RESUMO
AIM: To assess outcome after neonatal perforator stroke in the largest cohort to date. METHOD: Survivors from a cohort of children diagnosed with neonatal perforator stroke using cranial ultrasound or magnetic resonance imaging were eligible for inclusion. Recovery and Recurrence Questionnaire score, presence of cerebral palsy (CP), and crude outcome were assessed, specifically (1) the ability to walk independently, (2) participation in regular education, and (3) the presence of epilepsy. RESULTS: Thirty-seven patients (20 males, 17 females) aged 3 to 14 years (mean age 8y) were included in the study: 14 with isolated single perforator stroke, four with multiple isolated perforator strokes, and 19 with additional brain injury. Out of 18 children with isolated perforator stroke(s), four had CP, one could not walk independently, and one developed epilepsy. The posterior limb of the internal capsule was involved in four out of 18 patients; three of these patients had CP. Of 19 children with additional brain injury, 11 had CP and three were not able to walk independently. Three out of nine children with concomitant cortical middle cerebral artery stroke developed epilepsy. INTERPRETATION: Perforator stroke patterns can be of use in predicting long-term outcome and for guiding counselling and surveillance. Motor outcome was favourable in children with isolated perforator stroke(s), except when the posterior limb of the internal capsule was involved.
Assuntos
Paralisia Cerebral/etiologia , Epilepsia/etiologia , Doenças do Recém-Nascido , Limitação da Mobilidade , Avaliação de Resultados em Cuidados de Saúde , Acidente Vascular Cerebral/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Recém-Nascido , Infarto da Artéria Cerebral Média/complicações , MasculinoRESUMO
Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.
Assuntos
Colágeno Tipo IV/genética , Estudos de Associação Genética , Mutação , Fenótipo , Alelos , Segmento Anterior do Olho/anormalidades , Encéfalo/patologia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/genética , Estudos de Coortes , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Oftalmopatias Hereditárias , Família , Ordem dos Genes , Loci Gênicos , Genótipo , Humanos , Leucomalácia Periventricular/diagnóstico , Leucomalácia Periventricular/genética , Imageamento por Ressonância Magnética/métodos , Linhagem , Porencefalia/diagnóstico , Porencefalia/genéticaRESUMO
PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.
Assuntos
Eletroencefalografia , Epilepsia , Recém-Nascido , Humanos , Eletroencefalografia/métodos , Bloqueadores dos Canais de Sódio , Canal de Potássio KCNQ2/genética , Cognição , Canal de Sódio Disparado por Voltagem NAV1.2/genéticaRESUMO
BACKGROUND: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates. METHODS: In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (≥36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45-50â×â106 bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821. FINDINGS: Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38°C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus post-administration and, although thrombocyte levels increased (p=0·011), all were within the physiological range. Follow-up MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants. INTERPRETATION: This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS. FUNDING: Netherlands Organization for Health Research and Development (ZonMw).
Assuntos
Isquemia Encefálica , AVC Isquêmico , Células-Tronco Mesenquimais , Acidente Vascular Cerebral , Criança , Estudos de Viabilidade , Humanos , Lactente , Recém-Nascido , Países Baixos , Pesquisa , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Resultado do TratamentoRESUMO
Introduction: Children with early brain damage or dysfunction are at risk of developing cerebral visual impairment (CVI), including visual processing dysfunctions (VPD), which currently remain largely undetected until school age. Our aim was to systematically screen for possible VPD in children born very or extremely preterm from 1 to 2 years corrected age (CA) and to evaluate the effectiveness of early referral. Method: We included N = 48 children born < 30 weeks from 1 year CA. They underwent a two-step VPD screening based on (1) neurological signs indicative of visual brain damage evaluated by neonatologists and/or pediatric neurologist and (2) a functional assessment of visual orienting functions (VOF) with an eye tracking-based test. If at least one of these assessments was abnormal for their age, the children were classified as a risk of VPD and referred to undergo conventional visual diagnostics: ophthalmic exam and visual function assessment (VFA). At 2 years CA, VOF screening was repeated and neurodevelopment was assessed. Results: 18 children (38%) were classified as at risk of VPD at 1 year CA. 7 children had abnormal neurological signs, 5 children had abnormal VOF, and 6 children had both. Subsequent ophthalmic exams (N = 14) showed severe hypermetropia in 21% and strabismus in 14%. VFA (N = 10) showed abnormal visual function and behavior in only 1 child. At 2 years CA, the total group showed an increase in abnormal VOF. Whereas the children at risk showed some normalization, the group without VPD risk at 1 year CA showed deterioration of VOF. Neurodevelopmental outcome did not clearly differ between risk groups. Conclusion: Our findings show a substantial risk of VPD during visual screening (in 38%) at 1 year CA, but relatively few deficits on subsequent conventional ophthalmic exams and VFA. The data suggest that most conventional visual diagnostic methods at this young age are not related to the established VPD risks. VOF assessment should be used complimentary to these methods. The fact that at 2 years CA the number of children with a VPD risk based on abnormal VOF increased argues for more extensive and continuous screening in risk groups, at least until school age.
RESUMO
BACKGROUND: An increasing number of children are suffering from brain damage-related visual processing dysfunctions (VPD). There is currently a lack of evidence-based intervention methods that can be used early in development. We developed a visual intervention protocol suitable from 1 year of age. The protocol is structured, comprehensive and individually adaptive, and is paired with quantitative outcome assessments. Our aim is to investigate the effectiveness of this first visual intervention program for young children with (a risk of) VPD. METHODS: This is a single-blind, placebo-controlled trial that is embedded within standard clinical care. The study population consists of 100 children born very or extremely preterm (< 30 weeks) at 1 year of corrected age (CA), of whom 50% are expected to have VPD. First, children undergo a visual screening at 1 year CA. If they are classified as being at risk of VPD, they are referred to standard care, which involves an ophthalmic and visual function assessment and a (newly developed) visual intervention program. This program consists of a general protocol (standardized and similar for all children) and a supplement protocol (adapted to the specific needs of the child). Children are randomly allocated to an intervention group (starting upon inclusion at 1 year CA) or a control group (postponed: starting at 2 years CA). The control group will receive a placebo treatment. The effectiveness of early visual intervention will be examined with follow-up visual and neurocognitive assessments after 1 year (upon completion of the direct intervention) and after 2 years (upon completion of the postponed intervention). DISCUSSION: Through this randomized controlled trial we will establish the effectiveness of a new and early visual intervention program. Combining a general and supplement protocol enables both structured comparisons between participants and groups, and custom habilitation that is tailored to a child's specific needs. The design ensures that all included children will benefit from participation by advancing the age at which they start receiving an intervention. We expect results to be applicable to the overall population of children with (a risk of) VPD early in life. TRIAL REGISTRATION: Netherlands Trial Register: NTR6952. Registered 19 January 2018.
Assuntos
Transtornos do Neurodesenvolvimento/complicações , Transtornos da Percepção/prevenção & controle , Nascimento Prematuro/fisiopatologia , Transtornos da Visão/prevenção & controle , Percepção Visual/fisiologia , Encéfalo/fisiopatologia , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Cognição , Feminino , Seguimentos , Humanos , Lactente , Masculino , Países Baixos , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos da Percepção/diagnóstico , Transtornos da Percepção/etiologia , Transtornos da Percepção/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Fatores de Tempo , Tempo para o Tratamento , Resultado do Tratamento , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologiaRESUMO
OBJECTIVE: The aim was to establish any differences in the predictive value of EEG and MRI for outcome in infants treated and not-treated with therapeutic hypothermia (HT) for perinatal asphyxia. We hypothesize that they are equally predictive and that combining both has the highest predictive value. STUDY DESIGN: We retrospectively compared data of infants with hypoxic-ischemic encephalopathy (HIE) who received HT (n = 45) between September 2009 and December 2013 with those of infants with HIE born between January 2004 and August 2009, before HT was available (NT, n = 37). All received conventional and/or amplitude-integrated EEG during the first days and early MRI (day 4-5). Associations of EEG, MRI and severe neurodevelopmental outcome (death or Bayley's -2SD below mean), were tested with a multivariable logistic regression analysis, corrected for HT. RESULTS: Forty-eight hours' EEG background pattern had a PPV of 92% and a NPV of 81% in HT, versus 100% and 58% in NT. MRI had a PPV of 71% and a NPV of 93% in HT, versus 82% and 75% in NT. The adjusted OR for adverse outcome was 0.013 (95% CI 0.002-0.154, p < 0.001) for EEG background normalization within 48 h and 32.19 (95% CI 4.84-214.25, p < 0.001) for abnormal MRI. CONCLUSION: The predictive value of EEG and MRI is equal in cooled and non-cooled infants with HIE. Our data show a higher predictive value (death and severe outcome) for EEG compared to MRI. In HIE, persistent abnormal EEG background pattern until 48 h, combined with abnormal early MRI is strongly predictive for poor neurodevelopment.
Assuntos
Asfixia Neonatal/patologia , Eletroencefalografia/métodos , Hipóxia-Isquemia Encefálica/patologia , Imageamento por Ressonância Magnética/métodos , Asfixia , Asfixia Neonatal/complicações , Asfixia Neonatal/terapia , Encéfalo/patologia , Encéfalo/fisiopatologia , Feminino , Humanos , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/terapia , Lactente , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Gravidez , Estudos RetrospectivosRESUMO
Congenital hypomyelinating neuropathy is a rare condition characterized by prenatal, neonatal or early infantile onset of hypotonia, paresis and areflexia. Most of the few patients described in literature die within the first years of life. Histopathologically there are no or thin myelin sheaths. Mutations have been described in the following genes, MPZ, EGR2, PMP22, and MTMR2. Here we describe a family with a heterozygous mutation in MPZ, confirmed in two generations.
Assuntos
Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Bainha de Mielina/patologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Adulto , Análise Mutacional de DNA , Doenças Desmielinizantes/fisiopatologia , Eletromiografia , Feminino , Seguimentos , Marcadores Genéticos/genética , Testes Genéticos , Heterozigoto , Humanos , Recém-Nascido , Masculino , Microscopia Eletrônica , Mutação/genética , Proteína P0 da Mielina/genética , Condução Nervosa/genética , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fatores de TempoRESUMO
Cataplexy in childhood is a rare and often misdiagnosed symptom. It is described as a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions and in particular with unexpected laughter. This report presents a 9-year old male with progressive cerebellar and pyramidal symptoms and a cognitive decline since the age of 4. His recently developed "drop attacks" on laughter were recognized as cataplexy and led to the diagnosis of Niemann-Pick type C disease. With biochemical studies this diagnosis, a lysosomal storage disease, was confirmed. With cataplexy narcolepsy, Niemann-Pick type C disease, Norrie disease, Prader-Willi syndrome, and Coffin-Lowry syndrome are associated disorders. Recognition of cataplexy in children with concomitant neurologic symptoms may lead to an early and straight diagnosis of one of these disorders.
Assuntos
Cataplexia/diagnóstico , Doenças de Niemann-Pick/diagnóstico , Cataplexia/complicações , Criança , Humanos , Riso , Masculino , Doenças de Niemann-Pick/complicações , Síncope/complicações , Síncope/diagnósticoRESUMO
We report on a family with a not earlier described multiple congenital malformation. Several male family members suffer from laryngeal obstruction caused by bilateral vocal cord paralysis, outer and middle ear deformity with conductive and sensorineural hearing loss, facial dysmorphisms, and underdeveloped shoulder musculature. The affected female members only have middle ear deformity and hearing loss. The pedigree is suggestive of an X-linked recessive inheritance pattern. SNP-array revealed a deletion and duplication on Xq28 in the affected family members. A possible aetiology is a neurocristopathy with most symptoms expressed in structures derived from branchial arches.
Assuntos
Anormalidades Craniofaciais/genética , Orelha Externa/anormalidades , Orelha Média/anormalidades , Perda Auditiva Condutiva/genética , Músculo Esquelético/anormalidades , Paralisia das Pregas Vocais/genética , Anormalidades Múltiplas/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos X/genética , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Países Baixos , Linhagem , SíndromeRESUMO
OBJECTIVE: To investigate detection ability and feasibility of serial cranial ultrasonography (CUS) and early MRI in preterm brain injury. DESIGN: Prospective cohort study. SETTING: Level III neonatal intensive care unit. PATIENTS: 307 infants, born below 29â weeks of gestation. METHODS: Serial CUS and MRI were performed according to standard clinical protocol. In case of instability, MRI was postponed or cancelled. Brain images were assessed by independent experts and compared between modalities. MAIN OUTCOME MEASURES: Presence of preterm brain injury on either CUS or MRI and discrepant imaging findings on CUS and MRI. RESULTS: Serial CUS was performed in all infants; early MRI was often postponed (n=59) or cancelled (n=126). Injury was found in 146 infants (47.6%). Clinical characteristics differed significantly between groups that were subdivided according to timing of MRI. 61 discrepant imaging findings were found. MRI was superior in identifying cerebellar haemorrhage; CUS in detection of acute intraventricular haemorrhage, perforator stroke and cerebral sinovenous thrombosis. CONCLUSIONS: Advanced serial CUS seems highly effective in diagnosing preterm brain injury, but may miss cerebellar abnormalities. Although MRI does identify these lesions, feasibility is limited. Improved safety, better availability and tailored procedures are essential for MRI to increase its value in clinical care.
Assuntos
Lesões Encefálicas , Hemorragia Cerebral , Erros de Diagnóstico/prevenção & controle , Encéfalo/patologia , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/etiologia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/etiologia , Estudos de Coortes , Ecoencefalografia/métodos , Estudos de Viabilidade , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Imageamento por Ressonância Magnética/métodos , Masculino , Países Baixos , Estudos Prospectivos , Melhoria de Qualidade , Reprodutibilidade dos TestesRESUMO
Apneic neonatal seizures can present as apparent life-threatening events. We report a newborn with unexplained episodes of apnea associated with cyanosis and desaturation, starting on the first day postpartum. Biochemical tests were normal. Central nervous system infections as well as abnormalities of upper airways and cardiovascular system were excluded. Brain monitoring using amplitude-integrated electroencephalography (aEEG) was inconclusive. Continuous monitoring using video EEG revealed epileptic seizures originating from the left temporal region as the cause of the apneas. Magnetic resonance imaging (MRI) of the brain showed a developmental malformation of the left frontal and temporal lobes. The patient became seizure free after treatment with antiepileptic medication. This report illustrates that brain monitoring using amplitude-integrated EEG alone could miss focal neonatal seizures. When clinical suspicion of apneic seizures is high in infants with apparent life threatening events, multichannel polygraphic video-EEG monitoring is indicated. Prompt diagnosis and treatment can be life saving.
Assuntos
Epilepsia/complicações , Apneia do Sono Tipo Central/complicações , Apneia do Sono Tipo Central/psicologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância MagnéticaRESUMO
A sensitive and specific method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the determination of levetiracetam (LEV) in plasma of neonates. A plasma aliquot of 50 microl was deproteinized by addition of 500 microl methanol which contained 5 microg/ml UCB 17025 as an internal standard. After centrifugation, 50 microl of supernatant was diluted with 1000 microl of 0.1% formic acid-10 mM ammonium formate in water (pH 3.5) (mobile phase solution A) and 2 microl was injected onto the UPLC-system. Compounds were separated on a Acquity UPLC BEH C(18) 2.1 mm x 100 mm column using gradient elution with mobile phase solution A and 0.1% formic acid in methanol (mobile phase solution B) with a flow rate of 0.4 ml/min and a total runtime of 4.0 min. LEV and the internal standard were detected using positive ion electrospray ionization followed by tandem mass spectrometry (ESI-MS/MS). The assay allowed quantification of LEV plasma concentrations in the range from 0.5 microg/ml to 150 microg/ml. Inter-assay inaccuracy was within +/-2.7% and inter-assay precision was less than 4.5%. Matrix effects were minor: the recovery of LEV was between 97.7% and 100%. The developed method required minimal sample preparation and less plasma sample volume compared to earlier published LC-MS/MS methods. The method was successfully applied in a clinical pharmacokinetic study in which neonates received intravenous administrations of LEV for the treatment of neonatal seizures.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Recém-Nascido/sangue , Piracetam/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Anticonvulsivantes/sangue , Estabilidade de Medicamentos , Humanos , Levetiracetam , Modelos Lineares , Metanol/química , Piracetam/sangue , Piracetam/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeAssuntos
Acrocefalossindactilia/diagnóstico por imagem , Acrocefalossindactilia/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Feminino , Humanos , Recém-Nascido , Mutação , Linhagem , Poli-Hidrâmnios/diagnóstico por imagem , Gravidez , Nascimento Prematuro/etiologia , Ultrassonografia Pré-NatalRESUMO
We report a girl with severe manifestations of Townes-Brocks syndrome (TBS) and a previously unreported serious congenital dysphagia. She is unable to swallow her saliva and consequently chokes frequently with desaturations still existing beyond the second year of life. Involvement of the feet was more extensive than is usually seen in TBS. Mutation analysis of the SALL1 gene, responsible for TBS, resulted in the identification of the de novo hot-spot mutation p.Arg276X. This report adds another rare, but serious manifestation to the multiorgan involvement found in TBS.