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BRIEF REPORT
Zika Virus Associated with Microcephaly
Jernej Mlakar, M.D., Misa Korva, Ph.D., Nata?a Tul, M.D., Ph.D., Mara Popović, M.D., Ph.D., Mateja Polj?ak-Prijatelj, Ph.D., Jerica Mraz, M.Sc., Marko Kolenc, M.Sc., Katarina Resman Rus, M.Sc., Tina Vesnaver Vipotnik, M.D., Vesna Fabjan Vodu?ek, M.D., Alenka Vizjak, Ph.D., Jo?e Pi?em, M.D., Ph.D., Miroslav Petrovec, M.D., Ph.D., and Tatjana Av?ič ?upanc, Ph.D.
February 10, 2016DOI: 10.1056/NEJMoa1600651
...
We present a case of vertical transmission of ZIKV in a woman who was probably infected with ZIKV in northeastern Brazil at the end of the first trimester of pregnancy. Our discussion includes details of fetal imaging and pathological and virologic analyses.
CASE REPORT
In mid-October 2015, a 25-year-old previously healthy European woman came to the Department of Perinatology at the University Medical Center in Ljubljana, Slovenia, because of assumed fetal anomalies. Since December 2013, she had lived and worked as a volunteer in Natal, the capital of Rio Grande do Norte state. She had become pregnant at the end of February 2015. During the 13th week of gestation, she had become ill with high fever, which was followed by severe musculoskeletal and retroocular pain and an itching, generalized maculopapular rash. Since there was a ZIKV epidemic in the community, infection with the virus was suspected, but no virologic diagnostic testing was performed. Ultrasonography that was performed at 14 and 20 weeks of gestation showed normal fetal growth and anatomy.
The patient returned to Europe at 28 weeks of gestation. Ultrasonographic examination that was performed at 29 weeks of gestation showed the first signs of fetal anomalies, and she was referred to the Department of Perinatology. At that time, she also noticed reduced fetal movements. Ultrasonography that was performed at 32 weeks of gestation confirmed intrauterine growth retardation (estimated third percentile of fetal weight) with normal amniotic fluid, a placenta measuring 3.5 cm in thickness (normal size) with numerous calcifications, a head circumference below the second percentile for gestation (microcephaly), moderate ventriculomegaly, and a transcerebellar diameter below the second percentile. Brain structures were blurred, and there were numerous calcifications in various parts of the brain (Figure 1A and 1BFIGURE 1 Prenatal Ultrasonographic Images and Photographs of Coronal Slices of Brain.).
There were no other obvious fetal structural abnormalities. Fetal, umbilical, and uterine blood flows were normal on Doppler ultrasonography.
The clinical presentation raised suspicion of fetal viral infection. Because of severe brain disease and microcephaly, the fetus was given a poor prognosis for neonatal health. The mother requested that the pregnancy be terminated, and the procedure was subsequently approved by national and hospital ethics committees. Medical termination of the pregnancy was performed at 32 weeks of gestation. At the delivery, the only morphologic anomaly was the prominent microcephaly. Genetic consultation that included a detailed maternal family history revealed no suspicion of genetic syndromes or diseases. An autopsy was performed, as is mandatory in all cases of termination of pregnancy. The mother provided written informed consent for the publication of this case report.
...
DISCUSSION
This case shows severe fetal brain injury associated with ZIKV infection with vertical transmission. Recently, ZIKV was found in amniotic fluid of two fetuses that were found to have microcephaly, which was consistent with intrauterine transmission of the virus.10 Described cases are similar to the case presented here and were characterized by severely affected CNS and gross intrauterine growth retardation. Calcifications in the placenta and a low placental?fetal weight ratio,11 which were seen in this case, indicate potential damage to the placenta by the virus. Among the few reports of teratogenic effects of flaviviruses, investigators described the brain and eyes as the main targets.12,13 No presence of virus and no pathological changes were detected in any other fetal organs apart from the brain, which suggests a strong neurotropism of the virus.
The localization of immunofluorescence signal and the morphologic appearance of the calcifications, which resembled destroyed neuronal structures, indicate a possible location of the virus in neurons. The consequent damage might cause arrested development of the cerebral cortex at the embryonic age of approximately 20 weeks.14 The mechanism involved in the neurotropism of ZIKV is currently not clear. The association between ZIKV infection and fetal brain anomalies was also noted by findings on electron microscopy that were consistent with ZIKV detection in the fetal brain. Dense particles consistent with ZIKV were seen in damaged endoplasmic reticulum. Groups of enveloped structures with a bright interior resembling the remains of replication complexes that are characteristic of flaviviruses15,16 indicate viral replication in the brain. The findings on electron microscopy suggest a possible persistence of ZIKV in the fetal brain, possibly because of the immunologically secure milieu for the virus. The number of viral copies that were detected in the fetal brain were substantially higher than those reported in the serum obtained from adult ZIKV-infected patients17 but similar to those reported in semen samples.18
...
Full text:
http://www.nejm.org/doi/full/10.1056/NEJMoa1600651#t=articleTop
Zika Virus Associated with Microcephaly
Jernej Mlakar, M.D., Misa Korva, Ph.D., Nata?a Tul, M.D., Ph.D., Mara Popović, M.D., Ph.D., Mateja Polj?ak-Prijatelj, Ph.D., Jerica Mraz, M.Sc., Marko Kolenc, M.Sc., Katarina Resman Rus, M.Sc., Tina Vesnaver Vipotnik, M.D., Vesna Fabjan Vodu?ek, M.D., Alenka Vizjak, Ph.D., Jo?e Pi?em, M.D., Ph.D., Miroslav Petrovec, M.D., Ph.D., and Tatjana Av?ič ?upanc, Ph.D.
February 10, 2016DOI: 10.1056/NEJMoa1600651
...
We present a case of vertical transmission of ZIKV in a woman who was probably infected with ZIKV in northeastern Brazil at the end of the first trimester of pregnancy. Our discussion includes details of fetal imaging and pathological and virologic analyses.
CASE REPORT
In mid-October 2015, a 25-year-old previously healthy European woman came to the Department of Perinatology at the University Medical Center in Ljubljana, Slovenia, because of assumed fetal anomalies. Since December 2013, she had lived and worked as a volunteer in Natal, the capital of Rio Grande do Norte state. She had become pregnant at the end of February 2015. During the 13th week of gestation, she had become ill with high fever, which was followed by severe musculoskeletal and retroocular pain and an itching, generalized maculopapular rash. Since there was a ZIKV epidemic in the community, infection with the virus was suspected, but no virologic diagnostic testing was performed. Ultrasonography that was performed at 14 and 20 weeks of gestation showed normal fetal growth and anatomy.
The patient returned to Europe at 28 weeks of gestation. Ultrasonographic examination that was performed at 29 weeks of gestation showed the first signs of fetal anomalies, and she was referred to the Department of Perinatology. At that time, she also noticed reduced fetal movements. Ultrasonography that was performed at 32 weeks of gestation confirmed intrauterine growth retardation (estimated third percentile of fetal weight) with normal amniotic fluid, a placenta measuring 3.5 cm in thickness (normal size) with numerous calcifications, a head circumference below the second percentile for gestation (microcephaly), moderate ventriculomegaly, and a transcerebellar diameter below the second percentile. Brain structures were blurred, and there were numerous calcifications in various parts of the brain (Figure 1A and 1BFIGURE 1 Prenatal Ultrasonographic Images and Photographs of Coronal Slices of Brain.).
There were no other obvious fetal structural abnormalities. Fetal, umbilical, and uterine blood flows were normal on Doppler ultrasonography.
The clinical presentation raised suspicion of fetal viral infection. Because of severe brain disease and microcephaly, the fetus was given a poor prognosis for neonatal health. The mother requested that the pregnancy be terminated, and the procedure was subsequently approved by national and hospital ethics committees. Medical termination of the pregnancy was performed at 32 weeks of gestation. At the delivery, the only morphologic anomaly was the prominent microcephaly. Genetic consultation that included a detailed maternal family history revealed no suspicion of genetic syndromes or diseases. An autopsy was performed, as is mandatory in all cases of termination of pregnancy. The mother provided written informed consent for the publication of this case report.
...
DISCUSSION
This case shows severe fetal brain injury associated with ZIKV infection with vertical transmission. Recently, ZIKV was found in amniotic fluid of two fetuses that were found to have microcephaly, which was consistent with intrauterine transmission of the virus.10 Described cases are similar to the case presented here and were characterized by severely affected CNS and gross intrauterine growth retardation. Calcifications in the placenta and a low placental?fetal weight ratio,11 which were seen in this case, indicate potential damage to the placenta by the virus. Among the few reports of teratogenic effects of flaviviruses, investigators described the brain and eyes as the main targets.12,13 No presence of virus and no pathological changes were detected in any other fetal organs apart from the brain, which suggests a strong neurotropism of the virus.
The localization of immunofluorescence signal and the morphologic appearance of the calcifications, which resembled destroyed neuronal structures, indicate a possible location of the virus in neurons. The consequent damage might cause arrested development of the cerebral cortex at the embryonic age of approximately 20 weeks.14 The mechanism involved in the neurotropism of ZIKV is currently not clear. The association between ZIKV infection and fetal brain anomalies was also noted by findings on electron microscopy that were consistent with ZIKV detection in the fetal brain. Dense particles consistent with ZIKV were seen in damaged endoplasmic reticulum. Groups of enveloped structures with a bright interior resembling the remains of replication complexes that are characteristic of flaviviruses15,16 indicate viral replication in the brain. The findings on electron microscopy suggest a possible persistence of ZIKV in the fetal brain, possibly because of the immunologically secure milieu for the virus. The number of viral copies that were detected in the fetal brain were substantially higher than those reported in the serum obtained from adult ZIKV-infected patients17 but similar to those reported in semen samples.18
...
Full text:
http://www.nejm.org/doi/full/10.1056/NEJMoa1600651#t=articleTop
