Efficacy of high dose steroid therapy in children with severe acute transverse myelitis.

No effective treatment has been demonstrated for patients with acute transverse myelopathy. In a multicentre controlled study, 12 children with severe acute transverse myelopathy were treated with intravenous methylprednisolone (IVMP) and compared with a historical group of 17 patients. The treatment had a significant effect on the proportion of patients walking independently at 1 month and on the proportion with full recovery at 1 year, with no differences in the frequency of complications between the two groups.

Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.

Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.

Adaptation in neonatology of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit.

BACKGROUND: The bactericidal efficacy of aminoglycosides is directly related to peak serum concentration (Cmax), particularly the first one. Transitory high concentrations of aminoglycosides do not result in such a high drug uptake by renal and cochlear tissues because of the saturation of cell binding sites. These observations have led to the concept that less frequent administration of relatively larger doses of aminoglycosides would be of interest in treating infectious diseases. OBJECTIVE: Prospective evaluation of a dosing chart of amikacin (Ak) in high-risk neonates suspected of infection within the first 2 days of life. This dosing chart was based on a previous pharmacokinetic population study published elsewhere, treated accordingly to the new once-daily concept of aminoglycoside administration. STUDY DESIGN: One hundred and seventy-seven neonates (69 females and 108 males; mean gestational age (GA +/-SD: 33.6 +/- 4.1 weeks (W) received Ak regimen dosage according to the following dosing chart: Group (Gr) 1a GA <28 W: 20 mg/kg/42 h; Gr 1b GA 28 /= 37 W: 15.5 mg/kg/24 h. In case of asphyxia, hypoxic episode and intercourse treatment with indomethacin, the interval was systemically increased by 6 h whatever the GA groups. The mean duration time of Ak treatment (+/- 1 SD) was 5.00 +/- 2.01 days (range 2-13). Ak serum concentrations 1 h after completion of 30 min infusion (C1h), and successive Ak serum concentrations just before next administration depending on the difference of interval between each group (so defined minimum serum concentration (Cmin)), were determined in each neonate. Creatininemia during the fist postnatal weeks was used as an index of glomerular filtration rate; brainstem auditory evoked potentials (BEAPs) were used in 139 babies when reaching a postconceptional age of >/= 36 weeks to assess possible ototoxicity, and were compared to values from a group of term and a group of preterm babies, previously defined as our reference control groups. RESULTS: At day 1 of treatment, there was no correlation between the Ak C1hS and the GA at birth (mean 27.8 +/- 5.21 microgram/ml (+/- 1 SD); median 28; r = -0.003; range 10-40). In the same way, there was no correlation between the first Ak CminS and the GA at birth (mean 3.7 +/- 2.0 microgram/ml (+/- 1 SD); median 3.0; r = -0.33; range 0-10). The lack of correlation between these first observed C1hS and CminS and the GA at birth suggests the validity of our previous established dose regimen recommendations. Analyzing the data between groups, the mean value +/- 1 SD of Ak C1hS at day 1 of treatment was not significantly different (p > 0.05). Concerning the first Ak CminS, a significant difference (p < 0.01) was only observed when comparing groups 1a, 1b and 2 to group 4. However, this significant difference disappeared when comparing the successive next Ak CminS between groups while each interval remained the same, suggesting a positive postnatal maturation of the renal clearance. In the same way, creatininemia showed a significant and normal decrease (p < 0.01) in each group during the first postnatal weeks. Threshold values of BEAPs at 30 dB showed no significant difference (p > 0.05) between the treated groups (preterm group and term group) and the corresponding control groups. While the primary aim of the study was not to test the bactericidal efficacy of this new regimen, the recovery was excellent in 37 babies with proven or highly suspected infectious disease, except in 1 of them who died from septic shock (group B Streptococcus). After 5 years of using this kind of Ak administration in the unit, minimal inhibitory concentration profiles tested in 43 successive bacterial strains collected from inborn patients remained adequate. (ABSTRACT TRUNCATED)

Multimodality evoked potentials as a prognostic tool in term asphyxiated newborns.

Hypoxic-ischemic (HI) events may cause permanent brain damage, and it is difficult to predict the long-term neurological outcome of survivors. Multimodality evoked potentials (MEPs), using flash visual (fVEPs), somatosensory (SEPs), and brain-stem auditory evoked potentials (BAEPs) may assess the cerebral function in term neonates. MEPs were recorded in 40 hypoxic-ischemic term or near-term neonates during the first week of life in order to predict the neurological outcome. A 3 point grading system registered either mild, moderate, or severe abnormalities. At 24 months of corrected age, the infants were assessed with a blind protocol to determine neurological development. Grade 0 fVEPs and SEPs were associated with a normal neurological status with 100% (P < 0.001) of the infants. Abnormal SEPs or total grade (VEPs + SEPs) > I were not associated with normal outcomes (P < 0.0001). Normal BAEPs did not predict a normal outcome, but severely abnormal BAEPs did predict an abnormal outcome. A significant correlation was found between EP (VEPs + SEPs) grade (r = 0.9, P < 0.0001), Sarnat stage (r = 0.6, P < 0.001), and clinical outcome. This study confirmed that both fVEPs and SEPs are more accurate as prognostic indicators for term neonates. EPs (VEPs + SEPs) also are more accurate in predicting the ultimate neurological outcome compared with the Sarnat scoring.

Perisylvian dysgenesis. Clinical, EEG, MRI and glucose metabolism features in 10 patients.

We studied 10 patients who had neurological disorders with a MRI-based diagnosis of perisylvian dysgenesis based on the fact that the parasagittal and centrifugal extremity of the sylvian fissure was abnormally mesial. This abnormality was bilateral in seven cases; in the other three patients, the contralateral sylvian fissure appeared either normal (two cases) or enlarged (open operculum). The perisylvian cortex had a polymicrogyric appearance in most patients. Potential aetiopathogenic factors were determined in four patients. In two of them, ischaemia at mid-gestation was ascribed to death of a co-twin in a context of monozygotic twinning. In the other two patients, who were siblings, genetic factors were suspected. Pseudobulbar palsy was found in eight patients and epilepsy in five patients. We used PET with [18F]fluorodeoxyglucose to test the hypothesis that, despite this clinical and MRI heterogeneity, regional cerebral glucose distribution could have common features in these patients. The analysis of PET data was performed by visual inspection in two cases and by using statistical parametric mapping (SPM) in eight patients compared with a control group. Segmented grey matter MRIs of seven out these patients were also analysed using SPM. We found that the abnormal perisylvian cortex had normal grey matter activity in eight patients and in the other two there was a heterogeneous pattern with areas of preserved metabolism and of decreased metabolism. Metabolic changes were also detected outside the polymicrogyric-like cortex; three patients had hypometabolic areas in cortical regions where the MRI appeared normal and had a normal intensity. When polymicrogyria extended into the white matter, this ectopic dysgenetic cortex was associated with a grey matter pattern within the white matter territory, and was detected by SPM as areas of PET hypermetabolism and MRI hyperintensity. In order to detect possible metabolic changes undetected by the individual analyses, the group of patients was compared with the control group. This comparison revealed bilateral hypometabolism in the frontal opercular cortex. We propose that these PET data be considered in light of the presumed cyto-architectonic pattern of perisylvian dysgenesis, i.e. polymicrogyria. In this malformation, two dense cell layers are separated by a necrotic sparse cell layer. We speculate that the amount of synaptic activity preserved in these dense cell layers depends on the importance and timing of the necrotic process; this hypothesis accounts for the large range of metabolic patterns found, from profoundly decreased glucose metabolism to nearly normal activity.

Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity.

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age > or = 34 weeks; postnatal age < or = 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta 2-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of > or = 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.

Sjögren-Larsson-like syndrome with bone dysplasia and normal fatty alcohol NAD+ oxidoreductase activity.

We report a boy and girl with a "new" multiple congenital anomalies/mental retardation syndrome which resemblances Sjögren-Larsson syndrome. Both patients had a concordant pattern of anomalies consisting of congenital lamellar ichthyosis with spontaneous improvement, moderate mental retardation, mild pyramidal involvement, telecanthus, flat facies, stubby long bones, and coxa valga. Severe myopia, ventriculoseptal defect, and postaxial polydactyly were present in the girl who had more severe bone involvement with dense, enlarged metaphyses, vertebral dysplasia, and advanced skeletal maturation of the lower limbs. Long-chain fatty alcohol NAD+ oxidoreductase (FAO) and steroid sulfatase were normal.

Neonatal seizures and severe hypotonia in a male infant suffering from a defect in peroxisomal beta-oxidation.

In this paper, we describe a baby male born to healthy non-consanguineous parents presenting at birth with hypotonia and seizures. Additional salient clinical features included the development of glaucoma, the absence of significant facial dysmorphism and the absence of liver enlargement or renal cysts. The patient died at the age of 3 months. At autopsy, liver fibrosis and kidney glomerulosclerosis were noted. Neuropathological findings included pachygyria of the olivary nuclei and cerebellar neuronal heterotopias. There was no evidence for a demyelinating process. Biochemically, the patient was found to have elevated plasma levels of very-long-chain fatty acids (VLCFA) and abnormal bile acid intermediates, whereas other indicators of peroxisomal function (plasmalogen biosynthesis and plasma pipecolic acid) were normal. Catalase staining of a liver biopsy specimen revealed peroxisomes to be present in normal numbers, although some were abnormally large. Trilamellar inclusions typical of a peroxisomal fatty acid oxidation defect were present in macrophages. Indeed, beta-oxidation of the very-long-chain fatty acid hexacosanoic acid (C26:0) was found to be strongly deficient. Fatty acyl-CoA oxidase activity in the patient's liver was normal, however. Furthermore immunocytochemical studies using antibodies against acyl-CoA oxidase, bifunctional protein and peroxisomal thiolase, revealed the normal localization of all three enzyme proteins within the peroxisomes. We suggest that our patient has a selective peroxisomal beta-oxidation defect, a recently identified heterogeneous group of early-onset peroxisomal disorders distinct from the Zellweger syndrome and other generalized peroxisomal disorders.

Effects of phenobarbital on cerebral blood flow in the newborn piglet.

To determine the neonatal cerebrovascular effect of a therapeutic dose and a high dose of phenobarbital (Pb), the effect of Pb on cerebral blood flow (CBF) and total brain oxygen consumption (CMRO2) was studied in three groups of awake newborn piglets (aged 1-3.5 days). Group I (control n = 9) received normal saline solution, group II (n = 9) received a therapeutic dose of Pb (15 mg/kg i.v.) and group III (n = 9) received a high Pb dose (45 mg/kg i.v.). Four CBF measurements per piglet using radioactive microspheres (141Ce, 85Cr, 95Nb, 46Sc), arterial blood gases, O2 content, hematocrit and plasma glucose were obtained at 0, 15, 30, 60 min after saline or Pb injections. In all groups, pH, PaO2, PaCO2, blood pressure, heart rate, temperature and plasma glucose remained unchanged except a 14% decrease (p < 0.01) in blood pressure and an increase (p < 0.05) in PaCO2, 60 min after drug injection in groups II and III. Total CBF in group II decreased by 14% (p < 0.05) 15 min after drug injection and was significantly lower (p < 0.05) than control (group I) but returned to baseline after 30 min. High Pb dose progressively lowered CBF by 11% 15 min after drug injection and produced a significant decrease by 20% (p < 0.01) 30 min after drug injection with return to baseline after 60 min. Similar effects were noted in different brain regions (cerebrum and thalamus). CMRO2 remained unchanged in the control group; however, it was decreased by 35% (< 0.01 p > 0.05) 15 min after drug injection and returned to baseline after 60 min. In group III, high Pb dose lowered CMRO2 by 31% 30 min (p = 0.02) after drug injection. Data indicate that Pb exerts a minimal but transient dose-dependent effect on CBF and CMRO2.

Effects of ethacrynic acid in the newborn infant.

The effects of ethacrynic acid on electrolyte and water excretion were examined in 10 neonates with fluid overload states. Ethacrynic acid (1 mg/kg IV) produced a 10-fold increase in FENa+ and FECl - and a sixfold increase in urine volume and osmolar clearance. These effects peaked within 1 hour of ethacrynic acid administration, and progressively decreased to the baseline value by 5 hours after drug administration. The mean excretion of potassium increased by 280% in 1 hour, and returned to baseline value after 5 hours. The mean Ca++ excretion increased fourfold after 1 hour, and the effect lasted for 4 hours. Two infants developed mild hyponatremia. Our data emphasize the prolonged diuretic and saluretic effect of ethacrynic acid in neonates.