Structural Changes in the Cortico-Ponto-Cerebellar Axis at Birth are Associated with Abnormal Neurological Outcomes in Childhood.

White matter lesions in hypoxic-ischemic encephalopathy (HIE) are considered to be the important substrate of frequent neurological consequences in preterm infants. The aim of the study was to analyze volumes and tractographic parameters of the cortico-ponto-cerebellar axis to assess alterations in the periventricular fiber system and crossroads, corticopontine and corticospinal pathways and prospective transsynaptic changes of the cerebellum.Term infants (control), premature infants without (normotypic) and with perinatal HIE (HIE) underwent brain magnetic resonance imaging at term-equivalent age (TEA) and at 2 years. Cerebrum, cerebellum, brainstem divisions and ventrodorsal compartments volumetric analysis were performed, as well as fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of corticopontine, corticospinal pathways and middle cerebellar peduncles. Amiel-Tison scale at TEA and the Hempel test at 2 years were assessed.Cerebellum, brainstem and its compartments volumes were decreased in normotypic and HIE groups at TEA, while at 2 years volumes were significantly reduced in the HIE group, accompanied by decreased volume and FA and increased ADC of corticopontine and corticospinal pathways. Negative association of the brainstem, cerebellum, mesencephalon, pons, corticopontine volumes and corticospinal pathway FA at TEA with the neurological score at 2 years. Cerebellum and pons volumes presented as potential prognostic indicators of neurological outcomes.Our findings agree that these pathways, as a part of the periventricular fiber system and crossroads, exhibit lesion-induced reaction and vulnerability in HIE. Structural differences between normotypic and HIE group at the 2 years suggest a different developmental structural plasticity.

The visibility of the periventricular crossroads of pathways in preterm infants as a predictor of neurological outcome and occurrence of neonatal epileptic seizures.

AIM: To evaluate the relationship between the neurological outcome, neonatal epileptic seizures, and signal-intensity visibility of the frontal and parietal periventricular crossroads of pathways on brain magnetic resonance imaging (MRI) in preterm infants at term-equivalent age. METHODS: The study enrolled 48 preterm infants born between 2012 and 2016. The signal-intensity characteristics of the frontal and parietal periventricular crossroads were evaluated and classified into four grades. A non-favorable outcome was defined as a motor and functional disorder with developmental delay and/or cerebral palsy. RESULTS: Neonatal seizures, epilepsy, pathological EEG and brain ultrasound finding, and brain MRI abnormalities were mostly found in neonates with non-favorable outcomes. Visible frontal and parietal periventricular crossroads were associated with a normal neurologic outcome (P=0.0004; P=0.0009, respectively). Not-visible or slightly visible periventricular crossroads were associated with non-favorable outcomes in the case of frontal crossroads (P=0.036) and not-visible periventricular crossroads in the case of both frontal and parietal crossroads (P=0.001, P=0.015, respectively). The visibility of the frontal and parietal periventricular crossroads was associated with a lack of neonatal epileptic seizures (P=0.03; P=0.02, respectively). The frontal crossroads were more frequently slightly visible, while the parietal periventricular crossroads were more frequently visible. CONCLUSION: Poor visibility of the frontal and parietal crossroads of pathways on MRI is associated with neonatal epileptic seizures and poor neurological outcomes in preterm infants at term-equivalent age.

The Therapeutic Hypothermia in Treatment of Hyperammonemic Encephalopathy due to Urea Cycle Disorders and Organic Acidemias.

BACKGROUND: Hyperammonemic encephalopathy in newborns with urea cycle disorders and certain organic acidurias can cause severe brain injury, coma and death. Standard therapy includes protein restriction, nitrogen-scavenging drugs, prevention of catabolism and hemodialysis. Neuroprotective hypothermia as part of the treatment has been reported only 3 times. It has been suggested that mild systemic hypothermia can contribute to better neurological outcomes in hyperammonemic encephalopathy. However, the limited experience precludes accurate conclusions on safety and efficacy. METHODS: Whole body therapeutic hypothermia was included in the standard treatment of hyperammonemic encephalopathy in 4 neonates with urea cycle disorder or organic aciduria. RESULTS: Two patients survived the initial crisis. One patient has a developmental quotient of 0.8, while the other shows severe developmental delay. The cooling protocol had to be discontinued in 3 patients due to the otherwise untreatable complications (hypotension and hemorrhage). CONCLUSION: The efficacy and safety of therapeutic hypothermia in the treatment of neonatal hyperammonemic encephalopathy depend on various factors, requiring further evaluation.

Interactive histogenesis of axonal strata and proliferative zones in the human fetal cerebral wall.

Development of the cerebral wall is characterized by partially overlapping histogenetic events. However, little is known with regards to when, where, and how growing axonal pathways interact with progenitor cell lineages in the proliferative zones of the human fetal cerebrum. We analyzed the developmental continuity and spatial distribution of the axonal sagittal strata (SS) and their relationship with proliferative zones in a series of human brains (8-40 post-conceptional weeks; PCW) by comparing histological, histochemical, and immunocytochemical data with magnetic resonance imaging (MRI). Between 8.5 and 11 PCW, thalamocortical fibers from the intermediate zone (IZ) were initially dispersed throughout the subventricular zone (SVZ), while sizeable axonal "invasion" occurred between 12.5 and 15 PCW followed by callosal fibers which "delaminated" the ventricular zone-inner SVZ from the outer SVZ (OSVZ). During midgestation, the SS extensively invaded the OSVZ, separating cell bands, and a new multilaminar axonal-cellular compartment (MACC) was formed. Preterm period reveals increased complexity of the MACC in terms of glial architecture and the thinning of proliferative bands. The addition of associative fibers and the formation of the centrum semiovale separated the SS from the subplate. In vivo MRI of the occipital SS indicates a "triplet" structure of alternating hypointense and hyperintense bands. Our results highlighted the developmental continuity of sagittally oriented "corridors" of projection, commissural and associative fibers, and histogenetic interaction with progenitors, neurons, and glia. Histogenetical changes in the MACC, and consequently, delineation of the SS on MRI, may serve as a relevant indicator of white matter microstructural integrity in the developing brain.

Developmental dynamics of radial vulnerability in the cerebral compartments in preterm infants and neonates.

The developmental vulnerability of different classes of axonal pathways in preterm white matter is not known. We propose that laminar compartments of the developing cerebral wall serve as spatial framework for axonal growth and evaluate potential of anatomical landmarks for understanding reorganization of the cerebral wall after perinatal lesions. The 3-T MRI (in vivo) and histological analysis were performed in a series of cases ranging from 22 postconceptional weeks to 3 years. For the follow-up scans, three groups of children (control, normotypic, and preterms with lesions) were examined at the term equivalent age and after the first year of life. MRI and histological abnormalities were analyzed in the following compartments: (a) periventricular, with periventricular fiber system; (b) intermediate, with periventricular crossroads, sagittal strata, and centrum semiovale; (c) superficial, composed of gyral white matter, subplate, and cortical plate. Vulnerability of thalamocortical pathways within the crossroads and sagittal strata seems to be characteristic for early preterms, while vulnerability of long association pathways in the centrum semiovale seems to be predominant feature of late preterms. The structural indicator of the lesion of the long association pathways is the loss of delineation between centrum semiovale and subplate remnant, which is possible substrate of the diffuse periventricular leukomalacia. The enhanced difference in MR signal intensity of centrum semiovale and subplate remnant, observed in damaged children after first year, we interpret as structural plasticity of intact short cortico-cortical fibers, which grow postnatally through U-zones and enter the cortex through the subplate remnant. Our findings indicate that radial distribution of MRI signal abnormalities in the cerebral compartments may be related to lesion of different classes of axonal pathways and have prognostic value for predicting the likely outcome of prenatal and perinatal lesions.

Perinatal and early postnatal reorganization of the subplate and related cellular compartments in the human cerebral wall as revealed by histological and MRI approaches.

We analyzed the developmental history of the subplate and related cellular compartments of the prenatal and early postnatal human cerebrum by combining postmortem histological analysis with in vivo MRI. Histological analysis was performed on 21 postmortem brains (age range: 26 postconceptional weeks to 6.5 years) using Nissl staining, AChE-histochemistry, PAS-Alcian blue histochemistry, Gallyas' silver impregnation, and immunocytochemistry for MAP2, synaptophysin, neurofilament, chondroitin sulfate, fibronectin, and myelin basic protein. The histological findings were correlated with in vivo MRI findings obtained in 30 age-matched fetuses, infants, and children. We analyzed developmental reorganization of major cellular (cell bodies, growing axons) and extracellular (extracellular matrix) components of the subplate and the developing cortex/white matter interface. We found that perinatal and postnatal reorganization of these tissue components is protracted (extending into the second year of life) and characterized by well-delineated, transient and previously undescribed structural and molecular changes at the cortex/white matter interface. The findings of this study are clinically relevant because they may inform and guide a proper interpretation of highly dynamic and hitherto puzzling changes of cortical thickness and cortical/white matter interface as described in current in vivo MRI studies.

[Congenital hyperinsulinism--novel insights into etiology, diagnosis and treatment]. / Kongenitalni hiperinzulinizam- -novosti o nastanku, dijagnosticiranju i lijecenju bolesti.

Congenital hyperinsulinism (CHI) is a major cause of persistent hypoglycemia in the neonatal and early infancy periods. Althought the disease is relatively rare with incidence of about 1:25 000-50 000 live births, the importance of the disease should not be underestimated. Namely, prompt recognition and management of patients with CHI is essential, if permanent neurological impairment is to be avoided. CHI is caused by mutations in one of the 7 genes involved in the regulation of insulin secretion in pancreatic beta-cells. It is important to introduce specific medical therapy as soon as diagnosis is established. Severe, neonatal forms of CHI are often resistant to medications, thus they require surgical procedure. The preoperative genetic testing and scintigraphy are indicated to distinguish histological subtypes of the disease (focal vs. diffuse CHI). Patients with focal disease are usually cured after pancreatic resection, while diffuse disease has much worse prognosis. This manuscript offers novel insights into CHI and emphasizes the role of early diagnosis as crucial for succesful treatment that was recently enriched with novel options.

[Vitamin B12 deficiency in children--underestimated danger in the light of new knowledge]. / Manjak vitamina B12 u djece --podcijenjena opasnost u svjetlu novih spoznaja.

Vitamin B12 (cobalamin) has two active forms, adenosylcobalamin and methylcobalamin which have a key role in two important metabolic pathways in humans and their deficiency is responsible for clinical problems. Cobalamin is essential during whole life, but its sufficient amount is extra important in fetal and neonatal period, when it is essential for normal child growth and development as well as for normal development of the central nervous system. Because of very complex transport and metabolism, its deficiency can be manifested in numerous congenital and acquired disorders. Vitamin B12 deficiency mostly has non-specific clinical features, it carries a great risk of permanent consequences, but most frequently it is easily curable if diagnosed on time. In Croatia cobalamin deficiency in children has been diagnosed too rarely. Accordingly, the aim of this paper is to point to the recently gained knowledge on cobalamin metabolism, present typical case reports and to provide guidelines for rapid and proper diagnostic and therapeutic approach.

Magnetic resonance findings in a neonate with nonketotic hyperglycinemia: case report.

We present brain imaging and spectroscopy data in a neonate with a confirmed classic form of nonketotic hyperglycinemia (NKH), an autosomal-recessive metabolic disorder characterized by accumulation of glycine. To our knowledge, this is the first report of such complete analysis of the changes seen on conventional magnetic resonance imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy at such an early age. The findings in a neonate are consistent with reports in older children with NKH, confirming that pathological changes typical for NKH can be seen in the first postnatal week.

Changes of the corpus callosum in children who suffered perinatal injury of the periventricular crossroads of pathways.

There is a high incidence of periventricular leukomalacia, caused by hypoxia-ischemia, in preterm infants. These lesions damage the periventricular crossroads of commissural, projection and associative pathways, which are in a close topographical relationship with the lateral ventricles. We explored to what extent abnormalities of echogenicity of the periventricular crossroads correlate with changes in size of the corpus callosum. Our study included nine infants (gestation from 26-41 weeks; birth weight between 938-4450 grams) with perinatal brain injury. Periventricular areas, which topographically correspond to the frontal, main and occipital crossroad, were readily visualized by cranial ultrasound scans, performed during the first two weeks after birth. Corpus callosum mediosagittal area measurements were performed using magnetic resonance images, acquired between the first and sixth postnatal month (postmenstrual age 40-49 weeks). We found a statistically significant correlation between the increased echogenicity in the crossroad areas and the decrease of the corpus callosum midsagittal area (p < 0.05). This supports the hypothesis that callosal fibers can be damaged, during growth through the periventricular crossroads of pathways.

Transient cellular structures in developing corpus callosum of the human brain.

The corpus callosum connects two cerebral hemispheres as the most voluminous fiber system in the human brain. The developing callosal fibers originate from immature pyramidal neurons, grow through complex pathways and cross the midline using different substrates in transient fetal structures. We analyzed cellular structures in the human corpus callosum on postmortem brains from the age of 18 weeks post conception to adult, using glial fibrillary acidic protein, neuron-specific nuclear protein, and chondroitin sulphate immunocytochemistry. We found the presence of transient cellular structures, callosal septa, which divide major fiber bundles and ventrally merge with subcallosal zone forming grooves for callosal axons. The callosal septa are composed of glial fibrillary acidic protein reactive meshwork, neurones and the chondroitin sulphate immunoreactive extracellular matrix. The developmental window of prominence of the callosal septa is between 18-34 weeks post conception which corresponds to the period of most intensive growth of callosal axons in human. During the early postnatal period the callosal septa become thinner and shorter, lose their neuronal and chondroitin sulphate content. In conclusion, transient expression of neuronal, glial and extracellular, growing substrate in the callosal septa, as septa itself, indicates their role in guidance during intensive growth of callosal fibers in the human brain. These findings shed some light on the complex morphogenetic events during the growth of the corpus callosum and represent normative parameters necessary for studies of structural plasticity after perinatal lesions.