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Computed Tomographic Findings in Microcephaly Associated with Zika Virus[/h] N Engl J Med 2016; 374:2193-2195June 2, 2016DOI: 10.1056/NEJMc1603617
Article Metrics [h=3]To the Editor:[/h] Zika virus (ZIKV) is a mosquito-borne flavivirus that is transmitted primarily by Aedes aegyptimosquitoes.1 Starting in May 2015, an outbreak of ZIKV infection has been reported in Brazil in association with an increasing number of neonates with congenital microcephaly in ZIKV-affected regions.1 In these areas, the prevalence of congenital microcephaly increased by a factor of 20 over the prevalence before the outbreak.1 ZIKV RNA has been identified in the brain of a fetus with congenital microcephaly.2 In addition, ZIKV RNA was identified in the amniotic fluid of two women whose fetuses had congenital microcephaly detected on prenatal ultrasonography.1 These events and observations prompted concern about the possible association between congenital microcephaly and the recent outbreak of ZIKV infection in Brazil.3 Only limited imaging data about the brain anomalies that may be associated with intrauterine ZIKV infection are available.
We report findings obtained by means of head computed tomography (CT) in 23 infants (13 female) with congenital microcephaly in which the clinical and epidemiologic data are compatible with congenital ZIKV infection in the Pernambuco state of Brazil. Head CTs were obtained for clinical reasons between September and December 2015. Samples of cerebrospinal fluid were available for serologic testing in 7 of the 23 infants, and results on enzyme-linked immunosorbent assay for ZIKV IgM antibody were positive in all 7 samples. Findings on serologic analysis regarding TORCH infection (toxoplasmosis, other [syphilis, varicella, parvovirus, and human immunodeficiency virus], rubella, cytomegalovirus, and herpes simplex) were negative in all 23 infants.
Head CT images were obtained at a mean age of 36 days after birth (range, 3 days to 5 months). Intracranial calcifications were seen in all the infants and mainly involved the frontal lobe (in 69 to 78% of the infants) and the parietal lobe (in 83 to 87%) (Figure 1FIGURE 1
Computed Tomography in Eight Infants with Congenital Microcephaly.). The calcifications were located mainly at the corticomedullary junction (in 53 to 86%). The configuration of the calcifications was mostly punctate (in 72 to 100%), with a predominately bandlike distribution (in 56 to 75%). The calcifications were seen in the basal ganglia (in 57 to 65%) and in the thalamus (in 39 to 43%). Ventriculomegaly was found in all the infants and was rated as severe in the majority (53%) and involving only the lateral ventricles in 43%. All the infants had global hypogyration of the cerebral cortex that was severe (only the Sylvian fissure was obviously present) in 78% of the infants. Cerebellar hypoplasia was present in 17 of the infants (74%) and involved only one cerebellar hemisphere in 3 infants. In 2 infants, the brain stem was globally hypoplastic. In all the infants, there was abnormal hypodensity of the white matter, and in 87% of the patients it diffusely involved all the cerebral lobes. In 1 infant, chronic encephalomalacic changes from ischemic stroke in the vascular territory of the left middle cerebral artery were seen.
Intrauterine ZIKV infection appears to be associated with severe brain anomalies, including calcifications, cortical hypogyration, ventriculomegaly, and white-matter abnormalities, although we cannot determine with certainty when ZIKV infection may have occurred during fetal development in these 23 infants. Our findings are nonspecific and may be seen in other congenital viral infections. The global presence of cortical hypogyration and white-matter hypomyelination or dysmyelination in all the infants and cerebellar hypoplasia in the majority of them suggest that ZIKV is associated with a disruption in brain development rather than destruction of brain. The neuronal and glial proliferation as well as neuronal migration appear to be affected. The mothers of the microcephalic infants in our study population had symptoms (e.g., low-grade fever and cutaneous rash) that were compatible with ZIKV infection during the first or second trimester of pregnancy, similar to the findings in other studies.4 Tang et al. found that ZIKV directly infects human cortical neural progenitor cells with high efficiency, resulting in stunted growth of this cell population and transcriptional dysregulation.5 This observation supports the type of disruptive, anomalous brain development that we found in these infants.
Adriano N. Hazin, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Andrea Poretti, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD
aporett1@jhmi.edu
Danielle Di Cavalcanti Souza Cruz, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Marli Tenorio, Ph.D.
Research Center Aggeu Magalh?es, Recife, Brazil
Ana van der Linden, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Lindomar Jose Pena, M.D.
Carlos Brito, M.D., Ph.D.
Laura H. Vega Gil, Ph.D.
Research Center Aggeu Magalh?es, Recife, Brazil
Dem?crito de Barros Miranda-Filho, Ph.D.
Oswaldo Cruz University Hospital, Recife, Brazil
Ernesto Torres de Azevedo Marques, M.D., Ph.D.
Celina M. Turchi Martelli, M.D., Ph.D.
Research Center Aggeu Magalh?es, Recife, Brazil
Jo?o G. Bezerra Alves, M.D., Ph.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Thierry A. Huisman, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
This letter was published on April 6, 2016, at NEJM.org.
http://www.nejm.org/doi/full/10.1056/NEJMc1603617?query=featured_zika
Computed Tomographic Findings in Microcephaly Associated with Zika Virus[/h] N Engl J Med 2016; 374:2193-2195June 2, 2016DOI: 10.1056/NEJMc1603617
Article Metrics [h=3]To the Editor:[/h] Zika virus (ZIKV) is a mosquito-borne flavivirus that is transmitted primarily by Aedes aegyptimosquitoes.1 Starting in May 2015, an outbreak of ZIKV infection has been reported in Brazil in association with an increasing number of neonates with congenital microcephaly in ZIKV-affected regions.1 In these areas, the prevalence of congenital microcephaly increased by a factor of 20 over the prevalence before the outbreak.1 ZIKV RNA has been identified in the brain of a fetus with congenital microcephaly.2 In addition, ZIKV RNA was identified in the amniotic fluid of two women whose fetuses had congenital microcephaly detected on prenatal ultrasonography.1 These events and observations prompted concern about the possible association between congenital microcephaly and the recent outbreak of ZIKV infection in Brazil.3 Only limited imaging data about the brain anomalies that may be associated with intrauterine ZIKV infection are available.
We report findings obtained by means of head computed tomography (CT) in 23 infants (13 female) with congenital microcephaly in which the clinical and epidemiologic data are compatible with congenital ZIKV infection in the Pernambuco state of Brazil. Head CTs were obtained for clinical reasons between September and December 2015. Samples of cerebrospinal fluid were available for serologic testing in 7 of the 23 infants, and results on enzyme-linked immunosorbent assay for ZIKV IgM antibody were positive in all 7 samples. Findings on serologic analysis regarding TORCH infection (toxoplasmosis, other [syphilis, varicella, parvovirus, and human immunodeficiency virus], rubella, cytomegalovirus, and herpes simplex) were negative in all 23 infants.
Head CT images were obtained at a mean age of 36 days after birth (range, 3 days to 5 months). Intracranial calcifications were seen in all the infants and mainly involved the frontal lobe (in 69 to 78% of the infants) and the parietal lobe (in 83 to 87%) (Figure 1FIGURE 1
Computed Tomography in Eight Infants with Congenital Microcephaly.). The calcifications were located mainly at the corticomedullary junction (in 53 to 86%). The configuration of the calcifications was mostly punctate (in 72 to 100%), with a predominately bandlike distribution (in 56 to 75%). The calcifications were seen in the basal ganglia (in 57 to 65%) and in the thalamus (in 39 to 43%). Ventriculomegaly was found in all the infants and was rated as severe in the majority (53%) and involving only the lateral ventricles in 43%. All the infants had global hypogyration of the cerebral cortex that was severe (only the Sylvian fissure was obviously present) in 78% of the infants. Cerebellar hypoplasia was present in 17 of the infants (74%) and involved only one cerebellar hemisphere in 3 infants. In 2 infants, the brain stem was globally hypoplastic. In all the infants, there was abnormal hypodensity of the white matter, and in 87% of the patients it diffusely involved all the cerebral lobes. In 1 infant, chronic encephalomalacic changes from ischemic stroke in the vascular territory of the left middle cerebral artery were seen.Intrauterine ZIKV infection appears to be associated with severe brain anomalies, including calcifications, cortical hypogyration, ventriculomegaly, and white-matter abnormalities, although we cannot determine with certainty when ZIKV infection may have occurred during fetal development in these 23 infants. Our findings are nonspecific and may be seen in other congenital viral infections. The global presence of cortical hypogyration and white-matter hypomyelination or dysmyelination in all the infants and cerebellar hypoplasia in the majority of them suggest that ZIKV is associated with a disruption in brain development rather than destruction of brain. The neuronal and glial proliferation as well as neuronal migration appear to be affected. The mothers of the microcephalic infants in our study population had symptoms (e.g., low-grade fever and cutaneous rash) that were compatible with ZIKV infection during the first or second trimester of pregnancy, similar to the findings in other studies.4 Tang et al. found that ZIKV directly infects human cortical neural progenitor cells with high efficiency, resulting in stunted growth of this cell population and transcriptional dysregulation.5 This observation supports the type of disruptive, anomalous brain development that we found in these infants.
Adriano N. Hazin, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Andrea Poretti, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD
aporett1@jhmi.edu
Danielle Di Cavalcanti Souza Cruz, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Marli Tenorio, Ph.D.
Research Center Aggeu Magalh?es, Recife, Brazil
Ana van der Linden, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Lindomar Jose Pena, M.D.
Carlos Brito, M.D., Ph.D.
Laura H. Vega Gil, Ph.D.
Research Center Aggeu Magalh?es, Recife, Brazil
Dem?crito de Barros Miranda-Filho, Ph.D.
Oswaldo Cruz University Hospital, Recife, Brazil
Ernesto Torres de Azevedo Marques, M.D., Ph.D.
Celina M. Turchi Martelli, M.D., Ph.D.
Research Center Aggeu Magalh?es, Recife, Brazil
Jo?o G. Bezerra Alves, M.D., Ph.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil
Thierry A. Huisman, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
This letter was published on April 6, 2016, at NEJM.org.
http://www.nejm.org/doi/full/10.1056/NEJMc1603617?query=featured_zika