Long-term developmental outcomes of children with congenital Zika syndrome.

BACKGROUND: Eight years after the epidemics in Brazil, children with congenital Zika syndrome (CZS) and their families confront ongoing health challenges. OBJECTIVE: This study aims to characterize how virally induced prenatal brain injury impacts development and functional outcomes among children diagnosed with CZS. METHODS: We performed a cross-sectional study of a consecutive series of children diagnosed with CZS. Using validated neurodevelopmental assessments, we evaluated gross motor function, manual ability, communication, eating and drinking, and visual function. RESULTS: Sixty children (29 males, and 31 females) met the inclusion criteria for the study. Comorbidities such as epilepsy (90.0%) and undernutrition (38.3%), along with clinical conditions including dysphagia (68.3%) and dependence on tube feeding (31.7%), were observed. Our results demonstrate a majority of children at level V - the most severe level within a five-tier system - in the Gross Motor Function (86.7%), Manual Ability (85.0%), Communication Function (68.3%), Eating and Drinking Ability (40.0%) Classification Systems, and level IV in the Visual Function Classification System (38.3%). CONCLUSION: CZS is associated with severe functional impairments and comorbidities, adversely impacting child development and quality of life. These findings reveal persistent challenges affecting the functioning of children with CZS, underscoring the need for continued support and specialized care. IMPACT: This study aimed to characterize the long-term clinical and functional characteristics of a subset of children with Congenital Zika Syndrome (CZS). We found that eight years after the Brazilian Zika epidemic, this subset of children with CZS continues to demonstrate major functional limitations impacting mobility, vision, and the ability to eat and drink. Our analysis documented a very high level of disability in several key functional classification systems. Notably, applying a new instrument for visual ability among children diagnosed with cerebral palsy, we found that more than 60% of the study group have poor or very poor visual function.

Building a growing genomic data repository for maternal and fetal health through the PING Consortium.

Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Discordant outcomes among dizygotic twins could be explained by genetic susceptibly or protection. Among several well-recognized threats to the developing brain, Zika is a mosquito-borne, positive-stranded RNA virus that was originally isolated in Uganda and spread to cause epidemics in Africa, Asia, and the Americas. In the Americas, the virus caused congenital Zika syndrome and a multitude of neurodevelopmental disorders. As of now, there is no preventative treatment or cure for the adverse outcomes caused by prenatal Zika infection. The Prenatal Infection and Neurodevelopmental Genetics (PING) Consortium was initiated in 2016 to identify factors modulating prenatal brain injury and postnatal neurodevelopmental outcomes for Zika and other prenatal viral infections. Methods: The Consortium has pooled information from eight multi-site studies conducted at 23 research centers in six countries to build a growing clinical and genomic data repository. This repository is being mined to search for modifiers of virally induced brain injury and developmental outcomes. Multilateral partnerships include commitments with Children's National Hospital (USA), Instituto Nacional de Salud (Colombia), the Natural History of Zika Virus Infection in Gestation program (Brazil), and Zika Instituto Fernandes Figueira (Brazil), in addition to the Centers for Disease Control and Prevention and the National Institutes of Health. Discussion: Our goal in bringing together these sets of patient data was to test the hypothesis that personal and populational genetic differences affect the severity of brain injury after a prenatal viral infection and modify neurodevelopmental outcomes. We have enrolled 4,102 mothers and 3,877 infants with 3,063 biological samples and clinical data covering over 80 phenotypic fields and 5,000 variables. There were several notable challenges in bringing together cohorts enrolled in different studies, including variability in the timepoints evaluated and the collected clinical data and biospecimens. Thus far, we have performed whole exome sequencing on 1,226 participants. Here, we present the Consortium's formation and the overarching study design. We began our investigation with prenatal Zika infection with the goal of applying this knowledge to other prenatal infections and exposures that can affect brain development.

The Value of Adding Scribe Services to 2 Distinct Pediatric Subspecialties in the Era of the Electronic Medical Record.

To evaluate the impact of adding medical scribes to 2 distinct outpatient pediatric subspecialty clinics on provider burnout, visit length, and patient satisfaction. A total of 2 pediatric endocrinologists and 2 developmental-behavioral pediatrics/pediatrician (DBP) were randomly assigned based on days of the week to see patients aged 0 to 21 years in their clinics with and without in-person medical scribes from February 2019 to February 2020. Parent satisfaction rates were examined through pre- and postappointment surveys. Provider burnout rates were assessed through the Maslach Burnout Inventory-Human Services Survey. A retrospective comparative analysis of average appointment duration was undertaken considering the scribe/no scribe random allocation in the examination room. Funding for this pilot provided by the department of pediatrics budgeted funds. Over 2923 appointments during the project dates, 829 appointments were seen with a scribe. The average appointment time for a new DBP appointment was 61 minutes with scribes and 71 minutes without (P < .001). Return patient appointments in DBP averaged 31 minutes with scribes and 43 minutes without (P < .001). There was no significant difference in appointment duration for endocrinology with and without scribes. The average time for chart completion was reduced with the presence of scribes in DBP but not in endocrinology. Out of the 209 families surveyed, patient satisfaction rates with and without a scribe did not differ in that between 96% and 97% of respondents rated the appointment overall as "excellent" for each measure of provider communication with scribes present. Finally, from the Maslach Burnout Inventory-Human Services Survey, the average score across all 4 providers for Emotional Exhaustion and Depersonalization decreased during the project period, whereas Personal Accomplishment scores increased over the project period. Scribes might be more advantageous for some subspecialties that utilize prolonged narratives in clinic notes, like DBP, and an important avenue to consider in reducing provider burnout in busy ambulatory settings.

Neurodevelopmental outcomes in a cohort of children with congenital Zika syndrome at 12 and 24 months of age.

BACKGROUND: Early child development is a critical stage of life that influences social, educational and health outcomes worldwide. A few years after Zika epidemic, families of children born with congenital Zika syndrome (CZS) continue to face uncertainties when it comes to the development of their children. The present study sought to analyse the developmental trajectories of a subset of children born with CZS in the first 24 months of life. METHODS: Thirty-five children with CZS were assessed with the Bayley-III Scales at 12 and 24 months of age from November 2016 to December 2018 in a rehabilitation centre in Brazil. Inclusion criteria included children with established diagnosis of CZS. Exclusion criteria included the presence of arthrogryposis, prematurity, irregular follow-up, clinical complications or other causes of microcephaly. Children born with CZS who evolved with cerebral palsy (CP) were classified according to the Gross Motor Function Classification System (GMFCS) at 2 years of age. RESULTS: At 12 months of age mean composite scores on the Bayley cognitive, communication and motor scores were 57.71 (SD 7.11), 57.94 (SD 14.34) and 49.26 (7.20), respectively. At 24 months of age, composite scores were 57.43 (SD 7.11), 53.60 (SD 12.29) and 48.83 (7.76). In addition, 31 (88.57%) out of 34 children diagnosed with CP were classified as GMFCS levels IV and V. CONCLUSION: Zika virus congenital infection is a risk factor for functional impairments across all developmental domains having a direct and substantial negative impact in early child development.

Potential risk of brain damage and poor developmental outcomes in children prenatally exposed to sars-cov-2: a systematic review / Risco potencial de danos cerebrais e de alterações de desenvolvimento em crianças expostas ao sars-cov-2 no período pré-natal: uma revisão sistemática

ABSTRACT Objective: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. Data sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. Data synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. Conclusions: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

RESUMO Objetivo: Realizar uma revisão sistemática da literatura para analisar os dados existentes sobre os efeitos neurológicos do coronavírus em recém-nascidos. Fontes de dados: Esta revisão seguiu as diretrizes dos Principais Itens para Relatar Revisões Sistemáticas e Meta-Análises (Preferred Reported Items for Systematic Review - PRISMA) e dos Protocolos dos Principais Itens para Relatar Revisões Sistemáticas e Meta-Análises (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols - PRISMA-P), pesquisando as plataformas PubMed e Embase pelas palavras-chave [brain damage (dano cerebral) OU pregnancy (gravidez) OU developmental outcomes (alterações de desenvolvimento)] e [coronavirus (coronavírus) OU SARS-CoV-2 OU SARS-CoV OU MERS-CoV] entre 1º de janeiro de 2000 e 1º de junho de 2020. Síntese dos dados: Vinte e três relatos descreveram a evolução de mulheres grávidas expostas ao SARS-CoV-2, SARS-CoV ou MERS-CoV durante o período gestacional, oito ao SARS-CoV-2, oito ao SARS-CoV e sete ao MERS-CoV. Não foram encontrados dados sobre anormalidades no desenvolvimento cerebral ou sobre uma ligação direta entre o vírus e alterações neurológicas no embrião, feto ou crianças. Abortamento espontâneo, morte fetal e interrupção da gravidez foram algumas das complicações relacionadas à infecção por SARS/MERS-CoV. Até o momento, o SARS-CoV-2 não está associado a complicações no período gestacional. Conclusões: Não há dados na literatura que associem a exposição ao coronavírus durante a gravidez com malformações cerebrais e distúrbios do neurodesenvolvimento. No entanto, apesar da falta de relatos, o monitoramento do desenvolvimento de crianças expostas ao SARS-CoV-2 é essencial devido ao risco de complicações em gestantes e às potenciais propriedades neuroinvasivas e neurotrópicas encontradas em cepas anteriores.

POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW.

OBJECTIVE: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. DATA: sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. DATA: synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. CONCLUSIONS: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

Children Born With Congenital Zika Syndrome Display Atypical Gross Motor Development and a Higher Risk for Cerebral Palsy.

IMPORTANCE: Congenital Zika syndrome virus infection is said to interfere in children's development. OBJECTIVE: evaluate gross motor trajectories and the frequency of cerebral palsy in children with congenital Zika syndrome. DESIGN: Cohort study applying the Alberta Infant Motor Scale (AIMS) and the Bayley III Scales in infants from 6 to 18 months of age. SETTING: The SARAH network, Rio de Janeiro. PARTICIPANTS: Thirty-nine infants whose diagnoses were established through clinical history, serology tests, and neuroimaging findings. Main outcomes and measures: Congenital Zika syndrome is associated with severe motor delays and is a risk factor to the diagnosis of cerebral palsy. RESULTS: The Alberta Infant Motor Scale mean raw score at 6 months was 9.74 (SD 4.80) or equivalent to 2 to 3 months of motor developmental age. At the age of 12 months, 14.13 (SD 11.90), corresponding to 3 to 4 months of motor development age; the Bayley III Scales results correlated to the Alberta Infant Motor Scale ( P < .001) at this age. At 18 months, 15.77 (SD 13.80) or a motor development equivalent to 4 to 5 months of age. Thirty-five of 39 children (89.7%) met criteria for the diagnosis of cerebral palsy. Conclusions and relevance: Gross motor development marginally progresses from 6 to 18 months of age. These individuals also displayed a high frequency of cerebral palsy.

Microcephaly and arthrogryposis multiplex congenita: The full-blown CNS spectrum in newborns with ZIKV infection.

The recent alarming statements concerning the newborn ZIKV-induced microcephaly epidemics in the Northeast of Brazil, released by the Brazilian Ministry of Health, as well as important international health agencies, such as the World Health Organization and the Pan American Health Organization, raised many "why and how" questions so far, that will hopefully be scientifically answered, as more researches in that regard come up in the long term. In this paper, we describe another potentially ZIKV-induced central nervous system and musculoskeletal disorder that has accompanied microcephaly in these children: atrhogryposis multiplex congenita. The goal is to bring up some hypotheses for possible underlying molecular mechanisms based on published data taken from animal models, such as ovine and cattle, which once infected by other types of arboviroses and viruses that also belong to the Flaviviridae family, presented, too, with the full-blown CNS spectrum of malformations at birth.

12p deletion spectrum syndrome: a new case report reinforces the evidence regarding the potential relationship to autism spectrum disorder and related developmental impairments.

BACKGROUND: Autism Spectrum Disorders (ASD) now encompass a broad heterogeneous group of people who present in the early developmental years with a wide range of social and communication deficits, which are typically also associated with complex repetitive behaviors and circumscribed interests. The target goal is to heighten readers' perception into the trend to personalize the distinct autistic and related developmental conditions encompassing the 12p region. CASE PRESENTATION: This is a case-report of a 4-year-old male who presented the core signs of ASD, which were thought to be related to a rare 12p13.2 deletion.  We further reviewed the literature in order to outline the related developmental conditions in the 12p region. Aside from this patient reported here, we found an additional number of 43 cases described in the medical literature since 1974, that have been related to deletions in the 12p region. However, to the best of our knowledge, none of the previous had been specifically linked to the 12p13.2 band. CONCLUSIONS: The 12p deletion spectrum is rarely described as part of the selective genotypes thought to be related to ASD. Even inside of a small piece of the puzzle, there might be ample variation in the behavioral and clinical phenotypes of children and adults presenting with this particular genetic profile. In that regard, the particular 12p13.2 distal deletion presentation is one of the possible genotypes encompassed by the "12p deletion spectrum syndrome", that might be potentially connected to the diagnosis of ASD and related developmental disorders.

Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome.

BACKGROUND: Global developmental delay, lack of speech, and severe epilepsy are the characteristic hallmarks of Angelman syndrome (AS). The purpose of this study was to explore the utility of brain magnetic resonance imaging (MRI) as an ancillary tool for the diagnosis of AS. MATERIAL AND METHODS: Brain MRI images of nine laboratory-confirmed patients with AS from a neurorehabilitation center in Rio de Janeiro were reviewed. Each MRI was assessed by a set of two experienced neuroradiologists following a predefined protocol. RESULTS: The main neuroimaging findings revealed in our study were: Thinning of the corpus callosum in five patients; enlargement of lateral ventricles in four patients; and, cerebral atrophy with frontal and temporal predominance in one patient. All patients presented with an increased signal intensity in T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences. CONCLUSION: The lack of specific changes in the brain MRI of children with AS observed in this case series rendered brain MRI a less helpful complementary test. Thus, a definitive diagnosis of AS could only be established on molecular biology that was undertaken based on the clinical suspicion of AS.

Revisiting epilepsy and the electroencephalogram patterns in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder that severely affects global neurodevelopment due to modifications in the structure or functioning of UBE3A gene. Its prevalence ranges from 1:10,000 to 1:40,000. There are four main genetic types of AS transmission. A maternal deletion in 15q11.2-q13 is the most common type. There are three well-established electroencephalogram (EEG) patterns used as an ancillary tool for AS diagnosis. The main objectives are to scrutinize the EEG patterns in Angelman syndrome, their correlation to different types of seizures and to review the role of the EEG as an ancillary screening tool in the diagnosis of clinically suspected patients. Forty-three patients' charts and their previously recorded EEGs were reviewed. A set of 34 patients with deletion type, paternal uniparental disomy type and imprint defect type AS were enrolled. AS diagnosis was confirmed either by fluorescent in situ hybridization test or Methylation Specific-Multiplex Ligation Probe Amplification test. Sequencing of UBE3A was not available. Frequencies and Chi-square tests were used for statistic analysis. Pattern I type EEG was observed in 22 (64.7 %) individuals. Pattern II accounted for 6 (17.6 %); Pattern III was evident in 11 (32.4 %). The three distinguished EEG patterns, more frequently Pattern I, when observed in the appropriate clinical setting, may heighten the index of suspicion for selecting patients who will need a molecular biology test to confirm the diagnosis of AS.

Classic manifestations of Duchenne dystrophy in a young female patient: a case report.

Duchenne and Becker muscular dystrophies (DMD/DMB) are neuromuscular diseases linked to chromosome X and affect mainly male individuals. Duchenne muscular dystrophy is the most severe form of the disease, leading to a decreased patient survival compared with individuals with Becker type and female carriers of the mutated gene. In this paper we present the case of a female adolescent whose clinical picture and disease course closely resembled male individuals.

[Possible etiologies of West syndrome: evaluation of 95 patients]. / Possíveis etiologias da Síndrome de West: avaliação de 95 pacientes.

OBJECTIVE: To describe the etiologies of West syndrome (WS) among children followed in a rehabilitation center. METHOD: Retrospective study with emphasis in the following items: gender, age at the diagnosis of WS and its etiology. The etiologies were divided into three categories: symptomatic, cryptogenic and idiopathic. Symptomatic cases were classified as follows: pre, post and perinatal. RESULTS: Ninety-five patients were included. Fifty-nine were boys (62%). Mean age at the diagnosis was 4.9 (+/- 5.0) months. There were 25 cryptogenic (26.3%), one idiopathic (1.1%) and 69 (72.6%) symptomatic cases, most of them of perinatal origin. CONCLUSION: Our findings are in agreement with the literature. In the future, as our knowledge in the field of WS and its diagnostic methods increase, there will be a small number of cryptogenic and idiopathic cases.

Possíveis etiologias da Síndrome de West: avaliação de 95 pacientes / Possible etiologies of West syndrome: evaluation of 95 patients

OBJETIVO: Descrever as etiologias da síndrome de West (SW) em um grupo de crianças atendidas no ambiente de um centro de reabilitação. MÉTODO: Análise retrospectiva, avaliando-se os seguintes itens: gênero, idade por ocasião da definição do diagnóstico da SW e sua etiologia. Esta foi dividida em três categorias: sintomática, criptogênica e idiopática. Os casos sintomáticos foram divididos em pré, peri e pós-natais. RESULTADOS: Noventa e cinco pacientes foram incluídos, sendo 59 do gênero masculino (62 por cento). A idade do diagnóstico variou entre 1 e 24 meses, com média de 4,9 (±5,0) meses. Vinte e cinco casos foram considerados criptogênicos (26,3 por cento) e apenas um idiopático (1,1 por cento). Os demais foram classificados com sintomáticos (72,6 por cento), sendo predominantemente casos perinatais. CONCLUSÃO: Nossos achados se assemelham aos da literatura. Conforme se ampliam o conhecimento acerca da SW e os métodos complementares de diagnóstico, haverá tendência à diminuição dos casos hoje considerados criptogênicos ou idiopáticos.

OBJECTIVE: To describe the etiologies of West syndrome (WS) among children followed in a rehabilitation center. METHOD: Retrospective study with emphasis in the following items: gender, age at the diagnosis of WS and its etiology. The etiologies were divided into three categories: symptomatic, cryptogenic and idiopathic. Symptomatic cases were classified as follows: pre, post and perinatal. RESULTS: Ninety-five patients were included. Fifty-nine were boys (62 percent). Mean age at the diagnosis was 4.9 (±5.0) months. There were 25 cryptogenic (26.3 percent), one idiopathic (1.1 percent) and 69 (72.6 percent) symptomatic cases, most of them of perinatal origin. CONCLUSION: Our findings are in agreement with the literature. In the future, as our knowledge in the field of WS and its diagnostic methods increase, there will be a small number of cryptogenic and idiopathic cases.