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Background: Limited training in targeted neurological examination makes it challenging for frontline providers to identify newborns with perinatal asphyxia eligible for therapeutic hypothermia. This training is important in the era of telemedicine, where the experts can remotely guide further care of these newborns., Methods: This randomized controlled pilot study was conducted in a South Indian tertiary hospital. Neonatal nurses, who had no previous hands-on experience in MSEE, were trained in modified Sarnat staging by a didactic teaching session using online teaching module. The nurses were then randomized into two groups for hands-on demonstration by the same trainer (low-fidelity mannequin versus a healthy term newly born infant). After the training period, MSEEs of a normal newborn were performed independently by nurses and were video recorded and assessed by three blinded neonatologists with expertise in neonatal neurology. A follow-up examination was performed by the same nurses after three months to assess skill retention., Results: The 10 global ratings of the components of the MSEE were comparable among both groups in both initial and follow-up assessments. The overall diagnostic value was comparable between the simulation and traditional groups (93.75%, 94.11%, respectively). Follow-up examination after three months showed better skill retention in the simulation group (84%) compared with the traditional group (66.7%)., Conclusions: Online-based and low-fidelity mannequin training was equally effective as the traditional method of teaching MSEE in term neonates., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants., Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant., Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05)., Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

As with many body organs, the human central nervous system contains many structures and cavities that may have had functions in embryonic and fetal life but are vestigial or atrophic at maturity. Examples are the septum pellucidum, remnants of the lamina terminalis, Cajal-Retzius neurons, induseum griseum, habenula, and accessory olfactory bulb. Other structures are transitory in fetal or early postnatal life, disappearing from the mature brain. Examples are the neural crest, subpial granular glial layer of Brun over cerebral cortex, radial glial cells, and subplate zone of cerebral cortex. At times persistent fetal structures that do not regress may cause neurological problems or indicate a pathologic condition, such as Blake pouch cyst. Transitory structures thus can become vestigial. Examples are an excessively wide cavum septi pellucidi, suprapineal recess of the third ventricle, trigeminal artery of the posterior fossa circulation, and hyaloid ocular artery. Arrested maturation might be considered another aspect of vestigial structure. An example is the persistent microcolumnar cortical architecture in focal cortical dysplasia type Ia, in cortical zones of chronic fetal ischemia, and in some metabolic/genetic congenital encephalopathies. Some transitory structures in human brain are normal adult structures in lower vertebrates. Recognition of transitory and vestigial structures by fetal or postnatal neuroimaging and neuropathologically enables better understanding of cerebral ontogenesis and avoids misinterpretations., (Copyright © 2021. Published by Elsevier Inc.)

Background: The ratio between excitatory (glutamatergic) and inhibitory (GABAergic) inputs into maturing individual cortical neurons influences their epileptic potential. Structural factors during development that alter synaptic inputs can be demonstrated neuropathologically. Increased mitochondrial activity identifies neurons with excessive discharge rates., Methods: This study focuses on the neuropathological examinaion of surgical resections for epilepsy and at autopsy, in fetuses, infants, and children, using immunocytochemical markers, and electron microscopy in selected cases. Polymicrogyria and Down syndrome are highlighted., Results: Factors influencing afferent synaptic ratios include the following: (1) synaptic short-circuitry in fused molecular zones of adjacent gyri (polymicrogyria); (2) impaired development of dendritic spines decreasing excitation (Down syndrome); (3) extracellular keratan sulfate proteoglycan binding to somatic membranes but not dendritic spines may be focally diminished (cerebral atrophy, schizencephaly, lissencephaly, polymicrogyria) or augmented, ensheathing individual axons (holoprosencephaly), or acting as a barrier to axonal passage in the U-fiber layer. If keratan is diminished, glutamate receptors on the neuronal soma enable ectopic axosomatic excitatory synapses to form; (4) dysplastic, megalocytic neurons and balloon cells in mammalian target of rapamycin disorders; (5) satellitosis of glial cells displacing axosomatic synapses; (6) peri-neuronal inflammation (tuberous sclerosis) and heat-shock proteins., Conclusions: Synaptic ratio of excitatory/inhibitory afferents is a major fundamental basis of epileptogenesis at the neuronal level. Neuropathology can demonstrate subcellular changes that help explain either epilepsy or lack of seizures in immature brains. Synaptic ratios in malformations influence postnatal epileptogenesis. Single neurons can be hypermetabolic and potentially epileptogenic., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The area postrema in the caudal fourth ventricular floor is highly vascular without blood-brain or blood-cerebrospinal fluid barrier. In addition to its function as vomiting center, several others are part of the circumventricular organs for vasomotor/angiotensin II regulation, role in neuromyelitis optica related to aquaporin-4, and somatic growth and appetite regulation. Functions are immature at birth. The purpose was to demonstrate neuronal, synaptic, glial, or ependymal maturation in the area postrema of normal fetuses. We describe three area postrema tumors., Methods: Sections of caudal fourth ventricle of 12 normal human fetal brains at autopsy aged six to 40 weeks and three infants aged three to 18 months were examined. Immunocytochemical neuronal and glial markers were applied to paraffin sections. Two infants with area postrema tumors and another with neurocutaneous melanocytosis and pernicious vomiting also studied., Results: Area postrema neurons exhibited cytologic maturity and synaptic circuitry by 14 weeks'. Astrocytes coexpressed vimentin, glial fibrillary acidic protein, and S-100β protein. The ependyma is thin over area postrema, with fetal ependymocytic basal processes. A glial layer separates area postrema from medullary tegmentum. Melanocytes infiltrated area postrema in the toddler with pernicious vomiting; two children had primary area postrema pilocytic astrocytomas., Conclusions: Although area postrema is cytologically mature by 14 weeks, growth increases and functions mature during postnatal months. We recommend neuroimaging for patients with unexplained vomiting and that area postrema neuropathology includes synaptophysin and microtubule-associated protein-2 in patients with suspected dysfunction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

After sagittal division of the prosencephalon at 4.5 weeks of gestation, the early fetal cerebral hemisphere bends or rotates posteroventrally from seven weeks of gestation. The posterior pole of the telencephalon thus becomes not the occipital but the temporal lobe as the telencephalic flexure forms the operculum and finally the lateral cerebral or Sylvian fissure. The ventral part is infolded to become the insula. The frontal and temporal lips of the Sylvian fissure, as well as the insula, all derive from the ventral margin of the primitive telencephalon, hence may be influenced by genetic mutations with a ventrodorsal gradient of expression. The telencephalic flexure also contributes to a shift of the hippocampus from a dorsal to a ventral position, the early rostral pole of the hippocampus becoming caudal and dorsal becoming ventral. The occipital horn is the most recent recess of the lateral ventricle, hence most vulnerable to anatomic variations that affect the calcarine fissure. Many major malformations include lack of telencephalic flexure (holoprosencephaly, extreme micrencephaly) or dysplastic Sylvian fissure (lissencephalies, hemimegalencephaly, schizencephaly). Although fissures and sulci are genetically programmed, mechanical forces of growth and volume expansion are proposed to be mainly extrinsic (including ventricles) for fissures and intrinsic for sulci. In fetal hydrocephalus, the telencephalic flexure is less affected because ventricular dilatation occurs later in gestation. Flexures can be detected prenatally by ultrasound and fetal magnetic resonance imaging and should be described neuropathologically in cerebral malformations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Timing is primordial in initiating and synchronizing each developmental process in tissue morphogenesis. Maturational arrest, delay, and precociousness all are conducive to neurological dysfunction and may determine different malformations depending on when in development the faulty timing occurred, regardless of the identification of a specific genetic mutation or an epigenetic teratogenic event. Delay and arrest are distinguished by whether further progressive development over time can be expected or the condition is static. In general, retardation of early developmental processes, such as neurulation, cellular proliferation, and migration, leads to maturational arrest. Retardation of late processes, such as synaptogenesis and myelination, are more likely to result in maturational delay. Faulty timing of neuronal maturation in relation to other developmental processes causes neurological dysfunction and abnormal electroencephalograph maturation in preterm neonates. Precocious synaptogenesis, including pruning to provide plasticity, may facilitate prenatal formation of epileptic circuitry leading to severe postnatal infantile epilepsies. The anterior commissure forms 3 weeks earlier than the corpus callosum; its presence or absence in callosal agenesis is a marker for the onset of the initial insult. An excessively thick corpus callosum may be due to delayed retraction of transitory collateral axons. Malformations that arise at different times can share a common pathogenesis with variations on the extent: timing of mitotic cycles in mosaic somatic mutations may distinguish hemimegalencephaly from focal cortical dysplasia type 2. Timing should always be considered in interpreting cerebral dysgeneses in both imaging and neuropathological diagnoses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The fetal neocortical plate, from initiation of radial migration at 5 weeks' gestation until midgestation, exhibits radial microcolumnar architecture. Horizontal histologic layering or lamination becomes superimposed in the second half of gestation, although residua of the columnar pattern persist postnatally, particularly where the cortex bends: at the crowns of gyri and in the depths of sulci. Columnar architecture of the cortical plate in the first half of gestation mostly results from radial migration of neuroblasts, but the Cajal-Retzius neurons and GABAergic neuroblasts from tangential migration regulate a transition to horizontal lamination of the mature cortex. In children and adults, prominent columnar architecture is a feature of many focal cortical dysplasias and is now recognized as a distinctive pattern of focal cortical dysplasias in the new International League Against Epilepsy classification. It also occurs, however, in many genetic syndromes and chromosomopathic conditions, including 22q12 deletions (DiGeorge syndrome), in several primary cerebral malformations, in the contralateral cingulate gyrus in hemimegalencephaly, in cortical tubers of tuberous sclerosis, in the margins of porencephalic cysts resulting from prenatal infarcts, and in some inborn metabolic defects such as methylmalonic acidemia. Synaptophysin demonstrates both radial and horizontal lamination of synaptic layers. Persistent fetal cortical architecture is potentially epileptogenic. We conclude that columnar architecture is a maturational arrest in histogenesis of the neocortical plate and becomes a component of cortical dysplasia in the perinatal period. An initially physiological process thus becomes pathologic by virtue of advancing age, but traces of it persist in normal mature brains. It also occurs in many genetic and inborn metabolic diseases and after acquired ischemic insults of the fetal brain., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We report on an incidental finding of a markedly tortuous basilar artery in a 6-year-old child. The child underwent a computed tomography scan for minor head trauma, and a basilar artery abnormality was discovered, i.e., a markedly tortuous basilar artery without any other congenital anomalies or syndromes. After an exhaustive workup including computed tomography, magnetic resonance imaging, magnetic resonance angiography, computed tomographic angiography, and genetic tests for associated genetic syndromes, no intervention was deemed necessary. The embryonic etiology and clinical implications are discussed.

Multisystemic disorders with predominantly neurologic manifestations often present with mitochondrial abnormalities in striated muscle biopsies. Decreased respiratory complex activities and abnormalities in mitochondrial structure and DNA constitute the spectrum of mitochondrial changes used as diagnostic and prognostic indicators in patients with neuromuscular disorders. This study assessed mitochondrial defects present in a cohort of 154 young patients to determine diagnostic efficiency and probe the relationship of mitochondrial to clinical phenotype. Striated muscle biopsies were analyzed for mitochondrial structure and number, levels of enzyme activities of complex I-V and citrate synthase, mitochondrial DNA and specific mitochondrial DNA deletions, and presence of 15 pathogenic mitochondrial DNA point mutations. Reduced complex I, III, IV, and V activities were the most ubiquitous finding, with complex III most commonly affected. Mitochondrial structural defects (39%) included changes in mitochondria sizes/shapes and number and aberrant cristae formation. Mitochondrial DNA deletions were evident in 15 patients, three displayed mitochondrial DNA depletion, and only two harbored pathogenic point mutations. Reductions in specific enzyme activities may be the most sensitive diagnostic indicator, whereas defects in ultrastructure and mitochondrial DNA integrity were frequently accompanied by the full spectrum of mitochondrial abnormalities. Some phenotypes displayed specific mitochondrial abnormalities; however, most clinical phenotypes displayed little specificity with regard to mitochondrial phenotype.

We describe a 17-year-old male with neurologic and cardiovascular disorders characterized by complete atrioventricular block and a mitochondrial cytopathy with clinical, structural, biochemical, and molecular features shared by chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. The patient's manifestations included progressive external ophthalmoplegia, bilateral ptosis, muscle weakness, delayed development, and progressive hearing loss with multiple mitochondrial DNA deletions, including an abundant 11-kb novel deletion and reduced specific activities of respiratory complexes I, III, and IV present in skeletal muscle. Ultrastructural analysis of biopsied muscle revealed a heterogenous mixture of normal and abnormal mitochondria with unusual cristae. This unique mitochondrial DNA deletion, which eliminates the origin of mitochondrial DNA replication for the light strand, may be responsible for generating an intermediate clinical phenotype.

A group of 25 children (5 months to 20 years of age) presenting with intractable seizures, developmental delay, and severe hypotonia, who did not fall into the known categories of mitochondrial encephalomyopathies, underwent muscle biopsy for evaluation of mitochondrial function and were compared with age-matched control subjects. Biopsied skeletal muscle was analyzed for six mitochondrial enzyme-specific activities, mitochondrial DNA point mutations and deletions, and mitochondrial DNA levels. The data reveal a high incidence of specific mitochondrial enzyme activity defects. Reduced activity levels were evident in complex I (11 patients), III (24 patients), IV (nine patients), and V (10 patients). Two patients also exhibited pronounced reduction in mitochondrial DNA levels (80% reduction compared with control subjects). Two patients manifested increased levels of 5-kb and 7.4-kb mitochondrial DNA deletions. Pathogenic mutations previously described in association with mitochondrial encephalomyopathies were not evident. The data suggest that mitochondrial dysfunction, including extensive defects in specific enzyme activities, may be frequently present in children with seizures, developmental delay, and hypotonia that do not fall within the known mitochondrial encephalomyopathies. These mitochondrial deficiencies can be primarily ascertained by biochemical analysis and are rarely accompanied by mitochondrial ultrastructural changes. The molecular basis of these defects, their role in these disorders, and potential treatment warrant further study.

Fetal ependyma is an active secretory structure for the programming of developmental events, including the arrest of neuronogenesis, the guidance of axonal growth cones, motor neuron differentiation, and probably also the maintenance and transformation of radial glial cells that guide migratory neuroblasts. The floor plate, induced by the notochord, is the first part of the neuroepithelium to differentiate. It establishes polarity and growth gradients of the neural tube and has immunohistochemical features that differ from all other regions of the ependyma. The dorsal and ventral median septa, formed by floor and roof plate ependymal processes, prevent aberrant decussations of developing long tracts, but permit the passage of commissural axons. Fetal ependyma synthesizes several intermediate filament proteins absent from mature ependymal cells, although some are also expressed in undifferentiated neuroepithelial cells. Fetal ependyma also produces diffusible molecules, such as neural cell adhesion molecule, proteoglycans, nerve growth factor, and S-100 protein, all in specific temporal and spatial distributions. Maturation of the ependyma is not complete until the postnatal period. An abnormal fetal ependyma may play a primary role in the pathogenesis of some cerebral malformations, such as lissencephaly/pachygyria and holoprosencephaly.