Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury.

Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p < 0.05) and performed worse in beam walking tests (44% more mistakes, p < 0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI.

S100B - a potential biomarker for early detection of neonatal brain damage following asphyxia.

Birth asphyxia results in a significant percentage of neonatal morbidity and mortality. A key factor in the management of this complication is the early and accurate detection of brain damage following asphyxia. Currently, reliable tools for such diagnosis are absent. Extensive research has focused on biomarkers in an attempt to solve this matter. Recent data marked serum and urine elevation of the S100B protein as an established peripheral biomarker for detection of brain injury including traumatic head injuries and brain damage following cardiac arrest and stroke. In the past decade, a substantial number of studies illustrated the potential use of S100B testing in order to detect brain damage in asphyxiated newborns. This review summarizes the available data regarding the use of S100B as a biomarker of brain damage following birth asphyxia.

Role of epigenetic regulatory mechanisms in neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic brain injury is an important cause of neonatal mortality and subsequent serious neurological sequel. In neonatal brain the severity of hypoxic injury varies most probably due to the effects of multiple protective or deleterious factors. But the mechanisms under this difference are still not full understood. In recent years, some evidence has been found supporting the involvement of epigenetic mechanisms in many neurodegenerative diseases and stroke. We hypothesised that epigenetic mechanisms have been also involved in neonatal hypoxic-ischemic brain injury possibly by suppression of ischemia-induced cerebral inflammation and changing the expression of proapoptotic-antiapoptotic genes.

Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure.

Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.

[The significance of determination of the serum levels of nitrites for assessing severity of perinatal ischemia and predicting the nervous and mental development of a child].

The results of clinical and biochemical studies of 93 full-term neonatal infants with perinatal hypoxia-induced ischemic nervous system lesion are presented. Perinatal ischemia in the newborns has been found to cause an increase in the serum content of nitric oxide, more significant and stable in severe encephalopathy. The level of nitric oxide remained significantly elevated in the natural development of the disease in children with persistent neurological symptoms; its normalization was observed by the third month of life when the clinical syndromes regressed. The authors proposed to use the blood level of nitric oxide as a marker of acute cerebral ischemia and as an additional criterion for predicting the nervous and mental development of children with prior neonatal ischemia.

A follow-up study of infants with intracranial hemorrhage at full-term.

OBJECTIVE: To determine physical and cognitive outcomes of full-term infants who suffered intracranial hemorrhage (ICH) at birth. METHODS: A retrospective hospital-based, follow-up study of infants treated in London, Ontario between 1985 and 1996. Follow-up was conducted by telephone interviews and clinic visits. Outcome was measured according to physical and cognitive scales. Perinatal risk factors and hemorrhage characteristics were correlated with final outcome. RESULTS: For this study 66 infants with ICH were identified, of which seven died during the first week of life. We obtained follow-up in all but ten cases (median = 3-years; range 1.0 to 10.9 years). Overall, 57% of infants had no physical or cognitive deficits at follow-up. Death occurred most frequently among those with primarily subarachnoid hemorrhage (19%) and the most favorable outcomes occurred among those with subdural hemorrhage (80% had no disability). In univariate models, thrombocytopenia (platelet count < or = 70 x 10(9)/L), increasing overall hemorrhage severity, frontal location and spontaneous vaginal delivery as opposed to forceps-assisted delivery increased risk for poor outcome. In multivariate models, all these factors tended towards increased risk, but only thrombocytopenia remained significant for physical disability (OR = 7.6; 95% CI = 1.02 - 56.6); thrombocytopenia was borderline significant in similar models for cognitive disability (OR = 4.6; 95% CI = 0.9 - 23.9). CONCLUSION: Although forceps-assisted delivery may contribute to ICH occurrence, our study found better outcomes among these infants than those who had ICH following a spontaneous vaginal delivery. Hemorrhage in the frontal lobe was the most disabling hemorrhage location and if multiple compartments were involved, disability was also more likely to occur. However, in this report we found that the factor that was most likely to contribute to poor outcome was thrombocytopenia and this remained important in multivariate analysis.

Posterior fontanelle sonography: an acoustic window into the neonatal brain.

BACKGROUND AND PURPOSE: Sonographic brain studies are classically performed through the anterior fontanelle, but visualization of posterior supratentorial and infratentorial structures is poor with this approach. Posterior fontanelle sonography is recommended for better assessment of these structures. Our purpose was 1) to determine whether sonography of the brain through the posterior fontanelle (PF) improves visualization of brain lesions when added to the routine anterior fontanelle (AF) approach and 2) to describe standardized PF coronal and sagittal sections. METHODS: In this prospective study (conducted from February 1999 to January 2001), PF sonography was added to AF sonography in 165 consecutive premature neonates with a birth weight of < 2000 g. Sonograms were recorded in digital format for re-evaluation at the end of the study. Lesions were grouped as congenital, infectious, hemorrhagic, or hypoxic-ischemic. The chi2 test for paired data and the kappa coefficient were used to compare diagnoses with AF alone and diagnoses with AF plus PF. RESULTS: PF sonography was performed in 164 of 165 patients. Results were normal in 86 and abnormal in 78. The single posterior fossa malformation detected in this series was best delineated with the PF approach. PF sonography increased the diagnostic rate of grade II hemorrhage by 32%. Cerebellar hemorrhage (two patients) and cerebellar abscesses (one patient) were diagnosed by using the PF approach. PF sonography did not contribute to the diagnosis of periventricular leukomalacia. CONCLUSION: Study of the neonatal brain with the addition of PF sonography afforded greater accuracy in detecting intraventricular hemorrhage compared with AF sonography alone, especially when the ventricle was not dilated. The PF approach better defines posterior fossa malformations.

Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings.

Conventional MR, diffusion-weighted, and diffusion tensor imaging were performed in an 8-day-old girl with citrullinemia. She had severe hyperammonemia for several days. On conventional T2-weighted MR images, symmetric, confluent high signal intensity was found in the bilateral thalami, basal ganglia, cortex, and subcortical white matter. Diffusion-weighted imaging demonstrated decreased apparent diffusion coefficient in these areas, reflecting cytotoxic edema. Follow-up MR imaging at the age of 4 months revealed subcortical cysts, ulegyric changes, and atrophy, which were most prominent in the occipital lobes. Diffusion tensor imaging revealed decreased anisotropy throughout the brain, consistent with diffuse injury to the oligodendro-axonal unit. Diffusion-weighted and diffusion tensor imaging are valuable techniques for the detection of irreversible brain damage and for the characterization of hyperintense lesions on T2-weighted MR images in patients with the neonatal form of citrullinemia.

Diffusion imaging in neonates.

Diffusion imaging is a useful technique for the evaluation of many normal and pathologic processes occurring in the neonate and often provides complementary information for conventional MR and other imaging techniques.

[How early and how specifically can hypoxic-ischemic brain lesions be detected with diagnostic imaging?]. / Wie früh und wie spezifisch lassen sich hypoxisch-ischämische Hirnläsionen durch bildgebende Verfahren nachweisen?

Pathogenic events affecting the developing brain cause malformations or lesions, the pattern of which depend on the stage of brain development. While in the past diagnosis of these patterns was made by post mortem examinations, today advances of brain imaging allow this already during life time. The patterns of hypoxic-ischemic brain injuries on magnetic resonance imaging (MRI) are well known for the older child (after progress of myelination). This paper addresses the question how early and how specific these patterns can be recognized by two imaging methods, e.g. cranial ultrasound and magnetic resonance imaging. It concludes, that neonatal MRI but also neonatal ultrasound can reliably detect major lesions but may fail in the detection of less extensive patterns. Most authors therefore conclude, that a routine use of MRI for the detection of hypoxic-ischemic lesions during the neonatal period is not recommended and should rather be reserved for later controls.

Congenital erythroleukemia in a neonate with severe hypoxic ischemic encephalopathy.

We report a case of a neonate who presented with hypoxic ischemic encephalopathy, persistent hypoglycemia and hypotension, intractable metabolic acidosis, renal failure and a coagulopathy but who, at autopsy, was found to have massive infiltration of nonhematopoietic tissues with blasts. The diagnosis of congenital erythroleukemia was confirmed by the detection of glycophorin A, a major erythrocyte membrane protein, on the surface of the blasts. The clinical presentation and course of the case described here have not previously been reported for this extremely rare condition.

MR appearance of cerebral cortex in children with and without a history of perinatal anoxia: preliminary observations.

OBJECTIVES: The purpose of this study was to characterize the MR signal intensity of the cerebral cortex in children and to determine if the cortex is abnormal on MR images of patients with anoxia at birth (defined as persistent O2 saturation of less than 80% and requiring intubation or assisted ventilation for more than 24 hr). SUBJECTS AND METHODS: MR imaging was done in 10 patients with no history of anoxia and in nine patients with a history of anoxia. The T2 and T1 signals from the central gyri, the pre- and postcentral gyri, and the calcarine and insular regions of the gray matter were visually graded according to their intensity and to the degree that the low and high signal intensity each involved the entire length of that region. RESULTS: Low T2-signal intensity from the central gyri, the pre- and postcentral gyri, and the calcarine and insular regions of the gray matter was present on MR images made in patients without a history of anoxia and was absent in patients with a history of anoxia. High T1-signal intensity was seen in the central gyri in patients without a history of anoxia. Patients aged 1 year or older with a history of anoxia had no MR signal differences in any gray-matter region on either T1- or T2-weighted images. CONCLUSION: Low T2-signal intensity was seen in the central gyri, the pre- and postcentral gyri, and the calcarine and insular regions of the gray matter on MR images of patients with no history of anoxia but was not seen in those with a history of anoxia. Loss of the normal cortical T2 hypointensity may aid in establishing the diagnosis of anoxic brain injury.

Falling incidence of hypoxic-ischaemic encephalopathy in term infants.

OBJECTIVE: To examine trends in the incidence of hypoxic-ischaemic encephalopathy over a 13-year period. DESIGN: A retrospective analysis of medical records of all infants admitted in the years 1976-1980 and 1984-1988. SETTING: A large non-teaching district health authority in central England. SUBJECTS: Infants admitted to a district general hospital neonatal unit with clinical features of hypoxic-ischaemic encephalopathy. MAIN OUTCOME MEASURES: Incidence of three grades of hypoxic-ischaemic encephalopathy, handicap and mortality. RESULTS: During the first 5-year period the overall incidence of hypoxic-ischaemic encephalopathy was 7.7 per 1000 live births with 2.6 per 1000 live births being severely affected (grades II and III). In the second 5-year period the overall incidence was 4.6 per 1000 live births with 1.8 per 1000 live births being severely affected. The difference in the overall rate is statistically significant. Of the infants with severe encephalopathy 61% had Apgar scores below 4 at 1 min and 60% were born by instrumental or operative delivery. CONCLUSIONS: The fall in incidence of hypoxic-ischaemic encephalopathy has occurred during a period of falling perinatal mortality rate. It was instructive to find that infants born vaginally and without obstetric intervention formed a larger fraction of the severely affected infants in the later period.

The cerebellum of epileptics.

Five cases are presented with different types of cerebellar lesions which may be encountered in epileptics. Case 1 represents typical postical lesions, Case 2 perinatal anoxic-ischemic damage, Case 3 transneuronal degeneration causing crossed cerebellar atrophy, Case 4 iatrogenic cerebellar atrophy due to Phenytoin toxicity. Case 5 illustrates the interaction of two mechanisms, postictal lobular sclerosis and transneuronal degeneration. It is suggested that by attention to the type and distribution of the cerebellar lesions, to the clinical history and to the distribution of lesions in other parts of the brain the pathogenetic mechanisms can be elucidated in most cases.

Homicide of an aggressive adolescent boy with right temporal lesion: a case report.

The case is reported of a 14-year-old male who killed an 8-year-old child following an alleged insult. The subject had been known to be aggressive throughout his school career. He had suffered one nocturnal seizure at the age of 13, but he never was amnesic for any of his fights. There was a history of possible hypoxic birth trauma. Neuropsychiatric investigation revealed developmental lags in speech and other psychosocial skills and, on computer tomography, a circumscribed lesion (cystic defect) lateral to the right nucleus amygdalae.