Neonatal somatosensory evoked potentials: maturational aspects and prognostic value.

The aim of this prospective study was to evaluate the diagnostic role of somatosensory evoked potentials (SEP) during the neonatal period with regard to maturational changes and prognostic value in perinatal hypoxic-ischemic encephalopathy. Median nerve SEP analysis was performed in 31 healthy infants (group A1, 33-35 weeks, n = 10; group A2, 36-37 weeks, n = 11; group A3, 38-41 weeks, n = 10) and in 10 term infants with hypoxic-ischemic encephalopathy (group B). Cortical latency N1 and central conduction time values were analyzed for group A in relation to postconceptional age and postnatal age and for group B in relation to degree of hypoxic-ischemic encephalopathy and neurodevelopmental outcome (at the mean age of 6.6 + or - 1.6 years). Central latencies were correlated with postconceptional age but not postnatal age. Mean N1 latency and central conduction time values did not differ significantly between groups A1 and A2; the most pronounced decrease was between groups A2 and A3 (postconceptional ages 36-37 vs 38-41 weeks). In group B, central latencies were prolonged, compared with controls (P < 0.001), but were not significantly correlated with long-term outcome in patients with moderate hypoxic-ischemic encephalopathy (n = 6). Neonatal SEP analysis thus is an objective and noninvasive method for assessing functional integrity of the somatosensory pathway. In term infants, SEPs are a valuable additional tool for early diagnosis of hypoxic-ischemic encephalopathy, but are not prognostic of neurodevelopmental long-term outcome in moderate hypoxic-ischemic encephalopathy.

HIF-1-regulated vasoactive systems are differentially involved in acute hypoxic stress responses of the developing brain of newborn mice and are not affected by levetiracetam.

Hypoxia-inducible transcription factor-1 (HIF-1) is critically involved in adaptive endogenous mechanisms to hypoxic brain injury by transcriptional activation of specific target genes that restore oxygen supply. Exogenously, neuroprotective properties of levetiracetam (LEV) have been suggested in experimental cerebral ischemia and epilepsy. We aimed to elucidate 1) effects of acute hypoxic distress on HIF-1 and vasoactive target genes, and 2) effects of LEV on HIF-1-regulated mechanisms in the brain at early developmental stages. To this end, we studied the impact of hypoxia in the presence or absence of LEV on the O2-dependent HIF-1alpha subunit as well as on VEGF and iNOS in the developing brain of normoxic and hypoxic mice. C57BL/6 mice (P0, P7) were treated with saline or LEV (i.p.; 50 mg/kg) 1 h before exposure to either normoxia (21% O2; N) or hypoxia (8% O2 of 6 h; H) without reoxygenation. HIF-1alpha was analyzed by Western blot and immunohistochemistry and mRNA levels were quantified by TaqMan RT-PCR. Hypoxia led to prominent accumulation of cerebral HIF-1alpha protein in cortical neurons and glial cells and significant up-regulation of VEGF mRNA at P0 (N, 0.018+/-0.002, vs. H, 0.031+/-0.003, n=6; p<0.05) and P7 (N, 0.096+/-0.032, vs. H, 0.873+/-0.069, n=7; p<0.001). Interestingly, we detected a significant decrease of iNOS mRNA levels in hypoxic brains. LEV treatment did not alter HIF-1alpha accumulation either in normoxic or hypoxic brains (P0, P7). Moreover, significant changes of VEGF and NOS mRNA levels did not occur with the exception that hypoxia-induced decreased iNOS levels were not observed in P0 brains. We conclude that acute systemic hypoxia differentially affects expression of HIF-1-regulated vasoactive factors in the newborn mouse brain. Of clinical importance, LEV treatment did not alter crucial HIF-1-regulated neuroprotective mechanisms.

Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in young children.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.

A novel 5q35.3 subtelomeric deletion syndrome.

We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site. Subtracting the symptoms of Sotos syndrome from the published patients with larger 5q35.3 deletions allowed us to delineate a distinct phenotype of prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia and delay of reaching motor milestones, but speech development within normal limits, wide fontanels, failure to thrive with postnatal short stature, and multiple minor anomalies such as mildly bell-shaped chest, minor congenital heart disease, and a distinct facial gestalt, associated with the novel 3.5 Mb cryptic deletion. We further showed in our patient that the deletion of the LCT(4) synthase gene results in a reduction of cysteinyl leukotriene synthesis to about 65% compared to normal values. The prenatal nuchal lymphedema associated with this deletion syndrome my be related to the deletion of the FLT4 gene causing autosomal dominant primary lymphedema and contributes to the differential diagnosis of increased fetal nuchal translucency.