal necrosis has been associated with HSV encephalitis and meningitis.4,7 In our case, there was
●
2010
●
VOLUME 4
●
NUMBER 2
obvious evidence of central nervous system involvement through an MRI showing multiple areas of cystic encephalomalacia. Thus, when considering a diagnosis of ARN, the presence or absence of a history of central nervous system disease should be verified. The mechanism of ARN may involve reactivated herpes viruses. Herpes simplex virus ARN has been demonstrated in children with documented neonatal herpes infections.6,7 Furthermore, some authors suggest that cases of HSV ARN occurring in individuals without a history of neonatal herpes actually represent reactivation of subclinical congenital or neonatal HSV infection.2 However, our case, along with the case involving the 25-day-old infant, may suggest that HSV can cause primary necrotizing retinitis. The ages of these patients would seem to indicate cases of active neonatal herpes infections, because they would not have been able to build immunity to HSV yet. The visual outcomes of children afflicted with ARN varies widely with some authors reporting visual acuities of 20/20 and 20/40, whereas others show outcomes with vision limited to counting fingers and light perception.2,8,9 Nonetheless, the standard treatment of ARN is with intravenous acyclovir, but advanced cases may require laser treatment or vitrectomy. The role of steroids, on the other hand, is controversial. Some authors believe that steroid-induced immunosuppression may exacerbate the progression of ARN,5 whereas others believe steroids play an important role in reducing inflammation and may prevent complications such as retinal detachment.10 In our patient, treatment with systemic steroids, even with a temporary absence of antiviral therapy, resulted in reduction of vitritis and chorioretinitis. In conclusion, we report a case of an infant born at 30 weeks GA who developed ARN and HSV encephalomalacia. To our knowledge, this case represents the youngest patient with ARN reported and the first instance involving an infant born before term. We believe the case highlights the following: 1) the need to consider ARN in prematurely born infants; 2) the importance of considering HSV infection of the central nervous system with the MRI findings of cystic encephalomalacia; and 3) the possibility of posterior lesions appearing in cases of neonatal ARN. Key words: acute retinal necrosis syndrome, cystic encephalomalacia, premature infant. References 1.
2.
Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25:607– 619. Tan JCH, Byles D, Stanford MR, Frith PA, Graham EM.
205
NEONATAL ARN AND CYSTIC ENCEPHALOMALACIA
3. 4.
5.
6.
Acute retinal necrosis in children caused by herpes simplex virus. Retina 2001;21:344 –347. Kramer S, Brummer C, Zierhut M. Epstein-Barr virus associated acute retinal necrosis. Br J Ophthalmol 2001;85:114. Kychenthal A, Coombes A, Greenwood J, et al. Bilateral acute retinal necrosis and herpes simplex type 2 encephalitis in a neonate. Br J Ophthalmol 2001;85:629 – 630. Moesen I, Khemka S, Ayliffe W. Acute retinal necrosis secondary to herpes simplex virus type 2 with preexisting chorioretinal scarring. J Pediatr Ophthalmol Strabismus 2008;45:59 – 61. Tran TH, Stanescu D, Caspers-Velu L, et al. Clinical characteristics of acute HSV-2 retinal necrosis. Am J Ophthalmol 2004;137:872– 879.
7.
8. 9.
10.
Thompson WS, Culbertson WW, Smiddy WE, Robertson JE, Rosenbaum JT. Acute retinal necrosis caused by reactivation of herpes simplex virus type 2. Am J Ophthalmol 1994;118: 205–211. Iino Y, Tanaka M, Hatano N, et al. A case of a five-year-old boy with acute retinal necrosis. Retina 2002;22:225–228. Tran TH, Rozenberg F, Fillet AM, Bodaghi B. Diagnostic and therapeutic management of a severe acyclovir-resistant acute retinal necrosis in a young child. Graefes Arch Clin Exp Ophthalmol 2005;243:266 –268. Davis JL, Fox GM, Blumenkranz MS. Acute Retinal Necrosis. Albert and Jakobiec’s Principles and Practice of Ophthalmology. 3rd ed. Vol. 2. Philadelphia: Saunders Elsevier; 2008:2107–2124.
