Talk:Abnormal Development - Zika Virus

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Cite this page: Hill, M.A. (2021, September 26) Embryology Abnormal Development - Zika Virus. Retrieved from


Vianna RAO, Rua EC, Fernandes AR, Dos Santos TCS, Dalcastel LAB, Dos Santos MLB, de Paula PDS, de Carvalho FR, Pache de Faria AO, Almeida PL, Sales LF, Riley LW, de Oliveira SA & Cardoso CAA. (2020). Experience in diagnosing congenital Zika syndrome in Brazilian children born to asymptomatic mothers. Acta Trop. , 206, 105438. PMID: 32165128 DOI.

Experience in diagnosing congenital Zika syndrome in Brazilian children born to asymptomatic mothers

Typical symptoms of primary Zika virus infection are not specific and share similarities with other arbovirus infections such as dengue fever and chikungunya. As acute infection can be asymptomatic in up to 73% of cases, infants with microcephaly represent a diagnostic challenge for pediatricians. We describe the frequency of congenital Zika syndrome (CZS) in Brazilian children born to asymptomatic pregnant mothers and its differential diagnosis. METHODS: This longitudinal, observational study was conducted on children with suspected CZS whose mothers did not report rash during pregnancy, referred to the reference hospital in a metropolitan area of ​ Rio de Janeiro, Brazil. The diagnosis of suspected CZS was based on Brazilian Ministry of Health protocol. RESULTS: Forty-three (17%) of 246 referred children were born to mothers without rash history during pregnancy. Thirteen (30%) of 43 children met the Brazilian Ministry of Health criteria for CZS, all with microcephaly (two post-natal). The other children included 11 cases with post-natal microcephaly due to hypoxic-ischemic encephalopathy (6), non-progressive encephalopathy of unknown etiology (2), microcephaly under investigation (2) and congenital toxoplasmosis (1); 17 children were misdiagnosed with microcephaly and progressed with normal head circumference during the follow-up period; one child was included because of epidemiological link and one was loss to follow-up. All children who underwent laboratory investigation for ZIKV infection during neonatal period had negative RT-qPCR tests. CONCLUSION: We emphasize the increasing importance of CZS in differential diagnosis of microcephaly at birth or post-natal period. Detailed clinical investigation assisted by neuroimaging tests may clarify the diagnosis of CZS when laboratory tests are not available during the acute phase of the disease. Copyright © 2020 Elsevier B.V. All rights reserved. KEYWORDS: Congenital Zika syndrome; Microcephaly at birth; Post-natal microcephaly; RT-PCR; Zika virus DOI: 10.1016/j.actatropica.2020.105438


Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology

Nat Commun. 2018 Jan 17;9(1):263. doi: 10.1038/s41467-017-02499-9.

Hirsch AJ1,2, Roberts VHJ3, Grigsby PL3,4, Haese N5,6, Schabel MC7,8, Wang X7, Lo JO4, Liu Z7, Kroenke CD7, Smith JL5,6, Kelleher M3, Broeckel R5,6, Kreklywich CN5,6, Parkins CJ5, Denton M5, Smith P5, DeFilippis V5,6, Messer W9,10, Nelson JA5,6, Hennebold JD3,4, Grafe M11, Colgin L12, Lewis A12, Ducore R12, Swanson T6, Legasse AW6, Axthelm MK6, MacAllister R13, Moses AV5,6, Morgan TK4,14, Frias AE15,16, Streblow DN17,18.

Abstract Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development. PMID: 29343712 PMCID: PMC5772047 DOI: 10.1038/s41467-017-02499-9

Exhaustive TORCH Pathogen Diagnostics Corroborate Zika Virus Etiology of Congenital Malformations in Northeastern Brazil

mSphere. 2018 Aug 8;3(4). pii: e00278-18. doi: 10.1128/mSphere.00278-18.

Moreira-Soto A#1,2, Cabral R#3, Pedroso C4, Eschbach-Bludau M1, Rockstroh A5, Vargas LA4, Postigo-Hidalgo I2, Luz E4, Sampaio GS4, Drosten C2,6, Netto EM4, Jaenisch T6,7, Ulbert S5, Sarno M3,4, Brites C#4, Drexler JF#8,6.


The Latin American 2015-2016 Zika virus (ZIKV) outbreak was associated with an increase in microcephaly predominantly in northeastern Brazil. To comparatively investigate infectious causes of congenital malformations, we performed a nested case-control study in 32 mothers of cases of suspected congenital Zika syndrome (CZS) and 160 age-matched controls from Bahia, northeastern Brazil. We collected clinical and imaging data and assessed past exposure to ZIKV, Chikungunya virus (CHIKV), dengue virus, and 8 established TORCH (Toxoplasma gondii, Treponema pallidum, rubella virus, cytomegalovirus, herpes simplex virus 1 [HSV-1] and HSV-2, varicella-zoster virus, parvovirus B19) pathogens using multiple serological tests. Heterogeneous symptoms prevented unequivocal diagnosis of CZS on clinical grounds. Only ZIKV and CHIKV seroprevalence rates differed significantly between cases and controls (93.8% versus 67.8% for ZIKV [Fisher's exact text, P = 0.002] and 20.7% versus 8.2% for CHIKV [χ2, P = 0.039]). High ZIKV seroprevalence rates in cases could not be explained by previous dengue virus infections potentially eliciting cross-reactive antibody responses affecting ZIKV serological tests. In conditional logistic regression analyses, only ZIKV was significantly associated with congenital malformations (P = 0.030; odds ratio, 4.0 [95% confidence interval, 1.1 to 14.1]). Our data support an association between maternal ZIKV exposure and congenital malformations. Parallels between the discrepant ZIKV and CHIKV seroprevalence rates between cases and controls and similar seroprevalence rates between cases and controls for the sexually transmitted T. pallidum and HSV-2 may suggest the occurrence of predominantly vector-borne transmission in our study population. High seroprevalence of TORCH pathogens suggests that exhaustive diagnostics will be necessary in the aftermath of the ZIKV outbreak and provides baseline data for longitudinal studies on ZIKV pathogenesis.IMPORTANCE The Latin American Zika virus (ZIKV) outbreak had a major impact on reproductive health worldwide. The reasons for the massively increased reports of neonatal microcephaly in northeastern Brazil are still unclear. Beyond the technical limitations of laboratory diagnostics, unambiguous diagnosis of ZIKV as the cause of congenital malformations is hampered by similar clinical pictures elicited by other pathogens known as TORCH pathogens. We performed a case-control study comparing mothers of children with congenital malformations to age-matched controls from Salvador, Brazil, one of the areas most extensively affected by the ZIKV outbreak. The ZIKV and Chikungunya virus seroprevalence rates differed significantly, whereas the levels of maternal exposure to TORCH pathogens were similar between cases and controls. Our data support a link between maternal ZIKV infection and congenital malformations and suggest the occurrence of predominantly vector-borne ZIKV transmission in these cases. In addition, some highly prevalent TORCH pathogens may be misinterpreted as representative of ongoing ZIKV activity in the absence of exhaustive diagnostics in northeastern Brazil. KEYWORDS: Brazil; TORCH; Zika virus; microcephaly; parturient PMID: 30089647 PMCID: PMC6083096 DOI: 10.1128/mSphere.00278-18

Zika virus infection in a pregnant Canadian traveler with congenital fetal malformations noted by ultrasonography at 14-weeks gestation

Trop Dis Travel Med Vaccines. 2018 Apr 4;4:2. doi: 10.1186/s40794-018-0062-8. eCollection 2018.

Schwartz KL1,2,3, Chan T4, Rai N5, Murphy KE6,7, Whittle W6,7, Drebot MA8, Gubbay J1,4,9, Boggild AK1,4,10.


BACKGROUND: Following emergence of Zika virus in the Americas, a devastating new congenital syndrome has been documented, leading to significant morbidity among Zika-infected fetuses and neonates. CASE PRESENTATION: A 29-year-old pregnant woman infected with Zika virus at 9-weeks gestation in Trinidad presented with one-month of fever, headache, and myalgia with persistent viremia. Significant fetal abnormalities were identified at 14-week ultrasound, which is the earliest ultrasound to describe a severely affected fetus following Zika virus infection to our knowledge. CONCLUSIONS: We discuss the implications of prolonged maternal viremia and the spectrum of congenital Zika syndrome detectable by fetal ultrasound. KEYWORDS: Arbovirus; Congenital infections; Fetal sonography; Pregnancy and travel; Zika virus PMID: 29632700 PMCID: PMC5885377 DOI: 10.1186/s40794-018-0062-8


Vital Signs: Update on Zika Virus-Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure - U.S. Zika Pregnancy Registry, 2016

MMWR Morb Mortal Wkly Rep. 2017 Apr 7;66(13):366-373. doi: 10.15585/mmwr.mm6613e1.

Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, Brown CM, Martin S, Ahmad N, Bhatnagar J, Macdonald J, Gould C, Fine AD, Polen KD, Lake-Burger H, Hillard CL, Hall N, Yazdy MM, Slaughter K, Sommer JN, Adamski A, Raycraft M, Fleck-Derderian S, Gupta J, Newsome K, Baez-Santiago M, Slavinski S, White JL, Moore CA, Shapiro-Mendoza CK, Petersen L, Boyle C, Jamieson DJ, Meaney-Delman D, Honein MA; U.S. Zika Pregnancy Registry Collaboration. Collaborators (215) Author information Abstract BACKGROUND: In collaboration with state, tribal, local, and territorial health departments, CDC established the U.S. Zika Pregnancy Registry (USZPR) in early 2016 to monitor pregnant women with laboratory evidence of possible recent Zika virus infection and their infants. METHODS: This report includes an analysis of completed pregnancies (which include live births and pregnancy losses, regardless of gestational age) in the 50 U.S. states and the District of Columbia (DC) with laboratory evidence of possible recent Zika virus infection reported to the USZPR from January 15 to December 27, 2016. Birth defects potentially associated with Zika virus infection during pregnancy include brain abnormalities and/or microcephaly, eye abnormalities, other consequences of central nervous system dysfunction, and neural tube defects and other early brain malformations. RESULTS: During the analysis period, 1,297 pregnant women in 44 states were reported to the USZPR. Zika virus-associated birth defects were reported for 51 (5%) of the 972 fetuses/infants from completed pregnancies with laboratory evidence of possible recent Zika virus infection (95% confidence interval [CI] = 4%-7%); the proportion was higher when restricted to pregnancies with laboratory-confirmed Zika virus infection (24/250 completed pregnancies [10%, 95% CI = 7%-14%]). Birth defects were reported in 15% (95% CI = 8%-26%) of fetuses/infants of completed pregnancies with confirmed Zika virus infection in the first trimester. Among 895 liveborn infants from pregnancies with possible recent Zika virus infection, postnatal neuroimaging was reported for 221 (25%), and Zika virus testing of at least one infant specimen was reported for 585 (65%). CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: These findings highlight why pregnant women should avoid Zika virus exposure. Because the full clinical spectrum of congenital Zika virus infection is not yet known, all infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy should receive postnatal neuroimaging and Zika virus testing in addition to a comprehensive newborn physical exam and hearing screen. Identification and follow-up care of infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with possible congenital Zika virus infection can ensure that appropriate clinical services are available.

PMID 28384133 DOI: 10.15585/mmwr.mm6613e1

Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study

PLoS Negl Trop Dis. 2017 Feb 23;11(2):e0005363. doi: 10.1371/journal.pntd.0005363. eCollection 2017 Feb.

Xavier-Neto J1, Carvalho M1, Pascoalino BD1, Cardoso AC1, Costa ÂM1, Pereira AH1, Santos LN1,2, Saito Â1, Marques RE1, Smetana JH1, Consonni SR1, Bandeira C2, Costa VV3, Bajgelman MC1, Oliveira PS1, Cordeiro MT4, Gonzales Gil LH4, Pauletti BA1, Granato DC1, Paes Leme AF1, Freitas-Junior L1, Holanda de Freitas CB1, Teixeira MM3, Bevilacqua E2, Franchini K1.


The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.

PMID: 28231241 PMCID: PMC5322881 DOI: 10.1371/journal.pntd.0005363


Congenital Zika Virus Infection: Beyond Neonatal Microcephaly

JAMA Neurol. 2016 Oct 3. doi: 10.1001/jamaneurol.2016.3720. [Epub ahead of print]

Melo AS1, Aguiar RS2, Amorim MM3, Arruda MB2, Melo FO4, Ribeiro ST5, Batista AG6, Ferreira T7, Dos Santos MP8, Sampaio VV9, Moura SR9, Rabello LP9, Gonzaga CE6, Malinger G10, Ximenes R11, de Oliveira-Szejnfeld PS12, Tovar-Moll F13, Chimelli L14, Silveira PP2, Delvechio R2, Higa L2, Campanati L15, Nogueira RM16, Filippis AM16, Szejnfeld J17, Voloch CM2, Ferreira OC Jr2, Brindeiro RM2, Tanuri A2.


IMPORTANCE: Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.

OBJECTIVE: To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil.

DESIGN, SETTING, AND PARTICIPANTS: We observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

MAIN OUTCOMES AND MEASURES: Description of the major lesions caused by ZIKV congenital infection.

RESULTS: Of the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and brain). Phylogenetic analyses showed an intrahost virus variation with some polymorphisms in envelope genes associated with different tissues.

CONCLUSIONS AND RELEVANCE: Combined findings from clinical, laboratory, imaging, and pathological examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported. The term congenital Zika syndrome is preferable to refer to these cases, as microcephaly is just one of the clinical signs of this congenital malformation disorder.

PMID 27695855 DOI: 10.1001/jamaneurol.2016.3720

Possible Zika Virus Infection Among Pregnant Women - United States and Territories, May 2016

MMWR Morb Mortal Wkly Rep. 2016 May 27;65(20):514-9. doi: 10.15585/mmwr.mm6520e1.

Simeone RM, Shapiro-Mendoza CK, Meaney-Delman D, Petersen EE, Galang RR, Oduyebo T, Rivera-Garcia B, Valencia-Prado M, Newsome KB, Pérez-Padilla J, Williams TR, Biggerstaff M, Jamieson DJ, Honein MA; Zika and Pregnancy Working Group, Ahmed F, Anesi S, Arnold KE, Barradas D, Barter D, Bertolli J, Bingham AM, Bollock J, Bosse T, Bradley KK, Brady D, Brown CM, Bryan K, Buchanan V, Bullard PD, Carrigan A, Clouse M, Cook S, Cooper M, Davidson S, DeBarr A, Dobbs T, Dunams T, Eason J, Eckert A, Eggers P, Ellington SR, Feldpausch A, Fredette CR, Gabel J, Glover M, Gosciminski M, Gay M, Haddock R, Hand S, Hardy J, Hartel ME, Hennenfent AK, Hills SL, House J, Igbinosa I, Im L, Jeff H, Khan S, Kightlinger L, Ko JY, Koirala S, Korhonen L, Krishnasamy V, Kurkjian K, Lampe M, Larson S, Lee EH, Lind L, Lindquist S, Long J, Macdonald J, MacFarquhar J, Mackie DP, Mark-Carew M, Martin B, Martinez-Quiñones A, Matthews-Greer J, McGee SA, McLaughlin J, Mock V, Muna E, Oltean H, O'Mallan J, Pagano HP, Park SY, Peterson D, Polen KN, Porse CC, Rao CY, Ropri A, Rinsky J, Robinson S, Rosinger AY, Ruberto I, Schiffman E, Scott-Waldron C, Semple S, Sharp T, Short K, Signs K, Slavinski SA, Stevens T, Sweatlock J, Talbot EA, Tonzel J, Traxler R, Tubach S, Van Houten C, VinHatton E, Viray M, Virginie D, Warren MD, Waters C, White P, Williams T, Winters AI, Wood S, Zaganjor I.


Zika virus is a cause of microcephaly and brain abnormalities (1), and it is the first known mosquito-borne infection to cause congenital anomalies in humans. The establishment of a comprehensive surveillance system to monitor pregnant women with Zika virus infection will provide data to further elucidate the full range of potential outcomes for fetuses and infants of mothers with asymptomatic and symptomatic Zika virus infection during pregnancy. In February 2016, Zika virus disease and congenital Zika virus infections became nationally notifiable conditions in the United States (2). Cases in pregnant women with laboratory evidence of Zika virus infection who have either 1) symptomatic infection or 2) asymptomatic infection with diagnosed complications of pregnancy can be reported as cases of Zika virus disease to ArboNET* (2), CDC's national arboviral diseases surveillance system. Under existing interim guidelines from the Council for State and Territorial Epidemiologists (CSTE), asymptomatic Zika virus infections in pregnant women who do not have known pregnancy complications are not reportable. ArboNET does not currently include pregnancy surveillance information (e.g., gestational age or pregnancy exposures) or pregnancy outcomes. To understand the full impact of infection on the fetus and neonate, other systems are needed for reporting and active monitoring of pregnant women with laboratory evidence of possible Zika virus infection during pregnancy. Thus, in collaboration with state, local, tribal, and territorial health departments, CDC established two surveillance systems to monitor pregnancies and congenital outcomes among women with laboratory evidence of Zika virus infection(†) in the United States and territories: 1) the U.S. Zika Pregnancy Registry (USZPR),(§) which monitors pregnant women residing in U.S. states and all U.S. territories except Puerto Rico, and 2) the Zika Active Pregnancy Surveillance System (ZAPSS), which monitors pregnant women residing in Puerto Rico. As of May 12, 2016, the surveillance systems were monitoring 157 and 122 pregnant women with laboratory evidence of possible Zika virus infection from participating U.S. states and territories, respectively. Tracking and monitoring clinical presentation of Zika virus infection, all prenatal testing, and adverse consequences of Zika virus infection during pregnancy are critical to better characterize the risk for congenital infection, the performance of prenatal diagnostic testing, and the spectrum of adverse congenital outcomes. These data will improve clinical guidance, inform counseling messages for pregnant women, and facilitate planning for clinical and public health services for affected families.

PMID 27248295

Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study

BMJ. 2016 Apr 13;353:i1901. doi: 10.1136/bmj.i1901.

de Fatima Vasco Aragao M1, van der Linden V2, Brainer-Lima AM3, Coeli RR4, Rocha MA4, Sobral da Silva P4, Durce Costa Gomes de Carvalho M4, van der Linden A5, Cesario de Holanda A6, Valenca MM7. Author information Abstract OBJECTIVE: To 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. DESIGN: Retrospective study with a case series. SETTING: Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. PARTICIPANTS: 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. MAIN OUTCOME MEASURES: Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. RESULTS: Six 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, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases. CONCLUSION: Severe 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

PMID 27075009

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities

N Engl J Med. 2016 Mar 30. [Epub ahead of print]

Driggers RW1, Ho CY1, Korhonen EM1, Kuivanen S1, Jääskeläinen AJ1, Smura T1, Rosenberg A1, Hill DA1, DeBiasi RL1, Vezina G1, Timofeev J1, Rodriguez FJ1, Levanov L1, Razak J1, Iyengar P1, Hennenfent A1, Kennedy R1, Lanciotti R1, du Plessis A1, Vapalahti O1.


The current outbreak of Zika virus (ZIKV) infection has been associated with an apparent increased risk of congenital microcephaly. We describe a case of a pregnant woman and her fetus infected with ZIKV during the 11th gestational week. The fetal head circumference decreased from the 47th percentile to the 24th percentile between 16 and 20 weeks of gestation. ZIKV RNA was identified in maternal serum at 16 and 21 weeks of gestation. At 19 and 20 weeks of gestation, substantial brain abnormalities were detected on ultrasonography and magnetic resonance imaging (MRI) without the presence of microcephaly or intracranial calcifications. On postmortem analysis of the fetal brain, diffuse cerebral cortical thinning, high ZIKV RNA loads, and viral particles were detected, and ZIKV was subsequently isolated. PMID 27028667


Pyriproxyfen is a larvicide (manufactured by Sumitomo Chemical) was used in a massive government-run program tasked to control the mosquito population in the country. PMID 23843982


Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil

JAMA Ophthalmol. 2016 Feb 9. doi: 10.1001/jamaophthalmol.2016.0267. [Epub ahead of print]

de Paula Freitas B1, de Oliveira Dias JR2, Prazeres J2, Sacramento GA3, Ko AI4, Maia M2, Belfort R Jr2.


IMPORTANCE: The Zika virus (ZIKV) has rapidly reached epidemic proportions, especially in northeastern Brazil, and has rapidly spread to other parts of the Americas. A recent increase in the prevalence of microcephaly in newborn infants and vision-threatening findings in these infants is likely associated with the rapid spread of ZIKV. OBJECTIVE: To evaluate the ocular findings in infants with microcephaly associated with presumed intrauterine ZIKV infection in Salvador, Bahia, Brazil. DESIGN, SETTING, AND PARTICIPANTS: Case series at a tertiary hospital. Twenty-nine infants with microcephaly (defined by a cephalic circumference of ≤32 cm) with a presumed diagnosis of congenital ZIKV were recruited through an active search and referrals from other hospitals and health unities. The study was conducted between December 1 and December 21, 2015. INTERVENTIONS: All infants and mothers underwent systemic and ophthalmic examinations from December 1 through December 21, 2015, in the Roberto Santos General Hospital, Salvador, Brazil. Anterior segment and retinal, choroidal, and optic nerve abnormalities were documented using a wide-field digital imaging system. The differential diagnosis included toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and human immunodeficiency virus, which were ruled out through serologic and clinical examinations. MAIN OUTCOMES AND MEASURES: Ocular abnormalities associated with ZIKV. RESULTS: Twenty-three of 29 mothers (79.3%) reported suspected ZIKV infection signs and symptoms during pregnancy, 18 in the first trimester, 4 in the second trimester, and 1 in the third trimester. Of the 29 infants (58 eyes) examined (18 [62.1%] female), ocular abnormalities were present in 17 eyes (29.3%) of 10 children (34.5%). Bilateral findings were found in 7 of 10 patients presenting with ocular lesions, the most common of which were focal pigment mottling of the retina and chorioretinal atrophy in 11 of the 17 eyes with abnormalities (64.7%), followed by optic nerve abnormalities in 8 eyes (47.1%), bilateral iris coloboma in 1 patient (2 eyes [11.8%]), and lens subluxation in 1 eye (5.9%). CONCLUSIONS AND RELEVANCE: Congenital infection due to presumed ZIKV exposure is associated with vision-threatening findings, which include bilateral macular and perimacular lesions as well as optic nerve abnormalities in most cases. PMID 26865554

Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes

Rev Soc Bras Med Trop. 2015 Dec 22. pii: S0037-86822015005003102. [Epub ahead of print]

Marcondes CB1, Ximenes MF2.


Zika virus, already widely distributed in Africa and Asia, was recently reported in two Northeastern Brazilian: State of Bahia and State of Rio Grande do Norte, and one Southeastern: State of São Paulo. This finding adds a potentially noxious virus to a list of several other viruses that are widely transmitted by Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus in Brazil. The pathology and epidemiology, including the distribution and vectors associated with Zika virus, are reviewed. This review is focused on viruses transmitted by Aedes (Stegomyia) mosquitoes, including dengue, Chikungunya, Zika, Mayaro, and yellow fever virus, to emphasize the risks of occurrence for these arboviruses in Brazil and neighboring countries. Other species of Aedes (Stegomyia) are discussed, emphasizing their involvement in arbovirus transmission and the possibility of adaptation to environments modified by human activities and introduction in Brazil.

PMID 26689277

Zika virus and the never-ending story of emerging pathogens and transfusion medicine

Blood Transfus. 2015 Nov 5:1-6. doi: 10.2450/2015.0066-15. [Epub ahead of print]

Marano G1, Pupella S1, Vaglio S1,2, Liumbruno GM1, Grazzini G1.


In the last few years, the transfusion medicine community has been paying special attention to emerging vector-borne diseases transmitted by arboviruses. Zika virus is the latest of these pathogens and is responsible for major outbreaks in Africa, Asia and, more recently, in previously infection-naïve territories of the Pacific area. Many issues regarding this emerging pathogen remain unclear and require further investigation. National health authorities have adopted different prevention strategies. The aim of this review article is to discuss the currently available, though limited, information and the potential impact of this virus on transfusion medicine. PMID 26674815


Stress responses in flavivirus-infected cells: activation of unfolded protein response and autophagy

Front Microbiol. 2014 Jun 3;5:266. doi: 10.3389/fmicb.2014.00266. eCollection 2014.

Blázquez AB1, Escribano-Romero E1, Merino-Ramos T1, Saiz JC1, Martín-Acebes MA2.


The Flavivirus is a genus of RNA viruses that includes multiple long known human, animal, and zoonotic pathogens such as Dengue virus, yellow fever virus, West Nile virus, or Japanese encephalitis virus, as well as other less known viruses that represent potential threats for human and animal health such as Usutu or Zika viruses. Flavivirus replication is based on endoplasmic reticulum-derived structures. Membrane remodeling and accumulation of viral factors induce endoplasmic reticulum stress that results in activation of a cellular signaling response termed unfolded protein response (UPR), which can be modulated by the viruses for their own benefit. Concomitant with the activation of the UPR, an upregulation of the autophagic pathway in cells infected with different flaviviruses has also been described. This review addresses the current knowledge of the relationship between endoplasmic reticulum stress, UPR, and autophagy in flavivirus-infected cells and the growing evidences for an involvement of these cellular pathways in the replication and pathogenesis of these viruses. KEYWORDS: West Nile virus; autophagy; dengue virus; endoplasmic reticulum stress; flavivirus; unfolded protein response; virus replication

PMID 24917859