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Clinical features and neuroimaging CT and MRI findings in presumed Zika virus related congenital infection and microcephaly
AbstractObjectiveTo report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic.ResultsSix of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern,van cleef and arpels necklaces, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases.ConclusionSevere cerebral damage was found on imaging in most of the children in this case series with congenital infection presumably associated with the Zika virus. The features most commonly found were brain calcifications in the junction between cortical and subcortical white matter associated with malformations of cortical development, often with a simplified gyral pattern and predominance of pachygyria or polymicrogyria in the frontal lobes. Additional findings were enlarged cisterna magna, abnormalities of corpus callosum (hypoplasia or hypogenesis), ventriculomegaly, delayed myelination, and hypoplasia of the cerebellum and the brainstem.IntroductionSince October 2015 there has been an increase in the number of children with microcephaly in Pernambuco,1 a Brazilian state with nine million inhabitants. Several possible explanations for this phenomenon have been proposed, including an association with the current rise in Zika virus infections observed since March 2015.1The putative association between Zika virus infection in mothers during pregnancy and microcephalic offspring is based on epidemiological and laboratory evidence. These include the temporal association between the Zika virus epidemic and concomitant increase in the number of babies born with microcephaly1; the identification of the Zika virus genome (using reverse transcription polymerase chain reaction assay) in amniotic fluid samples from two pregnant women with microcephalic fetuses2; the detection of the Zika virus genome in the blood and tissue samples of a newborn baby with microcephaly who died five minutes after birth3; the demonstration of Zika virus neurotropism in experimental animals4; the discovery that Zika virus can cause death of neural cells5; and the finding of a higher frequency of abnormalities detected by ultrasonography in pregnant women with Zika virus infection compared with those without.6Zika virus is transmitted through the bite of an infected arthropod. The virus has been isolated from several species of mosquitoes: Aedes africanus, Aedes luteocephalus, and Aedes aegypti.7 The last of these is also known to transmit other diseases, such as dengue and yellow fever, which are endemic infections, and Chikungunya, which has also emerged recently.3 8 9 10 Zika virus epidemics have been described in several countries, especially in the most densely populated cities of tropical and subtropical regions.3 8 9 10 Although Zika virus was first described in 1947,3 11 no relation between Zika virus infection and microcephaly was confirmed until November 2015 in Brazil (table 1).2 Epidemiological data suggest that cases of microcephaly in Brazil might be associated with the introduction of Zika virus.1 This hypothesis was strongly supported in November 2015 by laboratory evidence from the amniotic fluid of women with microcephalic fetuses.1 In February 2016, the World Health Organization declared Zika virus a global health emergency.16Table 1 Brief history of Zika virus epidemic and its association with microcephalyView this table:View popupView inlineOf the 5280 notified cases of microcephaly in Brazil up to 13 February 2016 (fig 1), only 1345 have been investigated and classified. Of these, Zika virus infection has been diagnosed in 508, according to the definitions of the Brazilian Ministry of Health's protocol. In Pernambuco, the state with most notifications (n=1544), 182 cases have been investigated and confirmed as presumed Zika virus related infection.17Fig 1 of Brazil showing cities with notified cases of microcephaly in Brazil up to 13 February 2016. Adapted from Brazilian Ministry of Health17Even though microcephaly is the principal characteristic of a severe congenital infection during the early stages of pregnancy, to the best of our knowledge, the radiological features of children with presumed Zika virus related congenital infection or microcephaly have not been well characterised. A case series from Brazil described the computed tomography (CT) and transfontanellar cranial ultrasound characteristics of Zika virus related microcephaly, but the images were not shown. The features on magnetic resonance imaging (MRI) have not been described in children born with microcephaly.18 We describe the brain imaging (CT and MRI) features as well as principal clinical findings of children with microcephaly and presumed congenital infection related to the Zika virus during the epidemic in Pernambuco, Brazil.Patient involvementNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.MethodsThis is a retrospective report of a case series of 23 children with microcephaly and presumed Zika virus related congenital infection during the Brazilian epidemic, 2015 16. In the initial stages of the epidemic, microcephaly was defined as a head circumference of 33 cm or less. On 2 December 2015 the criterion for diagnosis changed to 32 cm or less for infants of gestational age 37 weeks or more, or, for preterm infants, 2 standard deviations below the mean for age and sex on the Fenton curve.According to the Brazilian Ministry of Health's protocol, all infants born with suspected microcephaly in Pernambuco should be referred to one of two paediatric infectious disease departments and to one of four rehabilitation centres. The Association for Assistance of Disabled Children (AACD) is one of the rehabilitation centres. All investigations described in this report were conducted as part of the routine clinical evaluation of these children as established by clinical protocols defined by the Brazilian Ministry of Health and the health secretary of Pernambuco state,1 and the differential diagnosis was based on clinical presentation, personal and family history, laboratory test results,replica van cleef & arpels necklace, and radiological findings. Parents or guardians gave consent before the procedures.In AACD, all children are initially examined by a neurologist or physician specialising in physical medicine and rehabilitation, and, as needed, an ophthalmologist, orthopaedic consultant, and a multidisciplinary team of rehabilitation specialists. All children undergo a CT brain scan without contrast. Some also undergo MRI of the brain, based on the results of the clinical evaluation,van cleef & arpels necklace price, mainly the presence of refractory seizures or suspicion of hydrocephalus and arthrogryposis.We used a standard form to collect personal and clinical data. Mothers gave information on illness during pregnancy compatible with Zika virus infection (eg, maculopapular rash, fever, headache, myalgia, arthralgia, and conjunctivitis), with or without serological confirmation,van cleef necklace price, as well as any neurological dysfunction or craniofacial disproportion in the newborn.The main agents of congenital infections that cause brain calcifications and microcephaly (cytomegalovirus, toxoplasmosis, rubella, and syphilis) were investigated with paired serology (IgM and IgG antibodies to Zika virus) of both mother and newborn. If IgG antibodies to cytomegalovirus were present in both, polymerase chain reaction was conducted on urine samples. We excluded from the study those children with known causes of microcephaly other than Zika virus. Cerebrospinal fluid samples from six children were tested by IgM antibody capture enzyme linked immunosorbent assay (the new specific test for Zika virus), following the protocol of the Centers for Disease Control and Prevention.19 Genetic testing is not included in the Brazilian government's protocol, and differential diagnosis is performed based on family history and imaging findings, as is done with all metabolic diseases. Other causes of microcephaly, such as prenatal and perinatal complications and exposure to licit and illicit drugs, toxic substances, and ionising radiation were excluded in the children.Children included in this report had microcephaly or craniofacial disproportion (diagnosed by ultrasound examination during pregnancy or at birth), or both; brain imaging suggestive of congenital infection; and negative test results for other known infectious causes of microcephaly (eg, toxoplasmosis, cytomegalovirus, rubella, syphilis, and HIV).CT and MRI scansAccording to the protocol of the Brazilian government, all children with microcephaly undergo non contrast brain CT after clinical examination. MRI is not included in the protocol, but it is performed when available, based on clinical indication. The evaluation of the images was exclusively qualitative.All CT scanning was performed using a multislice CT scanner without contrast, and all MRI was performed using a 1.5T MRI scanner. Only in one child was MRI done with contrast. We considered mainly T1 weighted images as the most useful sequence for assessing normal brain maturation in children during the first six months. T1 and T2 weighted images were available for all the children, except one, who underwent only T2 weighted imaging.Statistical analysisDescriptive statistics were used for data analysis, carried out using the Statistical Package for Social Sciences (SPSS), version 21.0.
AbstractObjectiveTo report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic.ResultsSix of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern,van cleef and arpels necklaces, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases.ConclusionSevere cerebral damage was found on imaging in most of the children in this case series with congenital infection presumably associated with the Zika virus. The features most commonly found were brain calcifications in the junction between cortical and subcortical white matter associated with malformations of cortical development, often with a simplified gyral pattern and predominance of pachygyria or polymicrogyria in the frontal lobes. Additional findings were enlarged cisterna magna, abnormalities of corpus callosum (hypoplasia or hypogenesis), ventriculomegaly, delayed myelination, and hypoplasia of the cerebellum and the brainstem.IntroductionSince October 2015 there has been an increase in the number of children with microcephaly in Pernambuco,1 a Brazilian state with nine million inhabitants. Several possible explanations for this phenomenon have been proposed, including an association with the current rise in Zika virus infections observed since March 2015.1The putative association between Zika virus infection in mothers during pregnancy and microcephalic offspring is based on epidemiological and laboratory evidence. These include the temporal association between the Zika virus epidemic and concomitant increase in the number of babies born with microcephaly1; the identification of the Zika virus genome (using reverse transcription polymerase chain reaction assay) in amniotic fluid samples from two pregnant women with microcephalic fetuses2; the detection of the Zika virus genome in the blood and tissue samples of a newborn baby with microcephaly who died five minutes after birth3; the demonstration of Zika virus neurotropism in experimental animals4; the discovery that Zika virus can cause death of neural cells5; and the finding of a higher frequency of abnormalities detected by ultrasonography in pregnant women with Zika virus infection compared with those without.6Zika virus is transmitted through the bite of an infected arthropod. The virus has been isolated from several species of mosquitoes: Aedes africanus, Aedes luteocephalus, and Aedes aegypti.7 The last of these is also known to transmit other diseases, such as dengue and yellow fever, which are endemic infections, and Chikungunya, which has also emerged recently.3 8 9 10 Zika virus epidemics have been described in several countries, especially in the most densely populated cities of tropical and subtropical regions.3 8 9 10 Although Zika virus was first described in 1947,3 11 no relation between Zika virus infection and microcephaly was confirmed until November 2015 in Brazil (table 1).2 Epidemiological data suggest that cases of microcephaly in Brazil might be associated with the introduction of Zika virus.1 This hypothesis was strongly supported in November 2015 by laboratory evidence from the amniotic fluid of women with microcephalic fetuses.1 In February 2016, the World Health Organization declared Zika virus a global health emergency.16Table 1 Brief history of Zika virus epidemic and its association with microcephalyView this table:View popupView inlineOf the 5280 notified cases of microcephaly in Brazil up to 13 February 2016 (fig 1), only 1345 have been investigated and classified. Of these, Zika virus infection has been diagnosed in 508, according to the definitions of the Brazilian Ministry of Health's protocol. In Pernambuco, the state with most notifications (n=1544), 182 cases have been investigated and confirmed as presumed Zika virus related infection.17Fig 1 of Brazil showing cities with notified cases of microcephaly in Brazil up to 13 February 2016. Adapted from Brazilian Ministry of Health17Even though microcephaly is the principal characteristic of a severe congenital infection during the early stages of pregnancy, to the best of our knowledge, the radiological features of children with presumed Zika virus related congenital infection or microcephaly have not been well characterised. A case series from Brazil described the computed tomography (CT) and transfontanellar cranial ultrasound characteristics of Zika virus related microcephaly, but the images were not shown. The features on magnetic resonance imaging (MRI) have not been described in children born with microcephaly.18 We describe the brain imaging (CT and MRI) features as well as principal clinical findings of children with microcephaly and presumed congenital infection related to the Zika virus during the epidemic in Pernambuco, Brazil.Patient involvementNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.MethodsThis is a retrospective report of a case series of 23 children with microcephaly and presumed Zika virus related congenital infection during the Brazilian epidemic, 2015 16. In the initial stages of the epidemic, microcephaly was defined as a head circumference of 33 cm or less. On 2 December 2015 the criterion for diagnosis changed to 32 cm or less for infants of gestational age 37 weeks or more, or, for preterm infants, 2 standard deviations below the mean for age and sex on the Fenton curve.According to the Brazilian Ministry of Health's protocol, all infants born with suspected microcephaly in Pernambuco should be referred to one of two paediatric infectious disease departments and to one of four rehabilitation centres. The Association for Assistance of Disabled Children (AACD) is one of the rehabilitation centres. All investigations described in this report were conducted as part of the routine clinical evaluation of these children as established by clinical protocols defined by the Brazilian Ministry of Health and the health secretary of Pernambuco state,1 and the differential diagnosis was based on clinical presentation, personal and family history, laboratory test results,replica van cleef & arpels necklace, and radiological findings. Parents or guardians gave consent before the procedures.In AACD, all children are initially examined by a neurologist or physician specialising in physical medicine and rehabilitation, and, as needed, an ophthalmologist, orthopaedic consultant, and a multidisciplinary team of rehabilitation specialists. All children undergo a CT brain scan without contrast. Some also undergo MRI of the brain, based on the results of the clinical evaluation,van cleef & arpels necklace price, mainly the presence of refractory seizures or suspicion of hydrocephalus and arthrogryposis.We used a standard form to collect personal and clinical data. Mothers gave information on illness during pregnancy compatible with Zika virus infection (eg, maculopapular rash, fever, headache, myalgia, arthralgia, and conjunctivitis), with or without serological confirmation,van cleef necklace price, as well as any neurological dysfunction or craniofacial disproportion in the newborn.The main agents of congenital infections that cause brain calcifications and microcephaly (cytomegalovirus, toxoplasmosis, rubella, and syphilis) were investigated with paired serology (IgM and IgG antibodies to Zika virus) of both mother and newborn. If IgG antibodies to cytomegalovirus were present in both, polymerase chain reaction was conducted on urine samples. We excluded from the study those children with known causes of microcephaly other than Zika virus. Cerebrospinal fluid samples from six children were tested by IgM antibody capture enzyme linked immunosorbent assay (the new specific test for Zika virus), following the protocol of the Centers for Disease Control and Prevention.19 Genetic testing is not included in the Brazilian government's protocol, and differential diagnosis is performed based on family history and imaging findings, as is done with all metabolic diseases. Other causes of microcephaly, such as prenatal and perinatal complications and exposure to licit and illicit drugs, toxic substances, and ionising radiation were excluded in the children.Children included in this report had microcephaly or craniofacial disproportion (diagnosed by ultrasound examination during pregnancy or at birth), or both; brain imaging suggestive of congenital infection; and negative test results for other known infectious causes of microcephaly (eg, toxoplasmosis, cytomegalovirus, rubella, syphilis, and HIV).CT and MRI scansAccording to the protocol of the Brazilian government, all children with microcephaly undergo non contrast brain CT after clinical examination. MRI is not included in the protocol, but it is performed when available, based on clinical indication. The evaluation of the images was exclusively qualitative.All CT scanning was performed using a multislice CT scanner without contrast, and all MRI was performed using a 1.5T MRI scanner. Only in one child was MRI done with contrast. We considered mainly T1 weighted images as the most useful sequence for assessing normal brain maturation in children during the first six months. T1 and T2 weighted images were available for all the children, except one, who underwent only T2 weighted imaging.Statistical analysisDescriptive statistics were used for data analysis, carried out using the Statistical Package for Social Sciences (SPSS), version 21.0.
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