Overexpression of corticotropin releasing factor in the central nucleus of the amygdala advances puberty and disrupts reproductive cycles in female rats.

Prolonged exposure to environmental stress activates the hypothalamic-pituitary-adrenal (HPA) axis and generally disrupts the hypothalamic-pituitary-gonadal axis. Because CRF expression in the central nucleus of the amygdala (CeA) is a key modulator in adaptation to chronic stress, and central administration of CRF inhibits the hypothalamic GnRH pulse generator, we tested the hypothesis that overexpression of CRF in the CeA of female rats alters anxiety behavior, dysregulates the HPA axis response to stress, changes pubertal timing, and disrupts reproduction. We used a lentiviral vector to increase CRF expression site specifically in the CeA of preweaning (postnatal day 12) female rats. Overexpression of CRF in the CeA increased anxiety-like behavior in peripubertal rats shown by a reduction in time spent in the open arms of the elevated plus maze and a decrease in social interaction. Paradoxically, puberty onset was advanced but followed by irregular estrous cyclicity and an absence of spontaneous preovulatory LH surges associated with proestrous vaginal cytology in rats overexpressing CRF. Despite the absence of change in basal corticosterone secretion or induced by stress (lipopolysaccharide or restraint), overexpression of CRF in the CeA significantly decreased lipopolysaccharide, but not restraint, stress-induced suppression of pulsatile LH secretion in postpubertal ovariectomized rats, indicating a differential stress responsivity of the GnRH pulse generator to immunological stress and a potential adaptation of the HPA axis to chronic activation of amygdaloid CRF. These data suggest that the expression profile of this key limbic brain CRF system might contribute to the complex neural mechanisms underlying the increasing incidence of early onset of puberty on the one hand and infertility on the other attributed to chronic stress in modern human society.

Plasmapheresis in fulminant acute disseminated encephalomyelitis.

We report an 11-year-old girl with acute disseminated encephalomyelitis (ADEM) who developed respiratory failure and coma despite the use of corticosteroid and intravenous immunoglobulin. We performed plasmapheresis four times, which improved her level of consciousness, hyperesthesia, external ophthalmoplegia and muscle weakness, and led to the normalization of brain and spinal cord MRI. Plasmapheresis might be an effective treatment in cases of fulminant ADEM.

Developmental changes in cyclooxygenase mRNA expression in the kidney of rats.

Prostaglandins, synthesized by cyclooxygenase (COX), regulate renal hemodynamics and also epithelial water and solute transport. To determine whether COX mRNA expression changes with age, we studied expression in renal medulla and in cortex in developing rats at various ages. We also examined age-related changes in COX mRNA expression induced by lipopolysaccharide (LPS). COX mRNA was quantitatively analyzed in a real-time polymerase chain reaction (PCR) with dual-labeled fluorogenic probes. COX-1 mRNA expression did not change with age in cortex or medulla. COX-2 mRNA expression was highest in 1-week-old rats and lowest in 4- and 8-week-old rats. Lipopolysaccharide treatment did not alter COX-1 mRNA expression in infantile or adult rats. In adults, LPS at 1, 5, and 10 mg/kg induced COX-2 mRNA expression in renal medulla; the higher doses, 5 and 10 mg/kg, induced COX-2 expression in cortex. In infantile rats, COX-2 mRNA, already high in the unmanipulated state, was further increased by only 1 mg/kg LPS in both renal cortex and medulla. Age-related changes in the expression of COX-2 mRNA might be responsible for changing physiologic characteristics of renal function during postnatal development in rats, and may be important in renal cortical development.

MR evaluation of the hippocampus in patients with congenital malformations of the brain.

BACKGROUND AND PURPOSE: Developmental changes in hippocampal formations (HFs) have been reported in association with agenesis of the corpus callosum, lissencephaly, and holoprosencephaly. The purpose of this study was to evaluate the developmental changes in HFs in patients with a variety of other congenital brain malformations. METHODS: MR images of 44 patients with congenital brain malformations associated with 11 different brain disorders were reviewed retrospectively. Five patients had more than two anomalies. Imaging and clinical findings were evaluated for the shape, size, degree of inversion, and side of abnormal HF. RESULTS: Vertically oriented or globular-shaped HFs were observed in 28 patients (64%) on coronal MR images. All patients with agenesis of the corpus callosum (n = 7), lissencephaly (n = 1), holoprosencephaly (n = 3), and Fukuyama muscular dystrophy (n = 3) had an abnormal HF. A high prevalence of abnormalities was observed in patients with polymicrogyria (11/12, 92%), heterotopia (4/5, 80%), tuberous sclerosis (2/3, 67%), and schizencephaly (2/4, 50%). Patients whose abnormalities were symmetrical had bilateral abnormal HFs, whereas those with polymicrogyria, schizencephaly, and heterotopia, whose abnormalities were localized, tended to have unilateral abnormal HFs. CONCLUSION: Hippocampal developmental abnormalities are found in a high percentage of patients with congenital malformations. Focusing on the morphologic abnormalities of the HF on coronal MR images may help in the detection of diseases associated with brain anomalies, especially subtle cortical disorders.

Acute cerebellar ataxia with abnormal MRI lesions after varicella vaccination.

A 2-year-old boy, with the primary difficulties of nausea and vomiting, developed a staggering gait and dysarthria 10 days after varicella vaccination. Magnetic resonance imaging demonstrated multiple areas of high signal intensity in the white matter of the cerebellum, predominantly in the parieto-occipital white matter and both globus pallidi. He did not present any signs of myelitis or encephalitis and thus his cerebellar dysfunction was diagnosed as acute cerebellar ataxia, which is, generally speaking, not an etiologic entity but a clinical syndrome. Magnetic resonance imaging may reveal a variety of abnormalities of the central nervous system in acute cerebellar ataxia.

Urinary N-acetyl-beta-glucosaminidase and guanidinoacetic acid levels in epileptic patients treated with anti-epileptic drugs.

We investigated potential renal functional impairment induced by chronic use of anti-epileptic drugs (AEDs) in 79 epileptic children. They were divided into five groups: valproic acid (VPA) monotherapy where the serum concentration (SC) of VPA was no less than 60 micrograms/ml (VPA [SC > or = 60]) (15 cases), VPA monotherapy where the SC VPA was less than 60 micrograms/ml (VPA [SC < 60]) (29 cases), phenobarbital monotherapy (PB) (7 cases), carbamazepine monotherapy (CBZ) (16 cases), and polytherapy containing VPA (12 cases). Urinalysis (proteinuria and hematuria) and serum creatinine were normal except for two cases of proteinuria and two cases of hematuria. The level of urinary excretion of N-acetyl-beta-glucosaminidase (u-NAG) was high in 29% of all patients, and 47% of VPA (SC > or = 60), 38% of CBZ, 25% of polytherapy, and 24% of VPA (SC < 60) groups. There was a significant positive correlation between serum concentration of VPA and u-NAG/urinary creatinine (u-Cr). The level of guanidinoacetic acid (u-GAA) excreted in the urine was normal except in one patient. U-NAG/u-Cr may be a more sensitive marker than u-GAA/u-Cr for renal functional impairment in AED therapy.

Krabbe's disease with giant lamellar bodies in Purkinje cells.

An autopsy case of Krabbe's disease in a child aged 6 years 7 months 1s reported. Histologically, globoid cells, loss of myelin, oligodendroglia and axons, and marked gliosis were observed in the white matter. In addition, there was severe neuronal loss in the thalamus, pontine nucleus, dentate nucleus and olivary nuclei. The cerebellar cortex showed extensive loss of granular cells and moderate loss of Purkinje cells. There were numerous eosinophilic inclusion bodies, ranging from 2 to 15 microns in diameter, in the dendrites of Purkinje cells. The ultrastructural findings for the inclusion bodies were consistent with those of giant lamellar bodies. In addition, smaller lamellar bodies were frequently observed in the perikarya and dendrites. Although loss of granular cells was more prominent in the hemispheres than in the vermis, the inclusion bodies were observed in hemispheres but were infrequently observed in the vermis. They were found in degenerated Purkinje cells which had lost afferent fibers. It is considered that these giant lamellar body inclusions are an unusual type of degenerative structure specific to Purkinje cells.

P300 event-related potentials in epileptic children.

To evaluate the cognitive function of epileptic children, we examined P300 in 50 patients, 32 with idiopathic generalized epilepsy (IGE) and 18 with temporal lobe epilepsy (TLE), and 39 normal children. There were significant negative correlations between age and P300 latencies at Pz and Cz in normal controls. For data analysis, we used the age-corrected latency, which was calculated as the interval between the actual and predicted P300 latencies. The predicted latency was calculated with the regression equation as the relationship between P300 latency and age in normal controls. The age-corrected P300 latencies recorded from Pz and Cz were significantly longer in patients with IGE (41.5 +/- 13.1, 42.0 +/- 12.5) than in control subjects (0 +/- 7.5, 0 +/- 7.9). There were no significant differences in age-corrected P300 latencies between patients with TLE (21.2 +/- 17.6, 31.5 +/- 17.0) and controls, or IGE and TLE. Recently, it was considered that the mesencephalic reticular formation and thalamus may play major roles in the genesis of generalized epilepsy, so we speculate that dysfunction of these systems may contribute to the prolongation of P300 in children with idiopathic generalized epilepsy.