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Congenital Zika Virus Syndrome
166 Congenital Zika Virus Syndrome
681
166 Congenital Zika Virus Syndrome GUSTAVO MALINGER | ILAN E. TIMOR-TRITSCH | MAURICIO HERRERA
Introduction Every few years the threat of a “new” infectious disease becomes the center of world attention, producing waves of fear and even mass panic. Until now, at least in the beginning, these diseases affected only adult populations. Although, since the Yap island epidemic in 2007,1 Zika virus (ZIKAV) was known to be able to produce epidemics, it remained unknown for the general population at large as well as for most of the medical profession. The situation changed in October and November of 2015 when it appeared in Brazil in the form of the “neonatal microcephaly epidemic.” The disproportionally large number and the severity of the cases affecting newborns brought the epidemic to the center of world attention, with countless articles in the press and in social/electronic media. By August 2016 the current epidemic has extended to immunologically naive populations in 67 countries. Quite rapidly it became apparent that the easily diagnosed microcephaly was only a first sign of severe brain involvement and imaging descriptions of the different brain pathologies associated with congenital Zika virus syndrome (CZVS) started to be reported.2,3 By the time of this writing in 2016, 20 countries have reported CZVS cases. In four of these countries, the cases resulted from travel-related infections. Questions regarding the different ways of transmission arose: • What is the possibility of transmission by other Aedes species, especially the more prevalent and longer-lived Aedes albopictus (Asian tiger mosquito)? • If currently only the most severe cases are being diagnosed, what is the full extent of fetal brain damage? • Are there available treatment options?
Disorder DEFINITION CZVS is defined as an intrauterine insult affecting mainly, but not only, the brain, and characterized by arrest of development
and even destruction of different portions of the cerebrum and cerebellum. ZIKAV is a ribonucleic acid mosquito-borne virus of the Flavivirus genus closely related to yellow fever, dengue, tick-borne encephalitis virus, chikungunya, and West Nile viruses. In adults and children, it may be either asymptomatic or cause a mild disease with fever, erythema, and arthralgia, or in its severe form cause Guillain-Barré syndrome.4 PREVALENCE AND EPIDEMIOLOGY Data regarding the prevalence and epidemiology of ZIKAV shows that once the disease starts to spread in a particular region, almost 80% of the population is infected but only around 20% have clinical disease.1 Using a theoretic model based on more of 30,000 cases in French Polynesia, Kucharski et al. found that an estimated 94% (95% confidence interval, 91–97%) of the total population of the six archipelagos were infected during the outbreak.5 The outbreak ended after 5–6 months, and since then there were no newly reported cases. The authors concluded that based on the demography of French Polynesia, the results imply that if ZIKAV infection provides complete protection against future infection, it would take 12–20 years before there are a sufficient number of susceptible individuals for ZIKAV to reemerge. This interesting point is also apparently applicable to the Yap epidemic, but still needs to be proved in noninsular countries. In Brazil, until May 2016 there were 174,003 reported cases for an incidence of 85.1 : 100,000 inhabitants. By August 20, 2016, the total number of children suspected to be infected and have CZVS was 90916; with 2968 of them being still investigated. Out of 6123 fully investigated cases, the diagnosis was confirmed in 1854 (30%) children including 129 (7%) cases of fetal or neonatal death. In only 51 cases was the diagnosis made using specific criteria (either serology or polymerase chain reaction [PCR]). According to these reports the number of declared and confirmed cases has decreased in the last months (Fig. 166.1). From Brazil, the ZIKAV traveled north, affecting fetuses and children and reaching the continental United States of America
682
PART 17 Infections 2500
Suspected cases 2000
Confirmed cases
1500
1000
500
0 Until Dec
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Fig. 166.1 Monthly report of new cases with suspected and confirmed congenital Zika virus syndrome as notified to the Brazil Ministry of Health.
through Miami, where there were 29 cases of autochthonous infections reported by August 24, 2016. ETIOLOGY AND PATHOPHYSIOLOGY ZIKAV is transmitted by the bite of mosquitos of the Aedes species, mainly by Aedes Aegypti; in addition, there are reports of transmission through sexual intercourse and probably also through blood products. It can also be transmitted vertically from pregnant women to their fetuses. As with other intrauterine infections (IUI), the virus enters the fetus after infecting the placenta. The central nervous system (CNS) infection is facilitated by the fact that the blood-brain barrier is not yet functional. Tang et al.7 showed that ZIKAV infects human embryonic cortical neural progenitor cells, multiplying in these cells and causing their death. Adult neurons and astrocytes can also be infected.8 Although until now most of the reported cases involved severely affected fetuses and newborns, it will not be surprising if cases with less severe pathologic features are diagnosed in the near future, as with cytomegalovirus (CMV) and toxoplasmosis. MANIFESTATIONS OF DISEASE Clinical Presentation A history of a febrile disease accompanied by arthralgia, rash, and conjunctivitis may be obtained in some patients, but many cases remain asymptomatic. The risk to develop severe complications is estimated to be low. Most of the cases diagnosed postpartum are recognized by the presence of microcephaly, usually severe with small fontanels, narrow sutures, and an abnormal head shape. In the absence of microcephaly, the diagnosis is more difficult and may be suspected by the presence of various degrees of ventriculomegaly, abnormal eyes, and limb abnormalities such as arthrogryposis.
Fig. 166.2 Congenital Zika virus syndrome at 31.6 weeks’ gestation. The head circumference is 24.5 cm, −3.5 SD below the norm for the gestational age. The lateral ventricle measurement is 13 mm.
Asymptomatic or mild involvement following transmission to the fetus have not yet been reported. Maternal serologic diagnosis is predominantly based on PCR or immunoglobulin M testing, based on timing since exposure or symptoms. As those clinical pathways are rapidly changing in response to new data, clinicians should consult local public health departments or the World Health Organization, Centers for Disease Control, or other authoritative web resources for current information. Imaging Technique and Findings Ultrasound. CNS findings include the following2,9,10: • microcephaly (Fig. 166.2) • ventriculomegaly, sometimes asymmetric (see Figs. 166.2 and 166.3)
Fig. 166.3 Congenital Zika virus syndrome at 24.4 weeks’ gestation. Transvaginal coronal ultrasound at the level of the thalami shows bilateral ventriculomegaly with parietal porencephalic cysts (arrows). Note the slightly increased amount of cerebrospinal fluid between the hemispheres. LV, Lateral ventricles.
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Fig. 166.5 Same fetus as in Fig. 166.1. Transvaginal parasagittal ultrasound shows hyperechogenic periventricular white matter (small arrows); delayed development of sulci and gyri (large arrows) and cortical destruction (arrowhead). LV, lateral ventricles.
Fig. 166.6 Same fetus as in Fig. 166.2. Microphthalmia. The orbits are small in relationship to the lenses. Fig. 166.4 Same fetus as in Fig. 166.1. Transvaginal coronal ultrasound at the level of the caudate nuclei shows a group of three punctuate calcifications at the border of the caudate (large arrow) and a calcified plaque in the contralateral side (arrowhead). A small porencephalic cyst is also present on this side (small arrow).
• widespread calcifications (cortical, parenchymatic, periventricular) punctuate or en plaque (Fig. 166.4) • periventricular echogenicity with or without cysts (Fig. 166.5) • porencephalic cysts, predominantly occipital (see Figs. 166.3–166.5) • cerebellar hypoplasia • brain-stem hypoplasia • callosal hypoplasia • malformations of cortical development (see Fig. 166.5) • intraventricular hemorrhage
Extracerebral findings include the following2,10: • microphthalmia, cataracts (Fig. 166.6) • arthrogryposis Interestingly, most cases of CZVS reported represent the severe spectrum of the disease; early prenatal detection of affected fetuses will need to focus on the presence of subtler single findings such as mild ventriculomegaly, focal calcification, periventricular cysts, smaller-than-expected transverse cerebellar diameter or corpus callosum length, or mega cisterna magna. In these cases, close follow-up at 1–2 weeks will be required. Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) findings are the same as those demonstrated by ultrasound (US).10 In some cases, particularly during the last stage of pregnancy, MRI may produce a better depiction of the brain,
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PART 17 Infections
Fig. 166.7 Congenital Zika virus syndrome at 32 weeks’ gestation. T2 weighted parasagittal magnetic resonance imaging shows very thin parenchyma without sulci and gyri, ventriculomegaly, and large subarachnoid space as a sign of brain atrophy/destruction.
Fig. 166.8 Severe congenital cytomegalovirus infection at 32 weeks. Note the similarities with the congenital Zika virus syndrome case in Fig. 166.4.
particularly when the fetus is in breach presentation and in cases of severe microcephaly when small or closed fontanels and sutures can be difficult for US wave penetration (Fig. 166.7).
WHAT THE REFERRING PHYSICIAN NEEDS TO KNOW
CLASSIC SIGNS The triad of fetal microcephaly, dense calcifications spread at different brain locations, and ventriculomegaly during a ZIKAV epidemic is highly suggestive of CZVS.
Differential Diagnosis From Imaging Findings In contrary to current understanding,11 we believe that other TORCH (toxoplasmosis, other [congenital syphilis and viruses], rubella, cytomegalovirus, and herpes simplex virus) IUIs, particularly CMV, can produce, in severe cases, brain insults similar and even identical to these produced by congenital zoster virus12 (Fig. 166.8). Two well-documented publications described similar findings apparently unrelated to IUIs.13,14
Primary providers need to be up to par with the ongoing and updated information provided by medical organizations and governmental bodies.15–17 They have to take a detailed medical history of the patients as well as their spouses’ travel history. Early referral for testing and imaging is of paramount importance. In seropositive patients and following clinical disease, pregnant patients should be examined by US every 3–4 weeks until delivery to look for subtle findings of CNS infection. Severely affected cases are usually easier to diagnose.
KEY POINTS • ZIKAV infection may cause serious fetal and neonatal consequences. • Transmission is by mosquito bites, sexual intercourse, blood product transfusion, and vertically from mother to fetus. • Although serologic tests are available for the diagnosis, their specificity and sensitivity are still limited. • CZVS causes infection of the brain, detectable by US and MRI.
SUGGESTED READINGS
Synopsis of Treatment Options PRENATAL No treatment has been reported until now. If available, the option for termination of pregnancy can be offered. POSTNATAL Symptomatic treatment followed by rehabilitation and support for the families of affected children is by now the only therapeutic alternative. In children with mild signs of the disease, antiviral treatments may be considered in experimental clinical trials.
Knowledge of congenital Zika virus infection changes rapidly with new publications on a frequent basis. In lieu of Suggested Readings, we refer the reader to the following websites, which are regularly updated: https://www.cdc.gov/zika/. http://www.ama-assn.org/ama/pub/physician-resources/public-health/zikaresource-center.page. http://www.nejm.org/page/zika-virus. http://www.acog.org/About-ACOG/ACOG-Departments/Zika-Virus. http://www.who.int/emergencies/zika-virus/en/ (also available in Portuguese).
All references available online at www.expertconsult.com
166 Congenital Zika Virus Syndrome
REFERENCES 1. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536-2543. 2. Oliveira Melo AS, Malinger G, Ximenes R, et al. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. 2016;47:6-7. 3. Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951-958. 4. Lessler J, Chaisson LH, Kucirka LM, et al. Assessing the global threat from Zika virus. Science. 2016;353:aaf8160. 5. Kucharski AJ, Funk S, Eggo RM, et al. Transmission dynamics of Zika virus in island populations: a modelling analysis of the 2013–14 French Polynesia outbreak. PLoS Negl Trop Dis. 2016;10:e0004726. 6. Brazil Ministry of Health. http://www.combateaedes.saude.gov.br/images/ sala-de-situacao/informe_microcefalia_epidemiologico40.pdf. 2016. 7. Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016;18:587-590. 8. Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534:267-271. 9. Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report. N Engl J Med. 2016;375: 2321-2334.
684.e1
10. Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, et al. Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology. 2016;161584. 11. Klase ZA, Khakhina S, Schneider Ade B, et al. Zika fetal neuropathogenesis: etiology of a viral syndrome. PLoS Negl Trop Dis. 2016;10:e0004877. 12. Malinger G, Lev D, Lerman-Sagie T. Imaging of fetal cytomegalovirus infection. Fetal Diagn Ther. 2011;29:117-126. 13. Nakamura K, Kato M, Sasaki A, et al. Congenital dysplastic microcephaly and hypoplasia of the brainstem and cerebellum with diffuse intracranial calcification. J Child Neurol. 2012;27:218-221. 14. Abdel-Salam GM, Abdel-Hamid MS, El-Khayat HA, et al. Fetal brain disruption sequence versus fetal brain arrest: a distinct autosomal recessive developmental brain malformation phenotype. Am J Med Genet A. 2015;167A:1089-1099. 15. World Health Organization. Pregnancy management in the context of Zika virus. 2016. http://www.who.int/csr/resources/publications/zika/pregnancymanagement/en/. 16. Papageorghiou AT, Thilaganathan B, Bilardo CM, et al. ISUOG interim guidance on ultrasound for Zika virus infection in pregnancy: information for healthcare professionals. Ultrasound Obstet Gynecol. 2016;47:530-532. 17. Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65:739-744.
681
166 Congenital Zika Virus Syndrome GUSTAVO MALINGER | ILAN E. TIMOR-TRITSCH | MAURICIO HERRERA
Introduction Every few years the threat of a “new” infectious disease becomes the center of world attention, producing waves of fear and even mass panic. Until now, at least in the beginning, these diseases affected only adult populations. Although, since the Yap island epidemic in 2007,1 Zika virus (ZIKAV) was known to be able to produce epidemics, it remained unknown for the general population at large as well as for most of the medical profession. The situation changed in October and November of 2015 when it appeared in Brazil in the form of the “neonatal microcephaly epidemic.” The disproportionally large number and the severity of the cases affecting newborns brought the epidemic to the center of world attention, with countless articles in the press and in social/electronic media. By August 2016 the current epidemic has extended to immunologically naive populations in 67 countries. Quite rapidly it became apparent that the easily diagnosed microcephaly was only a first sign of severe brain involvement and imaging descriptions of the different brain pathologies associated with congenital Zika virus syndrome (CZVS) started to be reported.2,3 By the time of this writing in 2016, 20 countries have reported CZVS cases. In four of these countries, the cases resulted from travel-related infections. Questions regarding the different ways of transmission arose: • What is the possibility of transmission by other Aedes species, especially the more prevalent and longer-lived Aedes albopictus (Asian tiger mosquito)? • If currently only the most severe cases are being diagnosed, what is the full extent of fetal brain damage? • Are there available treatment options?
Disorder DEFINITION CZVS is defined as an intrauterine insult affecting mainly, but not only, the brain, and characterized by arrest of development
and even destruction of different portions of the cerebrum and cerebellum. ZIKAV is a ribonucleic acid mosquito-borne virus of the Flavivirus genus closely related to yellow fever, dengue, tick-borne encephalitis virus, chikungunya, and West Nile viruses. In adults and children, it may be either asymptomatic or cause a mild disease with fever, erythema, and arthralgia, or in its severe form cause Guillain-Barré syndrome.4 PREVALENCE AND EPIDEMIOLOGY Data regarding the prevalence and epidemiology of ZIKAV shows that once the disease starts to spread in a particular region, almost 80% of the population is infected but only around 20% have clinical disease.1 Using a theoretic model based on more of 30,000 cases in French Polynesia, Kucharski et al. found that an estimated 94% (95% confidence interval, 91–97%) of the total population of the six archipelagos were infected during the outbreak.5 The outbreak ended after 5–6 months, and since then there were no newly reported cases. The authors concluded that based on the demography of French Polynesia, the results imply that if ZIKAV infection provides complete protection against future infection, it would take 12–20 years before there are a sufficient number of susceptible individuals for ZIKAV to reemerge. This interesting point is also apparently applicable to the Yap epidemic, but still needs to be proved in noninsular countries. In Brazil, until May 2016 there were 174,003 reported cases for an incidence of 85.1 : 100,000 inhabitants. By August 20, 2016, the total number of children suspected to be infected and have CZVS was 90916; with 2968 of them being still investigated. Out of 6123 fully investigated cases, the diagnosis was confirmed in 1854 (30%) children including 129 (7%) cases of fetal or neonatal death. In only 51 cases was the diagnosis made using specific criteria (either serology or polymerase chain reaction [PCR]). According to these reports the number of declared and confirmed cases has decreased in the last months (Fig. 166.1). From Brazil, the ZIKAV traveled north, affecting fetuses and children and reaching the continental United States of America
682
PART 17 Infections 2500
Suspected cases 2000
Confirmed cases
1500
1000
500
0 Until Dec
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Fig. 166.1 Monthly report of new cases with suspected and confirmed congenital Zika virus syndrome as notified to the Brazil Ministry of Health.
through Miami, where there were 29 cases of autochthonous infections reported by August 24, 2016. ETIOLOGY AND PATHOPHYSIOLOGY ZIKAV is transmitted by the bite of mosquitos of the Aedes species, mainly by Aedes Aegypti; in addition, there are reports of transmission through sexual intercourse and probably also through blood products. It can also be transmitted vertically from pregnant women to their fetuses. As with other intrauterine infections (IUI), the virus enters the fetus after infecting the placenta. The central nervous system (CNS) infection is facilitated by the fact that the blood-brain barrier is not yet functional. Tang et al.7 showed that ZIKAV infects human embryonic cortical neural progenitor cells, multiplying in these cells and causing their death. Adult neurons and astrocytes can also be infected.8 Although until now most of the reported cases involved severely affected fetuses and newborns, it will not be surprising if cases with less severe pathologic features are diagnosed in the near future, as with cytomegalovirus (CMV) and toxoplasmosis. MANIFESTATIONS OF DISEASE Clinical Presentation A history of a febrile disease accompanied by arthralgia, rash, and conjunctivitis may be obtained in some patients, but many cases remain asymptomatic. The risk to develop severe complications is estimated to be low. Most of the cases diagnosed postpartum are recognized by the presence of microcephaly, usually severe with small fontanels, narrow sutures, and an abnormal head shape. In the absence of microcephaly, the diagnosis is more difficult and may be suspected by the presence of various degrees of ventriculomegaly, abnormal eyes, and limb abnormalities such as arthrogryposis.
Fig. 166.2 Congenital Zika virus syndrome at 31.6 weeks’ gestation. The head circumference is 24.5 cm, −3.5 SD below the norm for the gestational age. The lateral ventricle measurement is 13 mm.
Asymptomatic or mild involvement following transmission to the fetus have not yet been reported. Maternal serologic diagnosis is predominantly based on PCR or immunoglobulin M testing, based on timing since exposure or symptoms. As those clinical pathways are rapidly changing in response to new data, clinicians should consult local public health departments or the World Health Organization, Centers for Disease Control, or other authoritative web resources for current information. Imaging Technique and Findings Ultrasound. CNS findings include the following2,9,10: • microcephaly (Fig. 166.2) • ventriculomegaly, sometimes asymmetric (see Figs. 166.2 and 166.3)
Fig. 166.3 Congenital Zika virus syndrome at 24.4 weeks’ gestation. Transvaginal coronal ultrasound at the level of the thalami shows bilateral ventriculomegaly with parietal porencephalic cysts (arrows). Note the slightly increased amount of cerebrospinal fluid between the hemispheres. LV, Lateral ventricles.
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Fig. 166.5 Same fetus as in Fig. 166.1. Transvaginal parasagittal ultrasound shows hyperechogenic periventricular white matter (small arrows); delayed development of sulci and gyri (large arrows) and cortical destruction (arrowhead). LV, lateral ventricles.
Fig. 166.6 Same fetus as in Fig. 166.2. Microphthalmia. The orbits are small in relationship to the lenses. Fig. 166.4 Same fetus as in Fig. 166.1. Transvaginal coronal ultrasound at the level of the caudate nuclei shows a group of three punctuate calcifications at the border of the caudate (large arrow) and a calcified plaque in the contralateral side (arrowhead). A small porencephalic cyst is also present on this side (small arrow).
• widespread calcifications (cortical, parenchymatic, periventricular) punctuate or en plaque (Fig. 166.4) • periventricular echogenicity with or without cysts (Fig. 166.5) • porencephalic cysts, predominantly occipital (see Figs. 166.3–166.5) • cerebellar hypoplasia • brain-stem hypoplasia • callosal hypoplasia • malformations of cortical development (see Fig. 166.5) • intraventricular hemorrhage
Extracerebral findings include the following2,10: • microphthalmia, cataracts (Fig. 166.6) • arthrogryposis Interestingly, most cases of CZVS reported represent the severe spectrum of the disease; early prenatal detection of affected fetuses will need to focus on the presence of subtler single findings such as mild ventriculomegaly, focal calcification, periventricular cysts, smaller-than-expected transverse cerebellar diameter or corpus callosum length, or mega cisterna magna. In these cases, close follow-up at 1–2 weeks will be required. Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) findings are the same as those demonstrated by ultrasound (US).10 In some cases, particularly during the last stage of pregnancy, MRI may produce a better depiction of the brain,
684
PART 17 Infections
Fig. 166.7 Congenital Zika virus syndrome at 32 weeks’ gestation. T2 weighted parasagittal magnetic resonance imaging shows very thin parenchyma without sulci and gyri, ventriculomegaly, and large subarachnoid space as a sign of brain atrophy/destruction.
Fig. 166.8 Severe congenital cytomegalovirus infection at 32 weeks. Note the similarities with the congenital Zika virus syndrome case in Fig. 166.4.
particularly when the fetus is in breach presentation and in cases of severe microcephaly when small or closed fontanels and sutures can be difficult for US wave penetration (Fig. 166.7).
WHAT THE REFERRING PHYSICIAN NEEDS TO KNOW
CLASSIC SIGNS The triad of fetal microcephaly, dense calcifications spread at different brain locations, and ventriculomegaly during a ZIKAV epidemic is highly suggestive of CZVS.
Differential Diagnosis From Imaging Findings In contrary to current understanding,11 we believe that other TORCH (toxoplasmosis, other [congenital syphilis and viruses], rubella, cytomegalovirus, and herpes simplex virus) IUIs, particularly CMV, can produce, in severe cases, brain insults similar and even identical to these produced by congenital zoster virus12 (Fig. 166.8). Two well-documented publications described similar findings apparently unrelated to IUIs.13,14
Primary providers need to be up to par with the ongoing and updated information provided by medical organizations and governmental bodies.15–17 They have to take a detailed medical history of the patients as well as their spouses’ travel history. Early referral for testing and imaging is of paramount importance. In seropositive patients and following clinical disease, pregnant patients should be examined by US every 3–4 weeks until delivery to look for subtle findings of CNS infection. Severely affected cases are usually easier to diagnose.
KEY POINTS • ZIKAV infection may cause serious fetal and neonatal consequences. • Transmission is by mosquito bites, sexual intercourse, blood product transfusion, and vertically from mother to fetus. • Although serologic tests are available for the diagnosis, their specificity and sensitivity are still limited. • CZVS causes infection of the brain, detectable by US and MRI.
SUGGESTED READINGS
Synopsis of Treatment Options PRENATAL No treatment has been reported until now. If available, the option for termination of pregnancy can be offered. POSTNATAL Symptomatic treatment followed by rehabilitation and support for the families of affected children is by now the only therapeutic alternative. In children with mild signs of the disease, antiviral treatments may be considered in experimental clinical trials.
Knowledge of congenital Zika virus infection changes rapidly with new publications on a frequent basis. In lieu of Suggested Readings, we refer the reader to the following websites, which are regularly updated: https://www.cdc.gov/zika/. http://www.ama-assn.org/ama/pub/physician-resources/public-health/zikaresource-center.page. http://www.nejm.org/page/zika-virus. http://www.acog.org/About-ACOG/ACOG-Departments/Zika-Virus. http://www.who.int/emergencies/zika-virus/en/ (also available in Portuguese).
All references available online at www.expertconsult.com
166 Congenital Zika Virus Syndrome
REFERENCES 1. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360:2536-2543. 2. Oliveira Melo AS, Malinger G, Ximenes R, et al. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. 2016;47:6-7. 3. Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951-958. 4. Lessler J, Chaisson LH, Kucirka LM, et al. Assessing the global threat from Zika virus. Science. 2016;353:aaf8160. 5. Kucharski AJ, Funk S, Eggo RM, et al. Transmission dynamics of Zika virus in island populations: a modelling analysis of the 2013–14 French Polynesia outbreak. PLoS Negl Trop Dis. 2016;10:e0004726. 6. Brazil Ministry of Health. http://www.combateaedes.saude.gov.br/images/ sala-de-situacao/informe_microcefalia_epidemiologico40.pdf. 2016. 7. Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016;18:587-590. 8. Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534:267-271. 9. Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report. N Engl J Med. 2016;375: 2321-2334.
684.e1
10. Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, et al. Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology. 2016;161584. 11. Klase ZA, Khakhina S, Schneider Ade B, et al. Zika fetal neuropathogenesis: etiology of a viral syndrome. PLoS Negl Trop Dis. 2016;10:e0004877. 12. Malinger G, Lev D, Lerman-Sagie T. Imaging of fetal cytomegalovirus infection. Fetal Diagn Ther. 2011;29:117-126. 13. Nakamura K, Kato M, Sasaki A, et al. Congenital dysplastic microcephaly and hypoplasia of the brainstem and cerebellum with diffuse intracranial calcification. J Child Neurol. 2012;27:218-221. 14. Abdel-Salam GM, Abdel-Hamid MS, El-Khayat HA, et al. Fetal brain disruption sequence versus fetal brain arrest: a distinct autosomal recessive developmental brain malformation phenotype. Am J Med Genet A. 2015;167A:1089-1099. 15. World Health Organization. Pregnancy management in the context of Zika virus. 2016. http://www.who.int/csr/resources/publications/zika/pregnancymanagement/en/. 16. Papageorghiou AT, Thilaganathan B, Bilardo CM, et al. ISUOG interim guidance on ultrasound for Zika virus infection in pregnancy: information for healthcare professionals. Ultrasound Obstet Gynecol. 2016;47:530-532. 17. Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65:739-744.