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Progressive postnatal subependymal necrosis in an infant with congenital cytomegalovirus infection
Progressive Postnatal Subependymal Necrosis in an Infant with Congenital Cytomegalovirus Infection James F. Bale, Jr, MD**, Yutaka Sato, MD*, and Douglas Eisert, MD* An infant with congenital cytomegalovirus infection developed subependymal cysts postnatally. This patient provides further support for the concept that congenitally-infected infants occasionally have postnatal progression of central nervous system lesions. Bale JF Jr, Sato Y, Eisert D. Progressive postnatal subependymal necrosis in an infant with congenital cytomegalovirus infection. Pediatr Neurol 1986; 2:367-70.
Introduction Cytomegalovirus (CMV), the most common congenital infection, can seriously damage the developing central nervous system (CNS) and can produce a wide range of structural CNS lesions [1-3[. Although the timing of infection relative to the pathogenesis of these lesions has not been established convincingly, the vast majority of structural CNS abnormalities due to congenital CMV infection are presumed to be the result of prenatal injury to the CNS [41. We report a newborn infant with congenital CMV infection who developed lesions consistent with subependymal necrosis posmatally. This case strongly supports the concept that CNS lesions associated with congenital CMV infection can develop or progress after birth and suggests that carefully selected infants with symptomatic congenital CMV infections may be candidates for therapy with antiviral medications.
From the Departments of *Pediatrics, tNeurology, and :~Radiology; University of Iowa College of Medicine; Iowa City, Iowa.
Case Report This 1,800 gm infant, born to a 22-year-old G3 P2 Abl mother, was the product of a 36 week gestation. The pregnancy had been complicated by unspecified ethanol intake and one pack per day of cigarette use. The infant was delivered by cesarean section because of breech position after spontaneous rupture of the membranes. His Apgar scores were 5 and 6 at 1 and 5 minutes, respectively. Examination 4 hours after birth disclosed jaundice, perechiae, and marked hepatosplenomegaly. The infant's white blood count was 17,700/mm 3, platelet count 35,000/mm 3, and total and direct bilirubin were 13.5 mg/dl and 5.8 mg/dl, respectively. At 16 hours of age on admission to the University of Iowa Hospital he was mildly somnolent with hypotonia, a weak cry, and decreased Moro response. The head circumference was 31 cm, appropriate for gestational age. He had a diffuse purpuric and petechial rash. His liver and spleen were palpable 5 cm below the costal margins. Ophthalmologic examination was normal. Additional laboratory studies included a serum aspartate aminotransferase (AST) level elevated to 1,521 IU (normal: < 45 IU), a prolonged prothrombin time of 18 sec (normal: < 12 sec), a partial thromboplastin time of 56 sec (normal: < 40 sec), and a low fibrinogen of 45 mg/dl. The cerebrospinal fluid protein concentration was 26 mg/dl (normal: < 55 mg/dl), and there were no cells. A chest radiograph demonstrated right upper lobe infiltrates. Cultures of the infant's urine obtained on the day of admission yielded CMV as well as did the granulocyte-enriched fraction of the peripheral blood. Over the next four weeks of hospitalization, the infant continued to have thrombocytopenia with platelet counts ranging from 7,000/mm 3 to 45,000/mm 3, and required occasional platelet transfusions because of cutaneous bleeding. His bilirubin level peaked at 26.1 mg/dl during the second week of life. His AST remained elevated but declined gradually to 320 IU/U He remained somnolent and hypotonic. On the 36th day of life he was transferred to the referring hospital. The infant continued to feed poorly and died one month later, apparently from complications of CMV hepatitis. Neumdiagnostic Studies. Serial ultrasonography of the brain demonstrated the postnatal development and progression of subependymal cysts in and adjacent to the lateral ventricles. The initial study performed on the second day of life was normal (Fig 1). The study on the 14th day of life depicted the development of a welldefined subependymal sonolucent area in the striato-thalamic junction of the lateral ventricles bilaterally (Fig 2). There was no evidence of subependymal hemorrhage.The subsequent study at one month of age demonstrated progressive enlargement of the cysts which extended anteriorly and protruded into the ventricular lumen. Multiple thick septi had developed giving the cysts a multilocular appearance (Fig 3). Magnetic resonance imaging (MRI) on the 15th day of life (Fig 4) and cranial computed tomography (CT) on the 22nd day of life confirmed the presence of cysts in the periventricular area, but the size, location, and configuration of the cysts were best defined by ultrasonography. Autopsy Findings. An autopsy performed at the local hospital revealed massive enlargement of the liver and spleen. Diffuse hepatic necrosis with early scarring was observed on microscopy, but no inclusions were identified. Inclusions characteristic of CMV, however, were observed in multiple organs, including the lung, adrenal glands, thyroid, and skin. The brain appeared smaller than normal and contained multiple cystic lesions which were most prominent in the subependymal zones adjacent to the lateral and third ventricles. Microscopically, the cyst walls contained small calcifications and hemosiderin-laden macrophages, but no inclusions were observed.
Communications should be addressed to: Dr. Bale; Department of Pediatrics; University of Iowa Hospitals and Clinics; Iowa City, IA 52242. Received July 21, 1986; accepted September 8, 1986. Bale et al: Postnatal Subependymal Necrosis
367
Figure 1. Left parasagittal sonogram of the kead obtained two days after bi?tk. T~is study and the right parasagittal sonogram were normal (t = thalamus).
CMV infects approximately 1% of all newborns in the Western world [1-3]. Although only 10% of infected newborns have symptoms linked to the virus at birth, CMV remains the most commonly recognized cause of virus-induced mental retardation [3]. Infants symptomatic at birth invariably have long-term sequelae as a result of virus-related damage to the brain, eye, and ear [2,5]. When studied by CT, the majority of symptomatic infants and young children have structural CNS abnormalities [6]. These abnormalities vary in severity and
range from mild cortical atrophy to encephaloclastic lesions that, in severe cases, resemble hydranencephaly. Approximately 25% of CMV-infected infants have periventricular calcifications, a feature that reflects the predilection of CMV to infect cells of the germinal matrix [6,7]. These lesions, attributed to chronic intrauterine meningoencephalitis, are static in the majority of cases [4]. The infant in this report had the characteristic clinical features of congenital CMV inclusion disease, which was confirmed by isolation of the virus from urine and blood. The infant's head circumference.
Figure 2. Left parasagittal sonogram obtained two weeks after birth. This study, as well as the right parasagittal sonogram, demonstrated subependymal cysts (arrow) at the caudothalaraic grooves (t = thalamus).
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Figure 3. Left parasagittal sonogram obtained one month after birth. The study demonstrates enlargement of the cysts and septum formation within the cysts. Similar findings were present on the right (t = thalamus).
skull radiographs, and cranial ultrasound study were normal initially. His first four weeks of life were complicated by persistent jaundice, abnormal liver function, and thrombocytopenia suggesting persistent viral involvement of liver and other organs. Coincidentally, serial cranial ultrasound studies demonstrated cystic lesions in the subependymal area of the striato-thalamic junction, compatible with subependymal necrosis. The cysts developed without evidence of preceding hemorrhage and enlarged progressively. Several conditions have been reported in association with subependymal cyst formation, such as periventricular-intraventricular hemorrhage in premature infants [8], intrauterine rubella infection [9], cerebrohepato-renal (Zellweger) syndrome [10], and neonatal ventriculitis. Clair et al. [8] described 11 cases of subependymal cysts evaluated by cranial ultrasound among 210 high-risk neonates less than 35 weeks gestational age and weighing < 2,000 gm. These subependymal cysts, presumably posthemorrhagic in origin, were unilocular, unilateral, size -< 10 ram, and did not change in character or size during serial ultrasound scanning over a 2 month period. Subependymal cystic lesions have been linked previously to congenital CMV infection [11,12]. However, in contrast to the present case, CMV-induced cystic lesions in the previously reported cases were presumed to have developed in utero, and progression posmatally has not been documented. Shackelford et al. [11] described a CMV-infected infant who had multiple, small subependymal cysts demonstrated by ultrasound on the second day of life. Shaw and Alvord, in an autopsy study of 30 infants with subependymal cysts, found evidence of CMV infection in four [12].
These four infants had lesions at the striato-thalamic junction bilaterally, a location identical to that of our patient. These authors found no evidence of hemorrhage in the CMV-infected infants and concluded that the subependymal cysts occurred in utero as a result of virus-related lysis of dividing cells of the germinal matrix. They termed the condition "subependymal germinolysis." Our patient demonstrates that subependymal cysts can develop posmatally in CMV-infected infants. The development of cysts in the absence of hemorrhage
Figure 4. Coronal MRI (TR 550 ms, TE 40 ms) reveals abnormal signals (arrow) in and adjacent to the slightly dilated right anterior horn, but delineation of the lesion is less than optimal. The le)q anterior horn and its internal structure are not clearly deft'ned.
Bale et al: Postnatal Subependymal Necrosis
369
strongly suggests that they were the result of subependymal germinolysis caused by CMV. Although the precise pathogenesis of these lesions has not been determined, CMV meningoencephalitis presumably has a major role. Our patient provides additional support for the concept that congenitally-infected infants occasionally have postnatal progression of CNS lesions [13]. Such observations indicate that carefully selected infants with congenital CMV infection may be candidates for postnatal therapy with antiviral agents effective against CMV. Although no agents have proved effective for congenital CMV infections, the development of 9-(1,3 dihydroxy-2-propoxymethyl) guanine (DHPG), which has been effective in treating CMV retinitis [14], suggests that therapy with such an agent may modify the outcome of congenital CMV infections for some infants. The authors wish to thank Dr. John Harris for performing the postmortem examination.
References [1] BaleJFJr. Human cytomegalovirus infection and disorders of the nervous system. Arch Neurol 1984;41:310-20. [21 Pass RF, Stagno S, Myers GJ, et al. Outcome of symptomatic congenital cytomegalovirus infection: Results of long-term longitudinal follow-up. Pediatrics 1980;66:758-62. [3] Weller TH, HanshawJB. Virological and clinical observations on cytomegalovirus inclusion disease. N Engl J Med 1962; 266:1233-44.
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[4] Becroft DM. Prenatal cytomegalovirus infection: Epidemiology, pathology and pathogenesis. In: Rosenberg HS, Bernstein J, eds. Perspectives in pediatric pathology, Vol. 6. Infectious diseases. New York: Masson, 1981;203-41. [5] Saigal S, Lanyk O, Larke RPB, et al. The outcome in children with congenital cytomegalovirus infection. Am J Dis Child 1982;136:896-901. [6] Bale JF Jr, Bray PF, Bell WE. Neuroradiographic abnormalities in congenital cytomegalovirus infection. Pediatr Neurol 1985;1:42-7. [7] McCracken GH, Shinefield HR, Cobb K, et al. Congenital cytomegalic inclusion disease. Am J Dis Child 1969;117: 522-39. [8] Clair MR, Zalneraitis EL, Balm RS, Goodman K, Perkes EA. Neurosonographic recognition of subependymal cysts in high-risk neonates. AJNR 1984;5: 761-7. [9] Rotke LB, Spiro AJ. Cerebral lesion in congenital rubella syndrome. J Pediatr 1967;70:243-55. [10] Danks DM, Tippett P, Adams C, Campbell P. Cerebrohepato -renal syndrome of Zellweger. J Pediatr 1975;88: 382-7. [11] Shackelfotd GD, Fulling KH, Giasier CM. Cysts of the subependymal germinal matrix: Sonographic demonstration with pathologic correlation. Radiology 1983; 149:117-21. [12] Shaw CM, Alvord ECJr. Subependymal germinolysis. Arch Neurol 1974;31:374-81. [13] Bray PF, Bale JF Jr, Anderson RE, Kern ER. Progressive neurologic disease associated with chronic cytomegalovirus infection. Ann Neurol 1981;9:499-501. [14] Rosecan LR, Staht-Bayliss CM, Kalman CM, Laskin OL. Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine. Am J Ophthalmol 1986; 101:405-18.
Introduction Cytomegalovirus (CMV), the most common congenital infection, can seriously damage the developing central nervous system (CNS) and can produce a wide range of structural CNS lesions [1-3[. Although the timing of infection relative to the pathogenesis of these lesions has not been established convincingly, the vast majority of structural CNS abnormalities due to congenital CMV infection are presumed to be the result of prenatal injury to the CNS [41. We report a newborn infant with congenital CMV infection who developed lesions consistent with subependymal necrosis posmatally. This case strongly supports the concept that CNS lesions associated with congenital CMV infection can develop or progress after birth and suggests that carefully selected infants with symptomatic congenital CMV infections may be candidates for therapy with antiviral medications.
From the Departments of *Pediatrics, tNeurology, and :~Radiology; University of Iowa College of Medicine; Iowa City, Iowa.
Case Report This 1,800 gm infant, born to a 22-year-old G3 P2 Abl mother, was the product of a 36 week gestation. The pregnancy had been complicated by unspecified ethanol intake and one pack per day of cigarette use. The infant was delivered by cesarean section because of breech position after spontaneous rupture of the membranes. His Apgar scores were 5 and 6 at 1 and 5 minutes, respectively. Examination 4 hours after birth disclosed jaundice, perechiae, and marked hepatosplenomegaly. The infant's white blood count was 17,700/mm 3, platelet count 35,000/mm 3, and total and direct bilirubin were 13.5 mg/dl and 5.8 mg/dl, respectively. At 16 hours of age on admission to the University of Iowa Hospital he was mildly somnolent with hypotonia, a weak cry, and decreased Moro response. The head circumference was 31 cm, appropriate for gestational age. He had a diffuse purpuric and petechial rash. His liver and spleen were palpable 5 cm below the costal margins. Ophthalmologic examination was normal. Additional laboratory studies included a serum aspartate aminotransferase (AST) level elevated to 1,521 IU (normal: < 45 IU), a prolonged prothrombin time of 18 sec (normal: < 12 sec), a partial thromboplastin time of 56 sec (normal: < 40 sec), and a low fibrinogen of 45 mg/dl. The cerebrospinal fluid protein concentration was 26 mg/dl (normal: < 55 mg/dl), and there were no cells. A chest radiograph demonstrated right upper lobe infiltrates. Cultures of the infant's urine obtained on the day of admission yielded CMV as well as did the granulocyte-enriched fraction of the peripheral blood. Over the next four weeks of hospitalization, the infant continued to have thrombocytopenia with platelet counts ranging from 7,000/mm 3 to 45,000/mm 3, and required occasional platelet transfusions because of cutaneous bleeding. His bilirubin level peaked at 26.1 mg/dl during the second week of life. His AST remained elevated but declined gradually to 320 IU/U He remained somnolent and hypotonic. On the 36th day of life he was transferred to the referring hospital. The infant continued to feed poorly and died one month later, apparently from complications of CMV hepatitis. Neumdiagnostic Studies. Serial ultrasonography of the brain demonstrated the postnatal development and progression of subependymal cysts in and adjacent to the lateral ventricles. The initial study performed on the second day of life was normal (Fig 1). The study on the 14th day of life depicted the development of a welldefined subependymal sonolucent area in the striato-thalamic junction of the lateral ventricles bilaterally (Fig 2). There was no evidence of subependymal hemorrhage.The subsequent study at one month of age demonstrated progressive enlargement of the cysts which extended anteriorly and protruded into the ventricular lumen. Multiple thick septi had developed giving the cysts a multilocular appearance (Fig 3). Magnetic resonance imaging (MRI) on the 15th day of life (Fig 4) and cranial computed tomography (CT) on the 22nd day of life confirmed the presence of cysts in the periventricular area, but the size, location, and configuration of the cysts were best defined by ultrasonography. Autopsy Findings. An autopsy performed at the local hospital revealed massive enlargement of the liver and spleen. Diffuse hepatic necrosis with early scarring was observed on microscopy, but no inclusions were identified. Inclusions characteristic of CMV, however, were observed in multiple organs, including the lung, adrenal glands, thyroid, and skin. The brain appeared smaller than normal and contained multiple cystic lesions which were most prominent in the subependymal zones adjacent to the lateral and third ventricles. Microscopically, the cyst walls contained small calcifications and hemosiderin-laden macrophages, but no inclusions were observed.
Communications should be addressed to: Dr. Bale; Department of Pediatrics; University of Iowa Hospitals and Clinics; Iowa City, IA 52242. Received July 21, 1986; accepted September 8, 1986. Bale et al: Postnatal Subependymal Necrosis
367
Figure 1. Left parasagittal sonogram of the kead obtained two days after bi?tk. T~is study and the right parasagittal sonogram were normal (t = thalamus).
CMV infects approximately 1% of all newborns in the Western world [1-3]. Although only 10% of infected newborns have symptoms linked to the virus at birth, CMV remains the most commonly recognized cause of virus-induced mental retardation [3]. Infants symptomatic at birth invariably have long-term sequelae as a result of virus-related damage to the brain, eye, and ear [2,5]. When studied by CT, the majority of symptomatic infants and young children have structural CNS abnormalities [6]. These abnormalities vary in severity and
range from mild cortical atrophy to encephaloclastic lesions that, in severe cases, resemble hydranencephaly. Approximately 25% of CMV-infected infants have periventricular calcifications, a feature that reflects the predilection of CMV to infect cells of the germinal matrix [6,7]. These lesions, attributed to chronic intrauterine meningoencephalitis, are static in the majority of cases [4]. The infant in this report had the characteristic clinical features of congenital CMV inclusion disease, which was confirmed by isolation of the virus from urine and blood. The infant's head circumference.
Figure 2. Left parasagittal sonogram obtained two weeks after birth. This study, as well as the right parasagittal sonogram, demonstrated subependymal cysts (arrow) at the caudothalaraic grooves (t = thalamus).
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Figure 3. Left parasagittal sonogram obtained one month after birth. The study demonstrates enlargement of the cysts and septum formation within the cysts. Similar findings were present on the right (t = thalamus).
skull radiographs, and cranial ultrasound study were normal initially. His first four weeks of life were complicated by persistent jaundice, abnormal liver function, and thrombocytopenia suggesting persistent viral involvement of liver and other organs. Coincidentally, serial cranial ultrasound studies demonstrated cystic lesions in the subependymal area of the striato-thalamic junction, compatible with subependymal necrosis. The cysts developed without evidence of preceding hemorrhage and enlarged progressively. Several conditions have been reported in association with subependymal cyst formation, such as periventricular-intraventricular hemorrhage in premature infants [8], intrauterine rubella infection [9], cerebrohepato-renal (Zellweger) syndrome [10], and neonatal ventriculitis. Clair et al. [8] described 11 cases of subependymal cysts evaluated by cranial ultrasound among 210 high-risk neonates less than 35 weeks gestational age and weighing < 2,000 gm. These subependymal cysts, presumably posthemorrhagic in origin, were unilocular, unilateral, size -< 10 ram, and did not change in character or size during serial ultrasound scanning over a 2 month period. Subependymal cystic lesions have been linked previously to congenital CMV infection [11,12]. However, in contrast to the present case, CMV-induced cystic lesions in the previously reported cases were presumed to have developed in utero, and progression posmatally has not been documented. Shackelford et al. [11] described a CMV-infected infant who had multiple, small subependymal cysts demonstrated by ultrasound on the second day of life. Shaw and Alvord, in an autopsy study of 30 infants with subependymal cysts, found evidence of CMV infection in four [12].
These four infants had lesions at the striato-thalamic junction bilaterally, a location identical to that of our patient. These authors found no evidence of hemorrhage in the CMV-infected infants and concluded that the subependymal cysts occurred in utero as a result of virus-related lysis of dividing cells of the germinal matrix. They termed the condition "subependymal germinolysis." Our patient demonstrates that subependymal cysts can develop posmatally in CMV-infected infants. The development of cysts in the absence of hemorrhage
Figure 4. Coronal MRI (TR 550 ms, TE 40 ms) reveals abnormal signals (arrow) in and adjacent to the slightly dilated right anterior horn, but delineation of the lesion is less than optimal. The le)q anterior horn and its internal structure are not clearly deft'ned.
Bale et al: Postnatal Subependymal Necrosis
369
strongly suggests that they were the result of subependymal germinolysis caused by CMV. Although the precise pathogenesis of these lesions has not been determined, CMV meningoencephalitis presumably has a major role. Our patient provides additional support for the concept that congenitally-infected infants occasionally have postnatal progression of CNS lesions [13]. Such observations indicate that carefully selected infants with congenital CMV infection may be candidates for postnatal therapy with antiviral agents effective against CMV. Although no agents have proved effective for congenital CMV infections, the development of 9-(1,3 dihydroxy-2-propoxymethyl) guanine (DHPG), which has been effective in treating CMV retinitis [14], suggests that therapy with such an agent may modify the outcome of congenital CMV infections for some infants. The authors wish to thank Dr. John Harris for performing the postmortem examination.
References [1] BaleJFJr. Human cytomegalovirus infection and disorders of the nervous system. Arch Neurol 1984;41:310-20. [21 Pass RF, Stagno S, Myers GJ, et al. Outcome of symptomatic congenital cytomegalovirus infection: Results of long-term longitudinal follow-up. Pediatrics 1980;66:758-62. [3] Weller TH, HanshawJB. Virological and clinical observations on cytomegalovirus inclusion disease. N Engl J Med 1962; 266:1233-44.
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PEDIATRIC NEUROLOGY
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[4] Becroft DM. Prenatal cytomegalovirus infection: Epidemiology, pathology and pathogenesis. In: Rosenberg HS, Bernstein J, eds. Perspectives in pediatric pathology, Vol. 6. Infectious diseases. New York: Masson, 1981;203-41. [5] Saigal S, Lanyk O, Larke RPB, et al. The outcome in children with congenital cytomegalovirus infection. Am J Dis Child 1982;136:896-901. [6] Bale JF Jr, Bray PF, Bell WE. Neuroradiographic abnormalities in congenital cytomegalovirus infection. Pediatr Neurol 1985;1:42-7. [7] McCracken GH, Shinefield HR, Cobb K, et al. Congenital cytomegalic inclusion disease. Am J Dis Child 1969;117: 522-39. [8] Clair MR, Zalneraitis EL, Balm RS, Goodman K, Perkes EA. Neurosonographic recognition of subependymal cysts in high-risk neonates. AJNR 1984;5: 761-7. [9] Rotke LB, Spiro AJ. Cerebral lesion in congenital rubella syndrome. J Pediatr 1967;70:243-55. [10] Danks DM, Tippett P, Adams C, Campbell P. Cerebrohepato -renal syndrome of Zellweger. J Pediatr 1975;88: 382-7. [11] Shackelfotd GD, Fulling KH, Giasier CM. Cysts of the subependymal germinal matrix: Sonographic demonstration with pathologic correlation. Radiology 1983; 149:117-21. [12] Shaw CM, Alvord ECJr. Subependymal germinolysis. Arch Neurol 1974;31:374-81. [13] Bray PF, Bale JF Jr, Anderson RE, Kern ER. Progressive neurologic disease associated with chronic cytomegalovirus infection. Ann Neurol 1981;9:499-501. [14] Rosecan LR, Staht-Bayliss CM, Kalman CM, Laskin OL. Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine. Am J Ophthalmol 1986; 101:405-18.