Child's Nervous System https://doi.org/10.1007/s00381-017-3682-9

ORIGINAL PAPER

Neuroimaging findings associated with congenital Zika virus syndrome: case series at the time of first epidemic outbreak in Pernambuco State, Brazil Pedro Pires 1 & Patricia Jungmann 2 & Jully Moura Galvão 1 & Adriano Hazin 3 & Luiza Menezes 1 & Ricardo Ximenes 4 & Gabriele Tonni 5 & Edward Araujo Júnior 6 Received: 29 August 2017 / Accepted: 27 November 2017 # Springer-Verlag GmbH Germany, part of Springer Nature 2017

Abstract Purpose This study aimed to describe the prenatal and postnatal neuroimaging and clinical findings in a clinical series following congenital Zika virus syndrome during the first epidemic Zika virus (ZIKV) outbreak in the State of Pernambuco, Brazil. Methods We (the authors) conducted a retrospective study of a prospectively collected case series of fetuses and neonates with microcephaly born to mothers with presumed/confirmed congenital ZIKV syndrome. Prenatal ultrasound findings were reviewed to identify potential central nervous system (CNS) abnormalities. Neonates underwent postnatal neuroimaging follow up by computed tomography (CT)-scan or magnetic resonance (MR) imaging. Results The prenatal and postnatal outcomes of eight fetuses/neonates born to mothers with presumed/confirmed congenital ZIKV syndrome were examined. The mean gestational age at ultrasound was 31.3 weeks. Severe microcephaly was identified in seven fetuses (87.5%), while ventriculomegaly and brain calcifications were detected in all fetuses. The mean gestational age at delivery and head circumference were 38 weeks and 30.2 cm, respectively. All cases of microcephaly but one was confirmed postnatally. Brain CT scans or MRIs were performed in seven newborns, and all had periventricular and/or parenchymal calcifications, symmetrical or asymmetrical ventriculomegaly, pachygyria, and reduced sulcation and gyration. MR imaging aided the detection of one undetected case of corpus callosum dysgenesis and was essential in documenting reduced mantel of the cerebral cortex and reduced gyration and sulcation, especially involving the parietal lobe. In addition, MR imaging was also able to display irregular interfaces with the subcortical white matter, a finding consistent with polymicrogyria, more frequently seen at the level of the frontal lobe and atrophic and thinned pons. Conclusion Severe microcephaly and CNS abnormalities may be associated with congenital ZIKV syndrome.

* Edward Araujo Júnior [email protected] 1

Department of Maternal and Child, Pernambuco University (UPE), Recife, PE, Brazil

2

Department of Pathology, Pernambuco University (UPE), Recife, PE, Brazil

3

Department of Radiology, Instituto de Medicina Integral Professor Fernandes Figueira (IMIP), Recife, PE, Brazil

4

Department of Tropical Medicine, Federal University of Pernambuco (UFPE), Recife, PE, Brazil

5

Department of Obstetrics and Gynecology, AUSL Reggio Emilia, Guastalla Civil Hospital, Reggio Emilia, Italy

6

Department of Obstetrics, Paulista School of Medicine, Federal University of São Paulo (EPM-UNIFESP), Rua Belchior de Azevedo, 156 apto. 111 Torre Vitoria, São Paulo, SP CEP 05089-030, Brazil

Keywords Congenital Zika virus syndrome . Microcephaly . Brain abnormalities . Ultrasound . Computed tomography . Magnetic resonance imaging

Introduction Although the pathogenesis of microcephaly-associated congenital Zika virus syndrome (CZS) has not been fully elucidated, it is postulated that Zika virus (ZIKV) infects the fetusproducing chronic placentitis with virus dissemination to the developing brain as pregnancy progresses. The damage to neural progenitor cells (NPCs) together with inhibition of cell proliferation, differentiation, and neuronal apoptosis as the end-stage might explain the mechanism of the reduced cerebral cortex associated with microcephaly (Bsmall head^)

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[1–3]. Although in many cases CZS does not produce specific neuroimaging findings, it is of vital importance that neuroradiologists be aware of some diagnostic clues that correlate with CZS such as asymmetric microcephaly, collapsed aspect of the skull with overlapping sutures and prominent occipital bones, redundant and folded occipital skin (Cutis verticis gyrata), or herniation of the orbital fat to the skull with phenotypic malformation of the head of the fetus and neonate [4]. The aim of this study is to describe the prenatal and postnatal neuroimaging findings in fetuses and neonates with microcephaly and brain abnormalities born to mothers with presumed/confirmed CZS diagnosed at the time of the first epidemic outbreak of ZIKV in the State of Pernambuco, Brazil.

Materials and methods We (the authors) conducted a retrospective study of a prospectively collected case series of fetuses and neonates with microcephaly born to mothers with presumed/confirmed congenital ZIKV syndrome. The study was undertaken between July 2015 and April 2016 at the Centro Integrado de Saúde Amaury Medeiros (CISAM/UPE) of Pernambuco University (UPE). The mothers were all from Pernambuco State (Brazil) mainly from the metropolitan area of Recife city. The study was approved by the ethics committee (number CRM 8539), and all mothers participating in this study gave signed informed consent. The prenatal ultrasound and postnatal CT scans and MR imaging findings of fetuses/neonates born to mothers who had had a maculopapular rash and presumed or confirmed congenital ZIKV syndrome (CZS) were followed up. CZS was defined according to the Brazilian Ministry of Health guidelines [5, 6]. At the time of study, the laboratory test for ZIKV was performed under research conditions, with diagnostic kits provided by the Centers for Disease Control and Prevention (CDC), Atlanta (USA). Exclusion criteria were positive TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes) and dengue virus (DENV) serology, genetic abnormalities, primary microcephaly, and teratogens. The ultrasound examinations were performed by a boardcertified operator (PP) using 2D/3D ultrasound apparatus equipped with both transabdominal and transvaginal realtime high-frequency probes. The fetal growth parameters were assessed according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines [7] while the estimated fetal weight (EFW) was assessed using the Hadlock’s 3 formula [8]. Mild to moderate microcephaly (small head) was defined as a head circumference (HC) below the value of the mean − 2 and − 3 standard deviations (SD) (HC < 32 cm) [9] while severe microcephaly (small brain) as an HC below the value of the mean − 3 SD for the expected

gestational age [10] (HC < 28 cm). All fetuses underwent a thorough ultrasound examination including a detailed neuroscan, and all images were saved and stored on an optical disk for further offline analysis. Mild, moderate, and severe ventriculomegaly (hydrocephalus) was defined as a posterior horn measurement between 10 and 12 mm, 13 and 15 mm, and > 15 mm, respectively [11]. All the fetuses included in the study underwent serial (fortnightly) ultrasound until delivery, and CT scans or MR imaging were arranged postnatally in neonates, with a mean time period of 2 months. A 64-slice CT scanner (Brilliance 64, Philips Medical System, Best, The Netherlands) and a 1.5 T Intera scanner (Philips Medical System, Best, The Netherlands) were used. No protocol or clinical guidelines were available from the WHO (World Health Organization) or the PAHO (Pan American Health Organization) at the time of the study.

Results Neuroimaging data from eight mothers with presumed/ confirmed congenital ZIKV syndrome were reviewed. The ZIKV test was positive in half of the mothers while DENV serology was negative in all cases. In 62.5% of mothers, a clinical finding of a maculopapular rash was present during the first trimester of pregnancy. The gestational age at prenatal neuroscan was 31.3 ± 10.7 weeks (23.7–38.9) of gestation. Ventriculomegaly and parenchymal calcifications were detected in all cases at prenatal ultrasound: in one fetus, brain calcifications were associated with cerebellar vermis hypoplasia. The ultrasound examination of the fetal profile identified, on a sagittal plane, an oblique frontal bone (so-called elusive profile) and an excess of redundant and folded skin, particularly in the occipital region (Cutis verticis gyrata) in six fetuses (75%) (Fig. 1). Extracranial abnormalities were polyhydramnios (two cases, defined as an amniotic fluid index > 25 cm) and arthrogryposis multiplex congenita (1 case). Micrencephaly was diagnosed at prenatal ultrasound in 87.5% of overall cases of microcephaly, and the calculated mean ± SD of HC values was 30.2 ± 5.3 cm (26–34). Postnatal CT scans or MR imaging were performed in seven out of eight neonates, and all of them had periventricular and/or parenchymal calcifications, symmetrical or asymmetrical ventriculomegaly, pachygyria and reduced sulcation, and gyration (case no. 1 in Fig. 2 and case no. 5 in Fig. 3). Compared with prenatal ultrasound, CT scanning was able to detect in the neonates two extra cases of cerebellar vermis hypoplasia and one case of corpus callosum dysgenesis that was undetected at the prenatal neuroscan (Fig. 4, case no. 7).

Childs Nerv Syst Fig. 1 Case no. 5. Thirty-five weeks and 2 days. Sagittal view of fetal profile with subcutaneous edema (so-called elusive profile) (arrow) (a). Axial view of the fetal head showing the same finding (arrow) (b)

The serology test for ZIKV was performed in three neonates (37.5%), and all of them were positive; the RT-PCR test on blood for ZIKV was performed in only one neonate with positive result whereas RT-PRC on cerebro-spinal fluid (CSF) performed in five (62.5%) neonates was positive in all cases. All the newborns with positive RT-PRC on CSF showed severe microcephaly after birth. Table 1 summarizes the main prenatal and postnatal outcomes of eight fetuses and neonates born to mothers with presumed/confirmed congenital ZIKV syndrome.

Discussion Congenital ZIKV syndrome has the potential to cause damage to the neural progenitor cells (NPCs) at different stages of fetal development [9], inducing apoptosis and cell death [12].

Fig. 2 Case no. 1. Postnatal computed tomography (CT) scan demonstrating multiple brain calcifications (black arrows) involving the thalami (a), the basal nuclei (a, b), the periventricular space (a, b), and corticosubcortical (a, b, c). d CT scan on a sagittal plane showing the external prominence at the level of occipital bone (white arrow). e–g. T1-w (e) and T2-w (f) resonance magnetic (MR) imaging on axial planes and T2-w (g) imaging on the sagittal plane demonstrating supratentorial ventricular

The spectrum of the neuropathology caused by CZS is wide and non-specific. The virus may cause brain damage at different levels, involving the cerebral cortex (calcifications, pachygyria, lissencephaly, and reduced gyration), the corpus callosum, and the cerebellar vermis. This neuropathology may represent a disruption in brain development rather than destruction of the brain [13]. When microcephaly is encountered at the prenatal scan, particularly if associated with brain abnormalities, the maternal serology test to exclude ZIKV, DENV, or chikungunya (CHIKV) viruses should be carried out. In addition, fetal MR imaging may be arranged, where available, as a complementary diagnostic investigation and genetic testing should be performed to exclude primary microcephaly, where indicated [13]. Recommendation for routine diagnosis of ZIKV infection in neonates includes detection of the viral RNA by RT-PCR, detection of ZIKV-specific IgM antibodies using ELISA followed

enlargement and reduced mantel of the cerebral cortex. Worthy of note (black arrows) is the reduced gyration and sulcation especially at the level of the parietal lobe with an irregular interface with the subcortical white matter, compatible with polymicrogyria at the level of the frontal lobe. h T1-w MR imaging on the sagittal plane documenting mild brain hypoplasia

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Fig. 3 Case no. 5. Postnatal computed tomography (CT) scan (a, b) and magnetic resonance imaging (MRI) (c–h). Brain calcifications at the level of the basal nuclei of the subcortical white matter were seen on CT and T1-w MRI on the axial plane (c): in this latter case, the calcifications appear as a hypointense signal on the SWI sequence (white arrow). e

T1-w MR imaging showing mild brain hypoplasia. f–h T2-w on axial (f), coronal (g), and detail on coronal planes (h) showing thickness of the frontal lobe and of the perisylvian cortex with an irregular interface between the Sylvian fissure and the white matter, a finding suggestive of polymicrogyria. Ventricular enlargement is visible in all the images

by PRNT (plaque reduction neutralization test) confirmation in case of positive ELISA, and exclusion of other Flaviviruses [14, 15]. Since maternal IgM antibodies do not cross either the

placenta or the blood-brain barrier, detection of virus-specific IgM in the cerebro-spinal fluid is considered diagnostic for congenital ZIKV syndrome acquired during pregnancy [16].

Fig. 4 Case no. 7. Postnatal computed tomography (CT) scan reconstructed on the sagittal (a, b), coronal (c, d) and axial planes (e–h). Ventricular enlargement involving the posterior horn is detected and compatible with a diagnosis of colpocephaly (b–h). In addition, an associated corpus callosum (CC) dysgenesis is prompted by failed reconstruction of the CC on the sagittal plane (curved arrow), although CT scanning may reduce CC reconstruction. The third and fourth ventricle showed normal

dimensions (white arrow in a, d, and f). There is an enlargement of the Sylvian fissure (white arrow in b, g) and reduced gyration and sulcation of the cerebral cortex in all the images, a typical finding in abnormal cortical developmental disease. Subcortical brain calcifications were also seen (c, d, g, and h). Mild cerebellar vermis hypoplasia is shown with its inferior aspect lying just above the brainstem plane (large white arrow in a)

Yes (1st trim.) No

Yes (2nd trim.)

NP Pos Pos

Yes (severe) Yes (severe)

38 28

39 C-s C-s

3400 860

Vaginal 2510

9 NR

9

2 NR 10 8

9 NR

9

7 NR 10 9

9

Apgar score at 5 min

33 NR

29

26 NR 29 30

26.5

NP NP

NP

Pos NP Pos Pos

NP

NP NP

NP

NP NP NP Pos

NP

Pos NP

Pos

Pos NP Pos Pos

NP

Neonate blood Neonate CSF Neonate Head circumference serology for RTC-PCR for RTC-PCR for ZIKV ZIKV ZIKV (cm)

CSF cerebro-spinal fluid, C-s Cesarean section, NP Not performed, NR Not reported, Pos positive, RT-PCR real-time polymerase chain reaction, trim trimester, US ultrasound, ZIKV Zika virus

37 + 4 32

33 + 4

2165 1100 2820 3175

9

18

Vaginal Vaginal C-s C-s

2925

24 17

39 + 4 29 38 38

C-s

7 8

Pos NP Pos NP

38

6

Yes (1st trim.) Yes (1st trim.) Yes (2nd trim.) Yes (1st trim.)

Yes (severe) Yes (severe) Yes (severe) Yes (moderate) Yes (severe)

Yes (severe)

36 + 1 29 34 + 1 35 + 2

NP

24 27 26 34

2 3 4 5

Yes (1st trim.)

27

1

25 + 5

Microcephaly Gestational age Mode Birth Apgar weight score at of at delivery at US 1 min delivery (g) examination (weeks)

Prenatal and postnatal outcomes of eight fetuses/neonates born to mothers with presumed/confirmed congenital ZIKV syndrome

Case Maternal Gestational age at Obstetric history Maternal serology test of US diagnosis age maculopapular for ZIKV (weeks) (years) rash

Table 1

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In a previous series of 19 cases of congenital ZIKV syndrome in Ceará State, microcephaly was identified in all cases, being of the severe type in 76.3% overall. Furthermore, brain malformations were present in 17 cases with 7 fetuses showing extracranial abnormalities [17]. On the other hand, Sarno et al. [18] identified microcephaly in only 7.7% of cases studying 52 fetuses with presumed CZS in Bahia State, Brazil. In these series, th e m ain ultrasound findings were ventriculomegaly (65.4%), cerebral calcifications (44.2%), and posterior fossa abnormalities (32.7%) while 9.6% presented with arthrogryposis as an associated finding. Although our study is a small case series, it represents an overview over the clinical and diagnostic efforts made to characterize the CZS at the time of the onset of the first ZIKV outbreak in Pernambuco State. At that time, the serology test for ZIKV was supported only by research funding and even at present, a great many mothers do not have access to the serology test and/or the ZIKV test is not available to healthcare providers. The high incidence of severe microcephaly seen in our series (87.5%) is in agreement with previous findings by Carvalho et al. [17] opposite to reports by Sarno et al. (7.7%) [18]. This significant difference might be partly explained by the fact that in the latter case, only mothers with suspected and not confirmed CZS were analyzed. A second explanation might be that the higher incidence of severe microcephaly seen in our series may be an expression of a particular pathogenic strain of ZIKV or be the result of long viral shedding. Finally, neonates with a positive CSF RT-PCR test had severe microcephaly in 80% of cases. Prenatal neuroimaging identified ventricular enlargement and brain calcifications as the most common specific brain abnormalities. Postnatal CT scan and MR imaging improved the diagnostic accuracy of brain abnormalities compared with prenatal ultrasound. While CT scanning enabled the detection of two extra cases of cerebellar vermis hypoplasia, MR imaging allowed the detection of a corpus callosum dysgenesis, undetected prenatally. Moreover, postnatal MR imaging was essential in documenting supratentorial ventricular enlargement and reduced mantel of the cerebral cortex. Furthermore, its role was critical in demonstrating reduced gyration and sulcation, especially involving the parietal lobe. MR imaging was also able to display irregular interfaces with the subcortical white matter, a finding consistent with polymicrogyria, more frequently seen at the level of the frontal lobe and mild brain hypoplasia (the pons was thin and atrophic). Although in our series there were two cases of preterm birth (25%), the selected criteria of HC < 32 cm (which corresponds almost to − 2 standard deviations below the mean for both boys and girls at term) as a diagnostic cutoff value for microcephaly can be considered appropriate, even if this threshold might include normally developed neonates in some cases.

CZS seems to be associated with a specific process of skull deformation, an important finding for neuroradiologists as it may represent two diagnostic clusters of the congenital disease: the initially enlarged fetal head (due to ventriculomegaly) undergoes further collapse as gestation advances [19], a finding contributing to the so-called elusive profile and redundant skin (Cutis verticis gyrata) in the occipital region. Our series is in agreement with previous observations [17, 20, 21] that CZS may be associated with neuroimaging findings of multiple brain abnormalities and to severe types of microcephaly, especially when the disease is acquired during the early stage of fetal development, where rapid brain growth occurs. Compliance with ethical standards Conflict of interest We Pedro PIRES, Patricia JUNGMANN, Jully Moura GALVÃO, Adriano HAZIN, Luiza MENEZES, Ricardo XIMENES, Gabriele TONNI, and Edward ARAUJO JÚNIOR hereby declare that all authors have no conflict of interest.

References 1.

2.

3.

4.

5.

6.

7.

8.

Atif M, Azeem M, Sarwar MR, Bashir A (2016) Zika virus disease: a current review of the literature. Infection 44(6):695–705. https:// doi.org/10.1007/s15010-016-0935-6 Noronha L, Zanluca C, Azevedo ML, Luz KG, Santos CN (2016) Zika virus damages the human placental barrier and presents marked fetal neurotropism. Mem Inst Oswaldo Cruz 111(5):287– 293. https://doi.org/10.1590/0074-02760160085 Klase ZA, Khakhina S, Schneider AB, Callahan MV, GlasspoolMalone J, Malone R (2016) Zika fetal neuropathogenesis: etiology of a viral syndrome. PLoS Negl Trop Dis 10(8):e0004877. https:// doi.org/10.1371/journal.pntd.0004877 de Freitas Ribeiro BN, Carvalho Muniz B, Gasparetto EL, Ventura N, Marchiori E (2017) Congenital Zika syndrome and neuroimaging findings: what do we know so far? Radiol Bras 50(5):314–322. https://doi.org/10.1590/0100-3984.2017.0098 França GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD, Nunes ML, Castro MC, Serruya S, Silveira MF, Barros FC, Victora CG (2016) Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 388(10047):891–897. https://doi.org/10. 1016/S0140-6736(16)30902-3 Novo protocolo sobre microcefalia e alterações do sistema nervoso central em bebês. Available from: http://portalarquivos.saude.gov. br/images/pdf/2016/dezembro/12/orientacoes-integradasvigilancia-atencao.pdf. Cited December 12, 20116 Salomon LJ, Alfirevic Z, Berghella V, Bilardo C, HernandezAndrade E, Johnsen SL, Kalache K, Leung KY, Malinger G, Munoz H, Prefumo F, Toi A, Lee W, ISUOG Clinoical Standards Committee (2011) Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 37(1):116–126. https://doi.org/10.1002/uog.8831 Hadlock FP, Harrist RB, Carpenter RJ, Deter RL, Park SK (1984) Sonographic estimation of fetal weight. The value of femur length in addition to head and abdomen measurements. Radiology 150(2): 535–540. https://doi.org/10.1148/radiology.150.2.6691115

Childs Nerv Syst 9.

10.

11.

12.

13.

14. 15.

16.

Victora CG, Schuler-Faccini L, Matijasevich A, Ribeiro E, Pessoa A, Barros FC (2016) Microcephaly in Brazil: how to interpret reported numbers? Lancet 387(10019):621–624. https://doi.org/10. 1016/S0140-6736(16)00273-7 Malinger G, Lev D, Zahalka N, Ben Aroia Z, Watemberg N, Kidron D, Sira LB, Lerman-Sagie T (2003) Fetal cytomegalovirus infection of the brain: the spectrum of sonographic findings. AJNR Am J Neuroradiol 24(1):28–32 Alagappan R, Browning PD, Laorr A, McGahan JP (1994) Distal lateral ventricular atrium: reevaluation of normal range. Radiology 193(2):405–408. https://doi.org/10.1148/radiology.193.2.7972753 Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, Ming G (2016) Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18(5):587–590. https://doi. org/10.1016/j.stem.2016.02.016 Araujo Júnior E, Carvalho FH, Tonni G, Werner H (2017) Prenatal imaging findings in fetal Zika virus infection. Curr Opin Obstet Gynecol 29(2):95–105. https://doi.org/10.1097/GCO. 0000000000000345 Musso D, Gubler DJ (2016) Zika Virus. Clin Microbiol Rev 29(3): 487–524. https://doi.org/10.1128/CMR.00072-15 Staples JE, Dziuban EJ, Fischer M, Cragan JD, Rasmussen SA, Cannon MJ, Frey MT, Renquist CM, Lanciotti RS, Muñoz JL, Powers AM, Honein MA, Moore CA (2016) Interim guidelines for the evaluation and testing of infants with possible congenital Zika virus infection—United States, 2016. MMWR Morb Mortal Wkly Rep 65(3):63–67. 10.15585/mmwr.mm6503e3 Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ, Infectious

Diseases Society of America (2008) The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 47(3):303–327. https://doi.org/10.1086/ 589747 17. Carvalho FH, Cordeiro KM, Peixoto AB, Tonni G, Moron AF, Feitosa FE, Feitosa HN, Araujo Júnior E (2016) Associated ultrasonographic findings in fetuses with microcephaly because of suspected Zika virus (ZIKV) infection during pregnancy. Prenat Diagn 36(9):882–889. https://doi.org/10.1002/pd.4882 18. Sarno M, Aquino M, Pimentel K, Cabral R, Costa G, Bastos F, Brites C (2016 Sep 19) Progressive lesions of central nervous system in microcephalic fetuses with suspected congenital Zika virus syndrome. Ultrasound Obstet Gynecol. https://doi.org/10.1002/ uog.17303. 19. Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, Amorim MM, Batista AG, Chimelli L et al (2016) Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology 281(1):203–216. https://doi.org/10.1148/ radiol.2016161584 20. Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispode Filippis AM (2016) Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol 47(1):6–7. https://doi.org/ 10.1002/uog.15831 21. Cavalheiro S, Lopez A, Serra S, Da Cunha A, da Costa MD, Moron A, Lederman HM (2016) Microcephaly and Zika virus: neonatal neuroradiological aspects. Childs Nerv Syst 32(6):1057–1060. https://doi.org/10.1007/s00381-016-3074-6