Brief Communication
Evolutive Leukoencephalopathy in Congenital Cytomegalovirus Infection
Journal of Child Neurology 2015, Vol. 30(1) 93-95 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813514292 jcn.sagepub.com
1 Goran Krakar, MD1, Ivana D , Sanja Delin, MD2, ¯ akovic´, MD 1 and Vlatka Mejasˇki Bosˇnjak, MD, PhD
Abstract Congenital cytomegalovirus infection is the most common infectious cause of congenital brain injury. Type and severity of congenital cytomegalovirus infection–related brain abnormalities depend on the developmental stage of the central nervous system at the time of fetal infection. The aim of this study was to follow the course of leukoencephalopathy in a patient with congenital cytomegalovirus infection. We describe brain magnetic resonance imaging (MRI) findings of a boy with symptomatic congenital cytomegalovirus infection performed at the age of 3 weeks, 13 months, and 4 and 7 years. Neonatal brain MRI showed most of characteristic findings in congenital cytomegalovirus infection with most prominent white matter abnormalities and cortical dysplasia. MRI follow-up images showed that cortical dysgenesis remained unchanged and static, whereas white matter abnormalities evolved over the years. We propose that leukoencephalopathy in congenital cytomegalovirus infection is not only nonprogressive or static but even evolutive and suggests both underlying disruption and delay of myelination. Keywords congenital cytomegalovirus infection, leukoencephalopathy, microcephaly, neuroimaging Received July 18, 2013. Received revised October 18, 2013. Accepted for publication October 31, 2013.
Cytomegalovirus (congenital cytomegalovirus infection) represents the most common transplacentally transmitted viral infection, asymptomatic in majority of cases. It is currently considered as the most important infectious cause of congenital brain injury. Wide spectrum of brain ultrasound and magnetic resonance imaging (MRI) abnormalities in children with congenital cytomegalovirus infection were reported: periventricular calcifications and/or lenticulostriate vasculopathy, ventricular dilation, periventricular (pseudo)cysts, periventricular leukoencephalopathy, hippocampal dysplasia, cerebellar hypoplasia, pachygyria/polymicrogyria, callosal abnormalities, disturbed myelination.1 MRI pattern of nonprogressive or static white matter abnormalities was previously described by van der Knaap et al2 and Gomes et al.3 Spectrum of neurologic abnormalities is most likely related to the stage of central nervous system development at which congenital infection occurred. The aim of this study is to report the evolutive course of leukoencephalopathy in a patient with congenital cytomegalovirus infection.
and suspected pachygyria. Congenital cytomegalovirus infection was confirmed by specific serology and congenital cytomegalovirus infection polymerase chain reaction in blood sample taken on the fifth day. Mother was not tested for congenital cytomegalovirus infection prenatally or during pregnancy, so her previous status is unknown. The boy received intravenous treatment with ganciclovir during the 3-week period. Control blood congenital cytomegalovirus infection polymerase chain reaction was negative, but a month later repeated viremia was detected, with 1740 copies, and he received 1 more cycle of ganciclovir therapy. Afterwards, repeated blood polymerase chain reaction tests were continuously negative. There were no other medications administered later on. Brain MRI 2 Tesla was performed at the age of 3 weeks and showed increased white matter signal intensity, periventricular leukoencephalopathy, dilated lateral ventricles especially occipitally, and temporal horns, ventricular septation, hypoplastic
1
Case Study Presented patient is first term born boy admitted to the neonatal unit because of microcephaly and intrauterine growth retardation. Neonatal brain ultrasonography showed wide lateral ventricles, especially occipitally, periventricular bilateral intraparenchymal calcifications, hypoplastic corpus callosum,
Children’s Hospital Zagreb, Pediatric Clinic, Department for Child Neurology, Zagreb, Croatia 2 County Hospital Zadar, Department for Pediatrics, Zadar, Croatia Corresponding Author: Goran Krakar, MD, Children’s Hospital Zagreb, Pediatric Clinic, Department for Child Neurology, Klaiceva 16, 10000 Zagreb, Croatia. Email: [email protected]
Downloaded from jcn.sagepub.com at Bobst Library, New York University on June 7, 2015
94
Journal of Child Neurology 30(1)
Figure 1. (A) Brain MRI (2 Tesla), age 3 weeks: Dilated lateral ventricles especially occipital horn, occipital ventricular septation, increased white matter signal intensity, and cortical dysplasia in terms of biparietal pachygyria/polymicrogyria. (B) Brain MRI (2 Tesla), age 13 months: Still large occipital horns but without septation, periventricular leukoencephalopathy, parietal pachygyria/polymicrogyria. (C) Brain MRI (1.5 Tesla), age 7 years: Only mild periventricular leukoencephalopathy, still mildly dilated occipital horns, minimal periventricular sequels, parietal bilateral pachygyria/polymicrogyria.
corpus callosum, cortical dysplasia in terms of biparietal pachygyria/polymicrogyria, and hippocampal dysplasia (Figure 1A). Brain MRI repeated at the age of 13 months showed periventricular leukoencephalopathy, mildly dilated lateral ventricles, still large occipital horns without septation, more thickened corpus callosum, parietal pachygyria/polymicrogyria, and hippocampal dysplasia (Figure 1B). At the age of 4 years, subsequent brain MRI (1.5 Tesla) was performed and showed reduced periventricular leukoencephalopathy, still mildly dilated occipital and temporal horns, more developed corpus callosum, patchy periventricular gliosis occipitally and temporally, and parietal bilateral pachygyria/polymicrogyria. The hippocampus normalized. Because of amelioration of brain lesions, especially white matter lesions, additional brain MRI was performed at the age of 7 years (1.5 Tesla) and revealed only mildly dilated occipital, and temporal horns, normal corpus callosum, minimal occipital and left temporal periventricular gliosis, parietal bilateral pachygyria/polymicrogyria (Figure 1C). Clinical course showed delayed motor milestones, he was unable to sit without support until the age of 13 months and had especially poor social contact. During the second year, feeding difficulties became prominent. At the age of 2.5 years, he was able to walk independently. There were no seizures and the electroencephalograph (EEG) was normal. He underwent continuous multidisciplinary habilitation from early infancy (physical, visual, speech and language, oromotor). Neurodevelopmental outcome at the age of 7 years showed moderate neuromotor dysfunction and severe mental impairment, absent language development, marked microcephaly, and no hearing loss or epilepsy so far.
Discussion It is becoming increasingly evident that the type and severity of the influence of congenital cytomegalovirus infection on the
developing brain depends on the maturity of the central nervous system at the time of fetal infection.2,4 Neuronal growth and migration to final destination happens early in brain development, and the disruption of neurogenesis due to congenital cytomegalovirus infection can cause lissencephaly, thin cortex, cerebellar hypoplasia, ventriculomegaly, periventricular calcification, and delayed myelination. The period of 18 to 24 weeks of postmenstrual age would have more migrational disruptions and can cause pachygyria/polymicrogyria, cerebellar hypoplasia, periventricular cysts, and occasionally schizencephaly. In addition, ventriculomegaly and calcifications can occur. Infection in the third trimester does not affect neuronal migration and lamination but disturbs the development of cerebral white matter.1,2,4 Ventriculomegaly, especially enlarged occipital horns, with ventricular septation and dilated temporal horns were found in our patient. When described in association with white matter abnormalities and microcephaly, they represent highly indicative congenital cytomegalovirus infection–related brain abnormality.1,2 Gomes et al3 described nonprogressive leukoencephalopathy with bilateral temporal cysts in congenital cytomegalovirus infection, and van der Knaap2 described static encephalopathy predominantly involving the deep parietal white matter. At birth, the forebrain almost completely lacks myelin, and immature axons are susceptible to damage, including viral infection. Although delayed or decreased myelination can occur, during the first year of life they can be difficult to differentiate because lesions and unmyelinated white matter might share a similar T2-weighted hyperintensity on conventional brain MRI. Parietal and posterior white matter involvement with a rim of periventricular and subcortical spared area are one of the characteristic patterns described in congenital cytomegalovirus infection.2 As for periventricular leukomalacia compared to congenital cytomegalovirus infection–related white
Downloaded from jcn.sagepub.com at Bobst Library, New York University on June 7, 2015
Krakar et al
95
matter changes, the MR spectroscopy study found that axonal loss and lack of myelin due to oligodendrocytic loss and astrogliosis occurs in both etiologies.5 White matter changes are not necessarily related to overlying cortical migration pathologies, but in children with gyral abnormalities, white matter abnormalities are found bilateralmultifocal or diffuse.2-5 Focal white matter changes with normal cortical development therefore are suggestive of infection after the 26th to 28th week of gestation. As previously reported, congenital cytomegalovirus infection leukoencephalopathy is considered static and nonprogressive, but in our patient repeated brain MRI showed even regression of leukoencephalopathy at age 4 years, suggesting that myelination improved.1-3 The possible influence of ganciclovir treatment also needs to be considered. At the age of 7 years, that observation was confirmed on follow-up brain MRI study. Starting from the age of 4 years, MRI features changed in terms of white matter abnormalities, meaning that myelination improved, the corpus callosum thickened, and ventriculomegaly reduced. Even hippocampal dysplasia showed improvement from vertical orientation at the neonatal age, possibly because of reduced anterior temporal horn dilation. MRI features of cortical dysgenesis remained unchanged. We propose that leukoencephalopathy in congenital cytomegalovirus infection is not only nonprogressive or static as previously reported but might even be evolutive in part of white matter abnormalities, suggesting both disturbed and delayed myelination. Author Contributions All coauthors cared for the patient. GK wrote the first draft of the manuscript. VMB is a mentor who contributed equally to this work.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Treatment and follow-up of the patient was funded by Croatian National Insurance. Authors received no funding for article preparation.
Ethical Approval The study was approved by the ethics committee of Children’s Hospital, Zagreb (04-1107-2006).
References 1. Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev. 2009;22:99-126. 2. van der Knaap MS, Vermeulen G, Barkhof F, et al. Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection. Radiology. 2004;230:529-536. 3. Gomes AL, Vieira JP, Saldanha J. Non-progressive leukoencephalopathy with bilateral temporal cysts. Eur J Paediatr Neurol. 2001; 5:121-125. 4. Lanari M, Capretti MG, Lazzarotto T, et al. Neuroimaging in CMV congenital infected neonates: how and when. Early Hum Dev. 2012;88(suppl 2):S3-S5. 5. van der Voorn JP, Pouwels PJ, Vermeulen RJ, et al. Quantitative MR imaging and spectroscopy in congenital cytomegalovirus infection and periventricular leukomalacia suggests a comparable neuropathological substrate of the cerebral white matter lesions. Neuropediatrics. 2009;40:168-173.
Downloaded from jcn.sagepub.com at Bobst Library, New York University on June 7, 2015
Evolutive Leukoencephalopathy in Congenital Cytomegalovirus Infection
Journal of Child Neurology 2015, Vol. 30(1) 93-95 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813514292 jcn.sagepub.com
1 Goran Krakar, MD1, Ivana D , Sanja Delin, MD2, ¯ akovic´, MD 1 and Vlatka Mejasˇki Bosˇnjak, MD, PhD
Abstract Congenital cytomegalovirus infection is the most common infectious cause of congenital brain injury. Type and severity of congenital cytomegalovirus infection–related brain abnormalities depend on the developmental stage of the central nervous system at the time of fetal infection. The aim of this study was to follow the course of leukoencephalopathy in a patient with congenital cytomegalovirus infection. We describe brain magnetic resonance imaging (MRI) findings of a boy with symptomatic congenital cytomegalovirus infection performed at the age of 3 weeks, 13 months, and 4 and 7 years. Neonatal brain MRI showed most of characteristic findings in congenital cytomegalovirus infection with most prominent white matter abnormalities and cortical dysplasia. MRI follow-up images showed that cortical dysgenesis remained unchanged and static, whereas white matter abnormalities evolved over the years. We propose that leukoencephalopathy in congenital cytomegalovirus infection is not only nonprogressive or static but even evolutive and suggests both underlying disruption and delay of myelination. Keywords congenital cytomegalovirus infection, leukoencephalopathy, microcephaly, neuroimaging Received July 18, 2013. Received revised October 18, 2013. Accepted for publication October 31, 2013.
Cytomegalovirus (congenital cytomegalovirus infection) represents the most common transplacentally transmitted viral infection, asymptomatic in majority of cases. It is currently considered as the most important infectious cause of congenital brain injury. Wide spectrum of brain ultrasound and magnetic resonance imaging (MRI) abnormalities in children with congenital cytomegalovirus infection were reported: periventricular calcifications and/or lenticulostriate vasculopathy, ventricular dilation, periventricular (pseudo)cysts, periventricular leukoencephalopathy, hippocampal dysplasia, cerebellar hypoplasia, pachygyria/polymicrogyria, callosal abnormalities, disturbed myelination.1 MRI pattern of nonprogressive or static white matter abnormalities was previously described by van der Knaap et al2 and Gomes et al.3 Spectrum of neurologic abnormalities is most likely related to the stage of central nervous system development at which congenital infection occurred. The aim of this study is to report the evolutive course of leukoencephalopathy in a patient with congenital cytomegalovirus infection.
and suspected pachygyria. Congenital cytomegalovirus infection was confirmed by specific serology and congenital cytomegalovirus infection polymerase chain reaction in blood sample taken on the fifth day. Mother was not tested for congenital cytomegalovirus infection prenatally or during pregnancy, so her previous status is unknown. The boy received intravenous treatment with ganciclovir during the 3-week period. Control blood congenital cytomegalovirus infection polymerase chain reaction was negative, but a month later repeated viremia was detected, with 1740 copies, and he received 1 more cycle of ganciclovir therapy. Afterwards, repeated blood polymerase chain reaction tests were continuously negative. There were no other medications administered later on. Brain MRI 2 Tesla was performed at the age of 3 weeks and showed increased white matter signal intensity, periventricular leukoencephalopathy, dilated lateral ventricles especially occipitally, and temporal horns, ventricular septation, hypoplastic
1
Case Study Presented patient is first term born boy admitted to the neonatal unit because of microcephaly and intrauterine growth retardation. Neonatal brain ultrasonography showed wide lateral ventricles, especially occipitally, periventricular bilateral intraparenchymal calcifications, hypoplastic corpus callosum,
Children’s Hospital Zagreb, Pediatric Clinic, Department for Child Neurology, Zagreb, Croatia 2 County Hospital Zadar, Department for Pediatrics, Zadar, Croatia Corresponding Author: Goran Krakar, MD, Children’s Hospital Zagreb, Pediatric Clinic, Department for Child Neurology, Klaiceva 16, 10000 Zagreb, Croatia. Email: [email protected]
Downloaded from jcn.sagepub.com at Bobst Library, New York University on June 7, 2015
94
Journal of Child Neurology 30(1)
Figure 1. (A) Brain MRI (2 Tesla), age 3 weeks: Dilated lateral ventricles especially occipital horn, occipital ventricular septation, increased white matter signal intensity, and cortical dysplasia in terms of biparietal pachygyria/polymicrogyria. (B) Brain MRI (2 Tesla), age 13 months: Still large occipital horns but without septation, periventricular leukoencephalopathy, parietal pachygyria/polymicrogyria. (C) Brain MRI (1.5 Tesla), age 7 years: Only mild periventricular leukoencephalopathy, still mildly dilated occipital horns, minimal periventricular sequels, parietal bilateral pachygyria/polymicrogyria.
corpus callosum, cortical dysplasia in terms of biparietal pachygyria/polymicrogyria, and hippocampal dysplasia (Figure 1A). Brain MRI repeated at the age of 13 months showed periventricular leukoencephalopathy, mildly dilated lateral ventricles, still large occipital horns without septation, more thickened corpus callosum, parietal pachygyria/polymicrogyria, and hippocampal dysplasia (Figure 1B). At the age of 4 years, subsequent brain MRI (1.5 Tesla) was performed and showed reduced periventricular leukoencephalopathy, still mildly dilated occipital and temporal horns, more developed corpus callosum, patchy periventricular gliosis occipitally and temporally, and parietal bilateral pachygyria/polymicrogyria. The hippocampus normalized. Because of amelioration of brain lesions, especially white matter lesions, additional brain MRI was performed at the age of 7 years (1.5 Tesla) and revealed only mildly dilated occipital, and temporal horns, normal corpus callosum, minimal occipital and left temporal periventricular gliosis, parietal bilateral pachygyria/polymicrogyria (Figure 1C). Clinical course showed delayed motor milestones, he was unable to sit without support until the age of 13 months and had especially poor social contact. During the second year, feeding difficulties became prominent. At the age of 2.5 years, he was able to walk independently. There were no seizures and the electroencephalograph (EEG) was normal. He underwent continuous multidisciplinary habilitation from early infancy (physical, visual, speech and language, oromotor). Neurodevelopmental outcome at the age of 7 years showed moderate neuromotor dysfunction and severe mental impairment, absent language development, marked microcephaly, and no hearing loss or epilepsy so far.
Discussion It is becoming increasingly evident that the type and severity of the influence of congenital cytomegalovirus infection on the
developing brain depends on the maturity of the central nervous system at the time of fetal infection.2,4 Neuronal growth and migration to final destination happens early in brain development, and the disruption of neurogenesis due to congenital cytomegalovirus infection can cause lissencephaly, thin cortex, cerebellar hypoplasia, ventriculomegaly, periventricular calcification, and delayed myelination. The period of 18 to 24 weeks of postmenstrual age would have more migrational disruptions and can cause pachygyria/polymicrogyria, cerebellar hypoplasia, periventricular cysts, and occasionally schizencephaly. In addition, ventriculomegaly and calcifications can occur. Infection in the third trimester does not affect neuronal migration and lamination but disturbs the development of cerebral white matter.1,2,4 Ventriculomegaly, especially enlarged occipital horns, with ventricular septation and dilated temporal horns were found in our patient. When described in association with white matter abnormalities and microcephaly, they represent highly indicative congenital cytomegalovirus infection–related brain abnormality.1,2 Gomes et al3 described nonprogressive leukoencephalopathy with bilateral temporal cysts in congenital cytomegalovirus infection, and van der Knaap2 described static encephalopathy predominantly involving the deep parietal white matter. At birth, the forebrain almost completely lacks myelin, and immature axons are susceptible to damage, including viral infection. Although delayed or decreased myelination can occur, during the first year of life they can be difficult to differentiate because lesions and unmyelinated white matter might share a similar T2-weighted hyperintensity on conventional brain MRI. Parietal and posterior white matter involvement with a rim of periventricular and subcortical spared area are one of the characteristic patterns described in congenital cytomegalovirus infection.2 As for periventricular leukomalacia compared to congenital cytomegalovirus infection–related white
Downloaded from jcn.sagepub.com at Bobst Library, New York University on June 7, 2015
Krakar et al
95
matter changes, the MR spectroscopy study found that axonal loss and lack of myelin due to oligodendrocytic loss and astrogliosis occurs in both etiologies.5 White matter changes are not necessarily related to overlying cortical migration pathologies, but in children with gyral abnormalities, white matter abnormalities are found bilateralmultifocal or diffuse.2-5 Focal white matter changes with normal cortical development therefore are suggestive of infection after the 26th to 28th week of gestation. As previously reported, congenital cytomegalovirus infection leukoencephalopathy is considered static and nonprogressive, but in our patient repeated brain MRI showed even regression of leukoencephalopathy at age 4 years, suggesting that myelination improved.1-3 The possible influence of ganciclovir treatment also needs to be considered. At the age of 7 years, that observation was confirmed on follow-up brain MRI study. Starting from the age of 4 years, MRI features changed in terms of white matter abnormalities, meaning that myelination improved, the corpus callosum thickened, and ventriculomegaly reduced. Even hippocampal dysplasia showed improvement from vertical orientation at the neonatal age, possibly because of reduced anterior temporal horn dilation. MRI features of cortical dysgenesis remained unchanged. We propose that leukoencephalopathy in congenital cytomegalovirus infection is not only nonprogressive or static as previously reported but might even be evolutive in part of white matter abnormalities, suggesting both disturbed and delayed myelination. Author Contributions All coauthors cared for the patient. GK wrote the first draft of the manuscript. VMB is a mentor who contributed equally to this work.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Treatment and follow-up of the patient was funded by Croatian National Insurance. Authors received no funding for article preparation.
Ethical Approval The study was approved by the ethics committee of Children’s Hospital, Zagreb (04-1107-2006).
References 1. Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev. 2009;22:99-126. 2. van der Knaap MS, Vermeulen G, Barkhof F, et al. Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection. Radiology. 2004;230:529-536. 3. Gomes AL, Vieira JP, Saldanha J. Non-progressive leukoencephalopathy with bilateral temporal cysts. Eur J Paediatr Neurol. 2001; 5:121-125. 4. Lanari M, Capretti MG, Lazzarotto T, et al. Neuroimaging in CMV congenital infected neonates: how and when. Early Hum Dev. 2012;88(suppl 2):S3-S5. 5. van der Voorn JP, Pouwels PJ, Vermeulen RJ, et al. Quantitative MR imaging and spectroscopy in congenital cytomegalovirus infection and periventricular leukomalacia suggests a comparable neuropathological substrate of the cerebral white matter lesions. Neuropediatrics. 2009;40:168-173.
Downloaded from jcn.sagepub.com at Bobst Library, New York University on June 7, 2015
