Computed Tomographic Findings in Zika Microcephaly - NEJM

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CORRESPONDENCE

Computed Tomographic Findings in Microcephaly Associated with Zika Virus

April 6, 2016DOI: 10.1056/NEJMc1603617

http://www.nejm.org/doi/full/10.1056/NEJMc1603617?query=featured_home

 

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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 
[email protected]

Danielle Di Cavalcanti Souza Cruz, M.D.
Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil

Marli Tenorio, Ph.D.
Research Center Aggeu Magalhães, 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 Magalhães, Recife, Brazil

Demócrito 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 Magalhães, Recife, Brazil

João 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

for the Microcephaly Epidemic Research Group

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.

Source Information

Additional members of the Microcephaly Epidemic Research Group are listed in the Supplementary Appendix, available with the full text of this letter at NEJM.org.

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To the Editor:

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 1Computed 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.

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5 References

1. 1

   Zika virus spreads to new areas — region of the Americas, May 2015–January 2016.MMWR Morb Mortal Wkly Rep 2016;65:55-58
   CrossRef | Web of Science | Medline

2. 2

   Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med 2016;374:951-958
   Free Full Text | Web of Science | Medline

3. 3

   Possible association between Zika virus infection and microcephaly — Brazil, 2015.MMWR Morb Mortal Wkly Rep 2016;65:59-62
   CrossRef | Web of Science | Medline

4. 4

   Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol 2016;47:6-7
   CrossRef | Web of Science | Medline

5. 5

   Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 2016 March 4 (Epub ahead of print).

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| Wed Apr 6, 2016 7:52pm EDT

Related: HEALTH, BRAZIL

Brain scans of microcephalic babies suggest Zika disrupts development

CHICAGO | BY JULIE STEENHUYSEN

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Therapist Rozely Fontoura holds Juan Pedro, who has microcephaly, in Recife, Brazil March 26, 2016.

REUTERS/PAULO WHITAKER

 

Brain scans of 23 Brazilian infants with the birth defect microcephaly showed widespread and severe abnormalities suggesting that Zika may invade fetal nerve cells and disrupt brain development.

The findings, published on Wednesday in a letter to the New England Journal of Medicine, are based on a large trove of computed tomography, or CT images, done in infants whose mothers are believed to have had Zika infections during pregnancy.

The study included researchers from Brazil's Northeastern state of Pernambuco, such as Dr. Ana van der Linden of the Instituto de Medicina Integral, who were among the first to sound the alarm about increasing cases of microcephaly in Brazil thought to be linked with Zika infections.

 

Microcephaly is a typically rare birth defect marked by unusually small head size, signaling a problem with brain development. Brazil is investigating thousands of cases of microcephaly and has confirmed more than 940 cases to be related to Zika infections in the mothers.

Scientists in the study ran several tests on the mothers to try to rule out other possible causes of microcephaly, including toxoplasmosis, cytomegalovirus, parovirus, HIV and rubella. All were all negative. All of the mothers had symptoms during their pregnancies - such as fever and rash - that were consistent with Zika infections. Testing on spinal fluid from seven of the infants was positive for Zika antibodies.

The researchers did CT scans when the babies were between three days and five months old. All showed signs of brain calcification, which is suggestive of brain inflammation. Many of the babies had other abnormalities, including brain swelling, disruptions in brain folds, underdeveloped brain structures and abnormalities in myelin, which forms protective sheaths on nerve fibers.

Researchers said the findings were consistent with a study published last month testing lab dishes full of nerve stem cells similar to those in the brains of human fetuses. They showed that the Zika virus was able to easily infect these cells, stunting their growth.

Researchers said evidence from the brain scans suggests the abnormalities occurred from a disruption of brain development, rather than a destruction of brain cells.

According to the World Health Organization, there is a strong scientific consensus that Zika can cause microcephaly, although conclusive proof may take months or years.

 

(Reporting by Julie Steenhuysen; Editing by Leslie Adler)

http://wordlink.com/l/3CMwb'

 

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NERVOUS SYSTEM HEALTH

Brain scans of microcephalic babies suggest Zika disrupts development

Published April 07, 2016 

 Reuters

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The Wider Image: Alternative therapies for microcephaly (Copyright Reuters 2016)

CHICAGO –  Brain scans of 23 Brazilian infants with the birth defect microcephaly showed widespread and severe abnormalities suggesting that Zika may invade fetal nerve cells and disrupt brain development.

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The findings, published on Wednesday in a letter to the New England Journal of Medicine, are based on a large trove of computed tomography, or CT images, done in infants whose mothers are believed to have had Zika infections during pregnancy.

The study included researchers from Brazil's Northeastern state of Pernambuco, such as Dr. Ana van der Linden of the Instituto de Medicina Integral, who were among the first to sound the alarm about increasing cases of microcephaly in Brazil thought to be linked with Zika infections.

Microcephaly is a typically rare birth defect marked by unusually small head size, signaling a problem with brain development. Brazil is investigating thousands of cases of microcephaly and has confirmed more than 940 cases to be related to Zika infections in the mothers.

Zika-Linked Abnormalities in Infants with Microcephaly | HealthGrove

Scientists in the study ran several tests on the mothers to try to rule out other possible causes of microcephaly, including toxoplasmosis, cytomegalovirus, parovirus, HIV and rubella. All were all negative. All of the mothers had symptoms during their pregnancies - such as fever and rash - that were consistent with Zika infections. Testing on spinal fluid from seven of the infants was positive for Zika antibodies.

The researchers did CT scans when the babies were between three days and five months old. All showed signs of brain calcification, which is suggestive of brain inflammation. Many of the babies had other abnormalities, including brain swelling, disruptions in brain folds, underdeveloped brain structures and abnormalities in myelin, which forms protective sheaths on nerve fibers.

Researchers said the findings were consistent with a study published last month testing lab dishes full of nerve stem cells similar to those in the brains of human fetuses. They showed that the Zika virus was able to easily infect these cells, stunting their growth.

http://www.foxnews.com/health/2016/04/07/brain-scans-microcephalic-babies-suggest-zika-disrupts-development.html