The 50 years experience of adrenocorticotropic hormone (ACTH) use in West Syndrome: literatura review and UNIFESP protocol

INTRODUÇÃO: A eficácia do ACTH no tratamento da Síndrome de West (SW) é extensivamente debatida na literatura, o mesmo ocorrendo em relação às doses, efeitos colaterais e protocolos de utilização. OBJETIVO: Revisar, analisar criticamente e discutir os achados das publicações mais recentes e relevantes relacionadas ao uso do ACTH no tratamento da SW. METODOLOGIA: Pesquisou-se as bases de dados MEDLINE e PUBMED, utilizando-se as palavras-chave ACTH e WEST SYNDROME, período de 1997 a 2007. RESULTADOS: Foram obtidos 96 títulos no MEDLINE e 158 no PUBMED, e dentre eles foram selecionados 22 publicações. Outros trabalhos anteriores ao período avaliado mas que apresentavam relevância especial no contexto desta revisão também foram incluídos. CONCLUSÕES: Há evidências de que o ACTH provavelmente apresente eficácia maior no controle imediato dos espasmos e da hipsarritmia. Entretanto, não há evidências concretas desta superioridade no longo prazo (controle de crises a longo prazo e interrrupção ou prevenção de comprometimento do desenvolvimento neuropsicomotor).INTRODUCTION: It is extensively discussed in the literature the efficacy of ACTH in West Syndrome (WS) as well, dosage, best protocols and side effects. OBJECTIVE: Analyze and discuss the most recent and relevant publication related to ACTH in patients with WS. METHODOLOGY: Literature publication was selected from MEDLINE and PUBMED between 1997 to 2007 using the following key words: "ACTH" and " West Syndrome". RESULTS: 96 titles were referral at medline and 158 at pubmed. 22 were selected and previous studies with special relevance were also included. CONCLUSIONS: There are evidences that ACTH probably has efficacy for immediately control of spasms and hypsarrhythmia. There is no evidence about the efficacy of ACTH in long term concerning seizures control and prevent delayed developmental)

Bilateral occipital calcification, epilepsy and coeliac disease: case report

We report a case of a six-year-old girl with frequent diarrhea episodes associated with ferroprive anemia from 6 months of age, normal neuromotor development and partial seizures initiated in her 3rd year which was controlled with carbamazepine. CT scan in her 5th year of age demonstrated gyral calcifications in the occipital and posterior parietal regions bilaterally. MRI has shown low signal areas in the axial T2 sequences corresponding to the gyral calcifications evident on the CT. Blood investigation for coeliac disease with antigliadin, endomysial and transglutaminase antibodies was positive and the intestinal biopsy has showed villous atrophy associated with an increased number of intraepithelial lymphocytes and hypertrophic criptae compatible with coeliac disease.Relatamos o caso de uma menina com 6 anos de idade que apresentava episódios recorrentes de diarréia desde os 6 meses de vida associada a anemia ferropriva com desenvolvimento neuromotor normal. Aos 3 anos de idade começou a apresentar crises parciais que foram controladas com carbamazepina. Tomografia computadorizada de crânio aos 5 anos demonstrou calcificações girais grosseiras nas regiões occipital e parietal posterior bilateralmente. A ressonância magnética de crânio evidenciou áreas de hipossinal em T2 na região parieto-occipital bilateralmente. Realizou investigação para síndrome de mal absorção incluindo estudo da função digestivo/absortiva (teste D-xilose), avaliação sorológica (anticorpos antigliadina, antiendomísio e antitransglutaminase) e biopsia de intestino delgado que demonstrou intensa atrofia de vilosidades com infiltrado linfoplasmocitário no córion compatível com doença celíaca.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Setor de Neurologia InfantilUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de PatologiaUNIFESP, EPM, Setor de Neurologia InfantilUNIFESP, EPM, Depto. de PatologiaSciEL

Characteristics of children of the Microcephaly Epidemic Research Group Pediatric Cohort who developed postnatal microcephaly.

The number of studies published on postnatal microcephaly in children with Congenital Zika Syndrome is small, clinical presentations vary and aspects of the evolution of these children remain unclarified. The present case series examined clinical characteristics and assessed the growth velocity of the head circumference, weight and height Z-scores in 23 children who developed postnatal microcephaly during follow-up in the Microcephaly Epidemic Research Group Pediatric Cohort. To estimate the change in the head circumference, weight and height Z-scores over time and compare the mean difference between sexes, we used multilevel mixed-effects linear regressions with child-specific random effects. Among these children, 60.9% (n = 14/23) presented with craniofacial disproportion, 60.9% (n = 14/23) with strabismus, 47.8% (n = 11/23) with early onset seizures, 47.8% (n = 11/23) with dysphagia and 43.5% (n = 10/23) with arthrogryposis. Of the 82.7% (n = 19/23) children who underwent neuroimaging, 78.9% (n = 15/19) presented with alterations in the central nervous system. Monthly growth velocity, expressed in Z-scores, of the head circumference was - 0.098 (95% CI % - 0.117 to - 0.080), of weight was: - 0.010 (95%-CI - 0.033 to 0.014) and of height was: - 0.023 (95%-CI - 0.046 to 0.0001). Postnatal microcephaly occurred mainly in children who had already presented with signs of severe brain damage at birth; there was variability in weight and height development, with no set pattern

Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco, Brazil.

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common-and clinically important-endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary

Pediatric neurodevelopment by prenatal Zika virus exposure: a cross-sectional study of the Microcephaly Epidemic Research Group Cohort.

BACKGROUND: The implications of congenital Zika Virus (ZIKV) infections for pediatric neurodevelopment and behavior remain inadequately studied. The aim of this study is to investigate patterns of neurodevelopment and behavior in groups of children with differening severities of ZIKV-related microcephaly and children with prenatal ZIKV exposure in the absence of microcephaly. METHODS: We conducted a cross-sectional study, nested in a cohort, of 274 children (aged 10-45 months) who were born during the peak and decline of the microcephaly epidemic in Northeast Brazil. Participants were evaluated between February 2017 and August 2019 at two tertiary care hospitals in Recife, Pernambuco, Brazil. We analyzed the children in four groups assigned based on clinical and laboratory criteria: Group 1 had severe microcephaly; Group 2 had moderate microcephaly; Group 3 had prenatal ZIKVexposure confirmed by maternal RT-PCR testing but no microcephaly; and Group 4 was a neurotypical control group. Groups were evaluated clinically for neurological abnormalities and compared using the Survey of Wellbeing of Young Children (SWYC), a neurodevelopment and behavior screening instrument validated for use in Brazil. Children with severe delays underwent further evaluation with an adapted version of the SWYC. RESULTS: Based on the SWYC screening, we observed differences between the groups for developmental milestones but not behavior. Among the 114 children with severe microcephaly of whom 98.2% presented with neurological abnormalities, 99.1% were 'at risk of development delay' according to the SWYC instrument. Among the 20 children with moderate microcephaly of whom 60% presented with neurological abnormalities, 65% were 'at risk of development delay'. For children without microcephaly, the percentages found to be 'at risk of developmental delay' were markedly lower and did not differ by prenatal ZIKV exposure status: Group 3 (N = 94), 13.8%; Group 4 (N = 46), 21.7%. CONCLUSIONS: Among children with prenatal ZIKV exposure, we found a gradient of risk of development delay according to head circumference. Children with severe microcephaly were at highest risk for delays, while normocephalic ZIKV-exposed children had similar risks to unexposed control children. We propose that ZIKV-exposed children should undergo first-line screening for neurodevelopment and behavior using the SWYC instrument. Early assessment and follow-up will enable at-risk children to be referred to a more comprehensive developmental evaluation and to multidisciplinary care management

The Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC): A Cohort Profile.

This cohort profile aims to describe the ongoing follow-up of children in the Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC). The profile details the context and aims of the study, study population, methodology including assessments, and key results and publications to date. The children that make up MERG-PC were born in Recife or within 120 km of the city, in Pernambuco/Brazil, the epicentre of the microcephaly epidemic. MERG-PC includes children from four groups recruited at different stages of the ZIKV microcephaly epidemic in Pernambuco, i.e., the Outpatient Group (OG/n = 195), the Microcephaly Case-Control Study (MCCS/n = 80), the MERG Pregnant Women Cohort (MERG-PWC/n = 336), and the Control Group (CG/n = 100). We developed a comprehensive array of clinical, laboratory, and imaging assessments that were undertaken by a 'task force' of clinical specialists in a single day at 3, 6, 12, 18 months of age, and annually from 24 months. Children from MCCS and CG had their baseline assessment at birth and children from the other groups, at the first evaluation by the task force. The baseline cohort includes 711 children born between February 2015 and February 2019. Children's characteristics at baseline, excluding CG, were as follows: 32.6% (184/565) had microcephaly, 47% (263/559) had at least one physical abnormality, 29.5% (160/543) had at least one neurological abnormality, and 46.2% (257/556) had at least one ophthalmological abnormality. This ongoing cohort has contributed to the understanding of the congenital Zika syndrome (CZS) spectrum. The cohort has provided descriptions of paediatric neurodevelopment and early epilepsy, including EEG patterns and treatment response, and information on the frequency and characteristics of oropharyngeal dysphagia; cryptorchidism and its surgical findings; endocrine dysfunction; and adenoid hypertrophy in children with Zika-related microcephaly. The study protocols and questionnaires were shared across Brazilian states to enable harmonization across the different studies investigating microcephaly and CZS, providing the opportunity for the Zika Brazilian Cohorts Consortium to be formed, uniting all the ZIKV clinical cohorts in Brazil

Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

The relation of Zika virus (ZIKV) with microcephaly is well established. However, knowledge is lacking on later developmental outcomes in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly. The objective of this analysis is to investigate the impact of prenatal exposure to ZIKV on neuropsychomotor development in children without microcephaly. We evaluated 274 children including 235 ZIKV exposed and 39 controls using the Bayley-III Scales of Infant and Toddler Development (BSIDIII) and neurological examination. We observed a difference in cognition with a borderline p-value (p = 0.052): 9.4% of exposed children and none of the unexposed control group had mild to moderate delays. The prevalence of delays in the language and motor domains did not differ significantly between ZIKV-exposed and unexposed children (language: 12.3% versus 12.8%; motor: 4.7% versus 2.6%). Notably, neurological examination results were predictive of neurodevelopmental delays in the BSIDIII assessments for exposed children: 46.7% of children with abnormalities on clinical neurological examination presented with delay in contrast to 17.8% among exposed children without apparent neurological abnormalities (p = 0.001). Overall, our findings suggest that relative to their unexposed peers, ZIKV-exposed children without microcephaly are not at considerably increased risk of neurodevelopmental impairment in the first 42 months of life, although a small group of children demonstrated higher frequencies of cognitive delay. It is important to highlight that in the group of exposed children, an abnormal neuroclinical examination may be a predictor of developmental delay. The article contributes to practical guidance and advances our knowledge about congenital Zika