Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder.

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.

Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging.

AIM: To characterize the adaptive behavior profile of children with neurofibromatosis type 1 (NF1) and determine its relationship to neuropsychological functioning and non-neoplastic T2-weighted hyperintense brain lesions on brain magnetic resonance imaging (MRI). METHOD: In this cross-sectional study, we retrospectively reviewed neuropsychological reports from 104 children with NF1 (56 males, 48 females; mean age 10y 4mo; standard deviation [SD] 3y 4mo; range 3y 5mo-17y 6mo), and extracted data from a range of cognitive and behavioral measures, including the Adaptive Behavior Assessment System (ABAS). Brain MRI was retrospectively reviewed in 42 individuals. RESULTS: Adaptive Behavior Assessment System scores were continuously distributed and pathologically shifted by 0.79 to 1.26SD across Conceptual, Social, and Practical domains, and 46.5% of individuals had a composite score in the borderline or impaired range. Impairment in adaptive functioning was correlated with deficits in executive function (r=-9.543, p<0.001), externalizing problems (r=-0.366, p<0.001), and attention (r=-9.467, p=0.001). Cluster analysis revealed three distinct phenotypic subgroups, one of which exhibited normal cognitive ability, but impaired adaptive functioning, with persistent deficits in executive function, behavioral problems, and attention-deficit/hyperactivity disorder symptomatology. There was no relationship between ABAS scores and the number or location of unidentified bright objects. INTERPRETATION: Adaptive functioning deficits are common among children with NF1 and are associated with impairment in other cognitive/behavioral domains, independent of general cognitive ability. WHAT THIS PAPER ADDS: Deficits in adaptive behavior are common in children with neurofibromatosis type 1 (NF1). Poor adaptive functioning is associated with impairments in executive function, externalizing behaviors, and attention, regardless of cognitive ability. The presence or location of unidentified bright objects do not predict adaptive behavior skills in children with NF1.

FUNCIONAMIENTO ADAPTATIVO EN NIÑOS CON NEUROFIBROMATOSIS TIPO 1: RELACIÓN ENTRE COGNICIÓN, COMPORTAMIENTO E IMÁGENES DE RESONANCIA MAGNÉTICA: OBJETIVO: Caracterizar el perfil del comportamiento adaptativo de niños con neurofibromatosis tipo 1 (NF1) y determinar la relación entre el funcionamiento neuropsicológico y las lesiones hiperintensas cerebrales no neoplásicas en T2-pesado de la resonancia magnética cerebral (RM). MÉTODO: En este estudio transversal, revisamos de forma retrospectiva reportes neuropsicológicos de 104 niños con NF1 (56 varones, 48 mujeres, media de edad 10 años 4 meses; desviación estándar (DE) 3 años 4 meses; rango 3 años 5 meses a 17 años 6 meses), y se extrajeron datos de una serie de mediciones cognitivas y conductuales, incluyendo el test sistema de evaluación de la conducta adaptativa (Adaptative Behaivor Assesment System ABAS). Se revisaron 42 RM cerebrales de forma retrospectiva. RESULTADOS: Los resultados ABAS fueron continuamente distribuidos y se cambiaron patológicamente entre 0,79 a 1,26 DE en los dominios de lo conceptual, social y práctico, y 46,5 por ciento de los individuos tuvieron un puntaje limítrofe o sin afectación. La afectación en las funciones adaptativas fue correlacionada con los déficits en funciones ejecutivas (r = -9,543, p < 0,001), externalizar problemas (r = -0,366, p < 0,001), y atención (r = -9,467, p = 0,001). El análisis de grupo revelo tres subgrupos fenotípicos distintos, uno de ellos exhibía una habilidad cognitiva tipica, pero afectación en el funcionamiento adaptativo, con déficits persistentes en función ejecutiva, problemas conductuales, y sintomatología de déficit de atención/hiperactividad. No hubo relación entre el puntaje ABAS y el número o localización de imágenes brillantes no identificadas en la RM cerebral. INTERPRETACIÓN: Los déficits de funcionamiento adaptativo son comunes entre niños con NF1 y son asociados con afectación de otros dominios cognitivo/conductual, independiente de la habilidad cognitiva en general.

FUNCIONAMENTO ADAPTATIVO EM CRIANÇAS COM NEUROFIBROMATOSE TIPO 1: RELAÇÃO COM COGNIÇÃO, COMPORTAMENTO, E IMAGEM DE RESSONÂNCIA MAGNÉTICA: OBJETIVO: Caracterizar o comportamento adaptativo de crianças com neurofibromatose tipo 1 (NF1) e determinar sua relação com funcionamento neuropsicológico e lesões em T2 hiperintensas não neoplásticas ao exame de ressonância magnética (RM). MÉTODO: Neste estudo transversal, revisamos retrospectivamente os relatórios neuropsicológicos de 104 crianças com NF1 (56 do sexo masculino, 48 do sexo feminino; média de idade 10a 4m; desvio padrão [DP] 3a 4m; variação 3a 5m-17a6m), e extraímos dados de uma variedade de medidas cognitivas e comportamentais, incluindo o Sistema de Avaliação do Comportamento Adaptativo (SACA). Imagens de RM cerebral foram retrospectivamente revisadas em 42 indivíduos. RESULTADOS: Os escores SACA foram distribuídos continuamente, e patologicamente deslocados em 0,79 a 1,26 DP nos domínios Conceitual, Social e Prático, e 46,5 por cento dos indivíduos tiveram escore composto na faixa limítrofe ou deficiente. Deficiências no comportamento adaptativo se correlacionaram com déficits na função executiva (r = −9,543, p < 0,001), problemas externalizantes (r = −0,366, p < 0,001), e atenção (r = −9,467, p = 0,001). Análise agrupada revelou três subgrupos genotípicos distintos, um dos quais exibiu capacidade cognitiva normal, mas funcionamento adaptativo deficiente, e sintomatologia de transtorno de deficit de atenção e hiperatividade. Não houve relação entre escores SACA e o número ou localização de objetos luminosos não identificados. INTERPRETAÇÃO: Déficits no funcionamento adaptativo são comuns entre crianças com NF1 e são associados com deficiência em outros domínios cognitivos/comportamentais, independente da capacidade cognitiva geral.

To Treat or Not to Treat: Ethics of Management of Refractory Status Myoclonus Following Pediatric Anoxic Brain Injury.

The development of status myoclonus (SM) in a postcardiac arrest patient has historically been thought of as indicative of not only a poor neurologic outcome but of neurologic devastation. In many instances, this may lead clinicians to initiate conversations about withdrawal of life sustaining therapies (WLST) regardless of the time from return of spontaneous circulation (ROSC). Recent studies showing a percentage of patients may make a good recovery has called into question whether a self-fulfilling prophecy has developed where the concern for a poor neurologic outcome leads clinicians to prematurely discuss WLST. The issue is only further complicated by changing terminology, lack of neuro-axis localization, and limited data regarding association with electroencephalogram (EEG) characteristics, all of which could aid in the understanding of the severity of neurologic injury associated with SM. Here we review the initial literature reporting SM as indicative of poor neurologic outcome, the studies that call this into question, the various definitions of SM and related terms as well as data regarding association with EEG backgrounds. We propose that improved prognostication on outcomes results from combining the presence of SM with other clinical variables (eg EEG patterns, MRI findings, and clinical exam). We discuss the ethical implications of using SM as a prognostic tool and its impact on decisions about life-sustaining care in children following cardiac arrest. We advocate for prognostication efforts to be delayed for at least 72 hours following ROSC and thus to treat SM in those early hours and days.

Histopathologic correlation with diffusion tensor imaging after chronic hypoxia in the immature ferret.

INTRODUCTION: Chronic hypoxia in rodents induces white matter (WM) injury similar to that in human preterm infants. We used diffusion tensor imaging (DTI) and immunohistochemistry to study the impact of hypoxia in the immature ferret at two developmental time points relevant to the preterm and term brain. RESULTS: On ex vivo imaging, the apparent diffusion coefficient (ADC) was decreased throughout the WM after 10 days of hypoxia (hypoxia from postnatal day 10 (P10) to P20 and killed at P20 (early hypoxia P20)), corresponding to increased astrocytosis and decreased myelination. Diffusion values normalized after 10 days of normoxia (hypoxia from P10 to P20 and killed at P30 (early hypoxia P30)), but immunohistochemistry revealed significant astrocytosis and hypomyelination. In contrast, ADC and anisotropy were increased after 10 days of hypoxia at a later developmental time point (hypoxia from P20 to P30 and killed at P30 (late hypoxia P30)), with less astrocytosis and more prominent myelination. DISCUSSION: The patterns of alteration in imaging and histology varied in relation to the developmental time at which hypoxia occurred. Normalization of diffusion measures did not correspond to the normalization of underlying histopathology. METHODS: Ferrets were subjected to 10% hypoxia and divided into three groups: early hypoxia P20, early hypoxia P30, and late hypoxia P30.

MR imaging correlates of white-matter pathology in a preterm baboon model.

INTRODUCTION: Cerebral white-matter (WM) abnormalities on magnetic resonance imaging (MRI) correlate with neurodevelopmental disability in infants born prematurely. RESULTS: Quantitative histological measures of WM and ventricular volumes correlated with qualitative MRI scores of WM volume loss and ventriculomegaly. Diffuse astrocytosis was associated with signal abnormality on T(2)-weighted imaging and higher apparent diffusion coefficient in WM. Loss of oligodendrocytes was associated with lower relative anisotropy characterized by higher radial diffusivity values. The relationship between histopathology and MRI abnormalities was more pronounced in animals in the 28 d model, equivalent to the term human infant. DISCUSSION: MRI reflects microstructural and anatomical abnormalities that are characteristic of WM injury in the preterm brain, and these changes are more evident on MRI at term-equivalent postmenstrual age. METHODS: We assessed the histopathological correlates of MRI abnormalities in a baboon model of premature birth. Baboons were delivered at 125 d of gestation (dg, term ~185 dg) and maintained in an animal intensive care unit for 14 (n = 26) or 28 d (n = 17). Gestational control animals were delivered at 140 dg (n = 9) or 153 dg (n = 4). Cerebral WM in fixed brains was evaluated using MRI, diffusion tensor imaging (DTI), and histopathology.

Macroperiodic Oscillations Are Associated With Seizures Following Acquired Brain Injury in Young Children.

PURPOSE: Seizures occur in 10% to 40% of critically ill children. We describe a phenomenon seen on color density spectral array but not raw EEG associated with seizures and acquired brain injury in pediatric patients. METHODS: We reviewed EEGs of 541 children admitted to an intensive care unit between October 2015 and August 2018. We identified 38 children (7%) with a periodic pattern on color density spectral array that oscillates every 2 to 5 minutes and was not apparent on the raw EEG tracing, termed macroperiodic oscillations (MOs). Internal validity measures and interrater agreement were assessed. We compared demographic and clinical data between those with and without MOs. RESULTS: Interrater reliability yielded a strong agreement for MOs identification (kappa: 0.778 [0.542-1.000]; P < 0.0001). There was a 76% overlap in the start and stop times of MOs among reviewers. All patients with MOs had seizures as opposed to 22.5% of the general intensive care unit monitoring population ( P < 0.0001). Macroperiodic oscillations occurred before or in the midst of recurrent seizures. Patients with MOs were younger (median of 8 vs. 208 days; P < 0.001), with indications for EEG monitoring more likely to be clinical seizures (42 vs. 16%; P < 0.001) or traumatic brain injury (16 vs. 5%, P < 0.01) and had fewer premorbid neurologic conditions (10.5 vs. 33%; P < 0.01). CONCLUSIONS: Macroperiodic oscillations are a slow periodic pattern occurring over a longer time scale than periodic discharges in pediatric intensive care unit patients. This pattern is associated with seizures in young patients with acquired brain injuries.

A Virtual Community of Practice: An International Educational Series in Pediatric Neurocritical Care.

Pediatric neurocritical care (PNCC) is a rapidly growing field. Challenges posed by the COVID-19 pandemic on trainee exposure to educational opportunities involving direct patient care led to the creative solutions for virtual education supported by guiding organizations such as the Pediatric Neurocritical Care Research Group (PNCRG). Our objective is to describe the creation of an international, peer-reviewed, online PNCC educational series targeting medical trainees and faculty. More than 1600 members of departments such as pediatrics, pediatric critical care, and child neurology hailing from 75 countries across six continents have participated in this series over a 10-month period. We created an online educational channel in PNCC with over 2500 views to date and over 130 followers. This framework could serve as a roadmap for other institutions and specialties seeking to address the ongoing problems of textbook obsolescence relating to the rapid acceleration in knowledge acquisition, as well as those seeking to create new educational content that offers opportunities for an interactive, global audience. Through the creation of a virtual community of practice, we have created an international forum for pediatric healthcare providers to share and learn specialized expertise and best practices to advance global pediatric health.

Continuous Electroencephalography Monitoring in Critically Ill Infants and Children.

Continuous video electroencephalography (CEEG) monitoring of critically ill infants and children has expanded rapidly in recent years. Indications for CEEG include evaluation of patients with altered mental status, characterization of paroxysmal events, and detection of electrographic seizures, including monitoring of patients with limited neurological examination or conditions that put them at high risk for electrographic seizures (e.g., cardiac arrest or extracorporeal membrane oxygenation cannulation). Depending on the inclusion criteria and clinical characteristics of the population studied, the percentage of pediatric patients with electrographic seizures varies from 7% to 46% and with electrographic status epilepticus from 1% to 23%. There is also evidence that epileptiform and background CEEG patterns may provide important information about prognosis in certain clinical populations. Quantitative EEG techniques are emerging as a tool to enhance the value of CEEG to provide real-time bedside data for management and prognosis. Continued research is needed to understand the clinical value of seizure detection and identification of other CEEG patterns on the outcomes of critically ill infants and children.

Characterization of brain development in the ferret via MRI.

Animal models with complex cortical development are useful for improving our understanding of the wide spectrum of neurodevelopmental challenges facing human preterm infants. MRI techniques can define both cerebral injury and alterations in cerebral development with translation between animal models and the human infant. We hypothesized that the immature ferret would display a similar sequence of brain development [both gray (GM) and white matter (WM)] to that of the preterm human infant. We describe postnatal ferret neurodevelopment with conventional and diffusion MRI. The ferret is born lissencephalic with a thin cortical plate and relatively large ventricles. Cortical folding and WM maturation take place during the first month of life. From the mid-second through the third week of postnatal life, the ferret brain undergoes a similar, though less complex, pattern of maturational changes to those observed in the human brain during the second half of gestation. GM anisotropy decreases rapidly in the first 3 wks of life, followed by an upward surge of surface folding and WM anisotropy over the next 2 wks.

The mTOR pathway in treatment of epilepsy: a clinical update.

Nearly a third of patients with epilepsy have seizures refractory to current medical therapies. In the search for novel drug targets, the mTOR pathway has emerged as key in the regulation of neuronal function, growth and survival, and other cellular processes related to epileptogenesis. Hyperactivation of the mTOR pathway has been implicated in tuberous sclerosis complex and other 'mTORopathies', clinical syndromes associated with cortical developmental malformations and drug-resistant epilepsy. Recently published clinical trials of mTOR inhibitors in tuberous sclerosis complex have shown that these drugs are effective at decreasing seizure frequency. Future studies may establish whether mTOR inhibitors can provide effective treatment for patients with diverse genetic and acquired epilepsies, including preventative, disease-modifying therapies.

Increased prevalence of brain tumors classified as T2 hyperintensities in neurofibromatosis 1.

BACKGROUND: We sought to define the radiologic features that differentiate neoplastic from non-neoplastic T2 hyperintensities (T2Hs) in neurofibromatosis type 1 (NF1) and identify those lesions most likely to require oncologic surveillance. METHODS: We conducted a single-center retrospective review of all available brain MRIs from 68 children with NF1 (n = 190) and 46 healthy pediatric controls (n = 104). All T2Hs identified on MRI were characterized based on location, border, shape, degree of T1 hypointensity, and presence of mass effect or contrast enhancement, and subsequently classified using newly established radiologic criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 10 NF1 cases. RESULTS: T2Hs were a highly sensitive (94.4%; 95% confidence interval [CI] 86.4%-98.5%) and specific (100.0%; 95% CI 92.3%-100.0%) marker for the diagnosis of NF1. UBOs constituted the majority of T2Hs (82%) and were most frequently located in cerebellar white matter, medial temporal lobe, and thalamus, where they were more likely than probable tumors to be bilateral (p < 0.001) and have nondiscrete borders (p < 0.001). Surprisingly, 57% of children with T2Hs harbored lesions classified as probable tumors, and 28% of children with probable tumors received treatment. In contrast to UBOs, probable tumors were most frequently located within the globus pallidus and medulla, and rarely occurred prior to 3 years of age. CONCLUSIONS: With the implementation of standardized radiologic criteria, a high prevalence of brain tumors was identified in this at-risk population of children, of which nearly one-third required treatment, emphasizing the need for appropriate oncologic surveillance for patients with NF1 harboring nonoptic pathway brain tumors.