André Pessoa

Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians

Importance Zika virus infection can be prenatally passed from a pregnant woman to her fetus. There is sufficient evidence to conclude that intrauterine Zika virus infection is a cause of microcephaly and serious brain anomalies, but the full spectrum of anomalies has not been delineated. To inform pediatric clinicians who may be called on to evaluate and treat affected infants and children, we review the most recent evidence to better characterize congenital Zika syndrome. Observations We reviewed published reports of congenital anomalies occurring in fetuses or infants with presumed or laboratory-confirmed intrauterine Zika virus infection. We conducted a comprehensive search of the English literature using Medline and EMBASE for Zika from inception through September 30, 2016. Congenital anomalies were considered in the context of the presumed pathogenetic mechanism related to the neurotropic properties of the virus. We conclude that congenital Zika syndrome is a recognizable pattern of structural anomalies and functional disabilities secondary to central and, perhaps, peripheral nervous system damage. Although many of the components of this syndrome, such as cognitive, sensory, and motor disabilities, are shared by other congenital infections, there are 5 features that are rarely seen with other congenital infections or are unique to congenital Zika virus infection: (1) severe microcephaly with partially collapsed skull; (2) thin cerebral cortices with subcortical calcifications; (3) macular scarring and focal pigmentary retinal mottling; (4) congenital contractures; and (5) marked early hypertonia and symptoms of extrapyramidal involvement. Conclusions and Relevance Although the full spectrum of adverse reproductive outcomes caused by Zika virus infection is not yet determined, a distinctive phenotype—the congenital Zika syndrome—has emerged. Recognition of this phenotype by clinicians for infants and children can help ensure appropriate etiologic evaluation and comprehensive clinical investigation to define the range of anomalies in an affected infant as well as determine essential follow-up and ongoing care.

Microcephaly in Brazil: how to interpret reported numbers?

Brazil is facing its first outbreak of Zika virus, particularly in the northeast region. Most cases of Zika virus infection are self-limited and without sequelae, but there have been clusters of cases of microcephaly in some areas of known Zika virus transmission. Although strongly suspected, the causal relation between in-utero exposure to Zika and microcephaly is yet to be established. The increased number of microcephaly cases in Brazil has led to a high level of concern among pregnant women throughout the country. On Feb 1, 2016, WHO’s International Health Regulations Emergency Committee advised that the clusters of microcephaly and other neurological disorders and their possible association with Zika virus constitutes a Public Health Emergency of International Concern. Measurement of newborn head circumference is useful as a screening tool for detecting microcephaly, independently of its cause. Before 2015, the annual numbers of reported cases of microcephaly in Brazil were consistently below 200. Between mid-2015 and Jan 30, 2016, 4783 suspected cases of microcephaly were reported, including newborn and fetal losses. Of these, 1103 cases have completed clinical, laboratory, and imaging examinations, and 404 (36·2%) were classified as confirmed cases of microcephaly. Among the confirmed cases, brain abnormalities were detected by imaging in 387 babies and Zika virus was detected in 17 babies, including in two fetal losses. The remaining 709 cases were discarded and 3670 suspected cases of microcephaly remain under investigation. Although 36·2% seems to be a high rate of true positives, it has to be interpreted with caution because in the present situation newborn babies with visible cranial deformities are likely to be fast-tracked for in-depth examination. This temporal increase in suspected cases of microcephaly could also be distorted given both raised awareness, with more children than usual being measured and reported, and changing definitions of microcephaly over time. The possibility of over-reporting and misdiagnosis was recently raised by the Latin American Network of Congenital Malformations, and their report led to speculation in the international scientific press on the magnitude of the increase in microcephaly cases. To help interpret these numbers, it is instructive to assess how head circumference criteria for defining suspected cases of microcephaly have evolved (table). Before Dec 8, 2015, Brazil’s Ministry of Health recommended a cutoff for head circumference of less than or equal to 33 cm for term newborn babies (both sexes and all gestational ages); for preterm babies, the cutoff was the 3rd centile of the Fenton curves of head circumference by gestational age and sex. On Dec 8, 2015, the Ministry of Health in Brazil revised the case definition for suspected microcephaly in newborn babies and reduced the head circumference criterion in term newborn babies to less than or equal to 32 cm. On Jan 21, 2016, the Pan American Health Organization

The phenotypic spectrum of congenital Zika syndrome

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM‐ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM‐ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

Hydrocephalus associated to congenital Zika syndrome: does shunting improve clinical features?

PurposeCongenital Zika syndrome (CZS) is a new entity with little information about its course and natural history. It is known that prenatal infection by Zika virus is associated to disrupted nervous system development, leading to typical neurological disabilities and deformities. Some children present progressive ventriculomegaly and hydrocephalus associated to aggravation of seizures and neurological impairment. The aim of this study is to evaluate the development of hydrocephalus and the impact of ventriculoperitoneal shunt insertion in the clinical condition of these children.MethodsData was obtained from chart review, direct interviews with patients’ parents, direct neurological examination, and analysis of pre- and postoperative neuroimages.ResultsA group of 115 patients had CZS diagnosis from November 2015 to July 2017. Among them, 21 (18.3%) patients had ventricular enlargement noted on follow-up CT scans. Six children (28.6%) underwent a ventriculoperitoneal shunt and all had some improvement after surgery concerning either waking time during the day and better interaction. Overall improvement was also noted in seizures. Spasticity decrease and more cervical control were also achieved. In two out of six cases, a slight increase in parenchymal length could be noted on the CT scans.ConclusionThis series points out the possibility of hypertensive hydrocephalus development in CZS patients. Affected children may benefit from VP shunt insertion. These findings suggest a dual pathology association: fetal brain disruption and primary cortical malformation by the virus itself and hypertensive hydrocephalus. This is already seen in some cases of congenital rubella, toxoplasmosis, or cytomegalovirus-associated hydrocephalus.

Sleep findings in Brazilian children with congenital Zika syndrome

Study Objectives Zika virus infection during pregnancy may result in congenital Zika syndrome (CZS), whose characteristics are being described. Methods The present study aimed to investigate the sleep characteristics of 136 infants/toddlers (88 with CZS and 48 with typical development (TD), age and gender matched, 60% girls and 40% boys in both groups) using the Brief Infant Sleep Questionnaire. The ages of children in both groups ranged from 5 to 24 months (CZS 15.9 ± 0.4 vs. TD 15.8 ± 1.0 months, P= 0.90). Results The results show that 34.1% of CZS and 2% of TD children were defined as poor sleepers, 15% of CZS and 2% of TD children remained awake at night for a period longer than 1 hour, and 24% of CZS and 2% of TD children slept less than 9 hours. The CZS group showed shorter total sleep time (CZS 11.24 ± 2.6 vs. TD 12.02 ± 1.9 hours, P= 0.03) and shorter nocturnal sleep duration than the TD group (CZS 8.2 ± 0.2 vs. TD 9.4 ± 0.2 hours, P= 0.0002). In contrast to the control group (P= 0.02, r= -0.34), in the CZS group, no correlation was found between age and nocturnal wakefulness. Future studies should explore these data in relation to the development and maturation of the central nervous system of these children. Conclusions Considering the well-known consequences of poor sleep quality on health in several populations, the presence of sleep disorders should be considered in CZS using multidisciplinary treatments.

Lingual Frenulum Phenotypes in Brazilian Infants With Congenital Zika Syndrome

Objective: The present study aimed to evaluate lingual frenulum in children affected by congenital Zika syndrome (CZS) and to analyze the association of lingual frenulum phenotypes with other variables. Design: This present work had a cross-sectional, descriptive study design. Setting: This study was carried out in Fortaleza (Brazil). The health professionals provided tertiary level of care. Data collection occurred during a multidisciplinary task force for evaluating infants affected by CZS in December 2 to 3, 2016. Patients: Fifty-four patients with CZS (1-12 months old; 32 girls and 22 boys) were recruited from a population of 70 infants. Interventions: A multidisciplinary group comprised of speech-language pathologist/audiologists and pediatric dentists evaluated all patients through an intraoral examination and a specific tongue maneuver protocol for infants. Main Outcome Measures: Lingual frenulum visibility was the primary outcome measure. Before initiating the study, we hypothesized that children with CZS had an absent lingual frenulum. Results: Lingual frenula were visible in 34 (63%) infants, whereas in 20 (37%) infants lingual frenula visibility required a specific maneuver to retract the tongue. Six of 20 infants presented posteriorly positioned lingual frenula that were visible after maneuver. Lingual frenula were covered by mucous tissue in 14 infants. Presence of posterior frenulum was associated with dysphagia (P = 0.038). However, the presence of dysphagia in a multivariate model did not associate with the presence of a posterior lingual frenulum (P = .069) or neurologic symptoms (P = .056). Conclusion: Children with CZS showed predominance of a posterior lingual frenula covered by an overlapping curtain-like mucous membrane.

Reply to the letter by Joob and Wiwanitkit regarding our article on congenital Zika syndrome and hydrocephalus

Dear Editor: We read with interest the comments made by Joob and Wiwanitkit [1] to our paper BHydrocephalus associated to congenital Zika syndrome: does shunting improve clinical features?^ [2] and we thank these authors for the careful reading of our article. However, the claim that Zika virus has been circulating in some areas of the world for years without any severe consequence beyond a mild febrile disease is being surmounted by molecular and experimental studies showing that the viral strain linked to congenital Zika syndrome (CZS) is mutated compared to the previously known strains and that it does provoke microcephaly in experimental models [3, 4]. In Brazil, CZS outbreak provoked an important public health challenge, with 2653 confirmed cases of microcephaly associated to prenatal Zika virus infection, according to the health ministry. Although the cases were detected predominantly in 2015 and 2016, with a pronounced decrease in the last months, a great cohort of affected children keeps needing the attention of health personnel like pediatric neurologists, pediatricians, physical therapists, and speech therapists due to severe neurological impairment [2, 5]. Regarding hydrocephalus, it is understandable that the topic elicits some discussion, provided that our article was the first to focus this complication in the context of CZS. Children selected for ventriculoperitoneal shunting in our service, as discussed in the original article, filled the criteria of progressive ventricular enlargement associated to clinical aggravation of seizures and neurological development status. Clinical amelioration after shunting reinforced the idea of a contribution of hydrocephalus in the pathological process. It has also happened in other pediatric neurosurgery centers in Brazil, with data still waiting for publication. In fact, hydrocephalus is a rare complication of some other prenatal infectious diseases like toxoplasmosis and cytomegalovirus, as well known by pediatricians and pediatric neurosurgeons [2, 6].Moreover, Chimelli et al. demonstrated several pathological features in CZS affected children that can explain hydrocephalus development from a structural point of view [7]. The link between prenatal Zika virus infection, mainly in the first trimester of pregnancy, and the development of a characteristic syndrome with remarkable neuroradiological and neurodevelopmental aspects, has also been demonstrated in many articles from different research groups and institutions in epidemiological, clinical, pathological, and molecular basis [3–5, 7–9]. Supported by all these evidences, the World Health Organization (WHO) has launched several statements and recommendations, considering the problem a Public Health Emergency of International Concern in 2016.

Epilepsy Profile in Infants with Congenital Zika Virus Infection

Seizures in Congenital Zika Virus Infection In this letter, aspects of epilepsy associated with congenital Zika virus infection are described.

Answer – Abortion and Zika Virus Congenital Infection

We would like to thank for the comments of the letter to the editor about our article “Abortion in Cases of Zika Virus Congenital Infection.”1 Intrauterine consequences have becomea focus of concernwhen it comes to Zikavirus infection.2 As for the first statement: “There is still no evidence that Zika virus infection in pregnantwomen is the cause of abortion,” in fact, there are records in the scientific literature that strongly suggest this associationand report intrauterine fetal death and spontaneousabortion,3,4bothprecocious4and late,2 causedby the Zika virus and confirmed by serological tests on the fetus and the placenta. We agree with our colleagues about the statement that not all cases ofmaternal infection by the Zika virus have as a result a fetuswithmicrocephaly. Thiswas initially demonstratedbya series of cases of babies bornwith normal cephalic perimeter, despite the confirmationof infection of themother.5 In viewof thesefindings, there is no doubt that thematernal infection by the Zika virus is not a reliable evidence of fetal infection. However, in our article,1 we present data that indicate that pregnant women throughout theworld, due to the psychological distress and the epidemiology of fetal infection, may be deciding whether to undergo an induced abortion after being infected by the Zika virus Thus, we reinforce the statement that: “Early diagnosismay be useful for some purposes such as epidemiological monitoring, but should not be the presumptive data for the decision on abortion for the pregnant woman infected with zika virus.” We believe that an early diagnosis provides the woman with a better understanding of the fetal situation, which empowers and enables her to decide what would be the best for her and the fetus, according to the law of each country.