Yasuhiko Kawakami

A comparative study of nitric oxide, glutathione, and glutathione peroxidase activities in cerebrospinal fluid from children with convulsive diseases/children with aseptic meningitis.

It has been reported that active oxygen and/or free radicals are produced in the central nervous system (CNS) compartment in patients with bacterial meningitis, so it is supposed that the levels of endogenous antioxidative scavengers in the cerebrospinal fluid (CSF) are elevated as an adaptive reaction to bacterial meningitis, which exerts severe stress on the human body. We assumed that they are also elevated in patients with convulsive diseases. Nitric oxide (NO) and endogenous antioxidative scavengers (glutathione (GSH), glutathione peroxidase (GPX), (total) superoxide dismutase (T-SOD), manganese superoxide dismutase (Mn-SOD), and catalase) were measured in CSF from a group of child patients with various neurological diseases and a control group. NO, GSH, and GPX activities in CSF from the patients with convulsive diseases were significantly higher than in those with aseptic meningitis or in the controls. Furthermore, all parameters in CSF from patients with bacterial meningitis were significantly higher than in any other group. The present study suggests that oxidative stress may be associated with the pathophysiology of convulsion and that its clinical attenuation will lead to improvement in the prognosis for convulsive diseases.

Clinical and immunological significance of neopterin measurement in cerebrospinal fluid in patients with febrile convulsions

Neopterin is synthesized mainly by monocytes/macrophages and is considered to be a marker for activation of the cellular immune system. It has been reported that cerebrospinal fluid (CSF) neopterin levels are significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or non-pleocytotic CSF. In this study levels of neopterin and interferon-gamma (IFN-gamma) were measured in children with non-pleocytotic CSF. The CSF neopterin levels were significantly higher in patients with typical febrile convulsions (FCs) (15.0 +/- 4.5 nmol/l) than in those with pyrexia without convulsions (6.5 +/- 2.7 nmol/l) or convulsions without pyrexia, namely, epilepsy (4.8 +/- 2.4 nmol/l). The CSF neopterin/serum neopterin ratio (C/S ratio) was also higher in patients with typical FCs (1.54 +/- 0.83) than in those with pyrexia without convulsions (0.32 +/- 0.18) or convulsions without pyrexia (0.77 +/- 0.28). Patients with prolonged FCs tended to have higher CSF neopterin levels than those with typical FCs. There was also a tendency for CSF IFN-gamma levels to be higher in patients with FCs than in those with pyrexia without convulsions or convulsions without pyrexia. The results of the present study suggest that some immune activation in the central nervous system (CNS) compartment may be related to the mechanisms of FCs.

An 8-year-old boy with vertebral artery dissection with cerebellar ataxia featuring suspected vertebral artery hypoplasia

We report an 8-year-old boy with left vertebral artery dissection featuring cerebellar ataxia in which congenital vertebral artery hypoplasia was suspected as a predisposing factor in the dissection. The patient suddenly suffered from vertigo and vomiting while swimming, and he was brought to our department. The initial brain Computed Tomography (CT) demonstrated no abnormalities, and his symptoms disappeared the next morning. However, one month after onset, brain Magnetic Resonance Imaging (MRI) revealed ischemic changes (infarction) in the left cerebellum. Transfemoral angiography showed complete occlusion at the C2 portion of the left vertebral artery, suggesting dissection and diffuse narrowing of the proximal segment of the occlusion site. Three-dimensional CT angiography also revealed diffuse narrowing of the left vertebral artery from the bifurcation of the subclavian artery. He has since been living daily life without any difficulties. The detailed etiology of cerebral artery dissection remains unknown, but arterial anomalies should be considered as a predisposing factor.

Treatment with flunitrazepam of continuous spikes and waves during slow wave sleep (CSWS) in children

We describe our treatment of two boys with continuous spikes and waves during slow wave sleep (CSWS). One of the boys was suffering from non-convulsive status epilepticus and the other from conscious disturbance with automatism. Their ictal EEG readings showed continuous diffuse spike and wave complexes, which were considered to show electrical status. The boys were diagnosed as having CSWS, and were later diagnosed with Landau-Kleffner syndrome (LKS). EEG readings returned to normal on intravenous injection of flunitazepam (FZP) at a dose of 0.02 mg/kg, suggesting that FZP is an effective treatment for CSWS.

Theophylline-induced changes in mouse electroencephalograms.

Theophylline can induce life-threatening seizures in humans, especially in infants, but the mechanism of induction remains unknown. We investigated the effects of orally administered theophylline on mouse electroencephalograms (EEGs). ddY mice, which are generally completely free of seizures, were used for the experiments. While EEGs, used as controls, showed no paroxysmal spike discharges, theophylline induced clear spike discharges. This study demonstrated that theophylline administered at doses that achieve low serum concentrations can cause spike discharges in mouse EEGs even without causing clinical seizures, indicating that theophylline plays a potent role in subclinical epileptogenicity.

Serum KL-6 and surfactant protein D in children with 2009 pandemic H1N1 influenza infection

Background:  A global pandemic influenza A (H1N1) outbreak occurred in 2009. Rapid progress of respiratory distress is one of the characteristic features of pandemic influenza A (H1N1) infection. The physiologic mechanism causing hypoxia in pandemic influenza A (H1N1) infection, however, has not been elucidated.

Effects of Edaravone on Hippocampal Antioxidants in EL Mice

BACKGROUND The role of oxidative stress in susceptibility to seizures has been the focus of several recent studies. The aim of the present study was to evaluate the antiepileptic effects of the free radical scavenger edaravone on EL mice, a strain that is highly susceptible to convulsive seizures. METHODS EL mice were treated intraperitoneally with edaravone or saline for 1 week. The levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and 3 isozymes of superoxide dismutase (SOD) (cytoplasmic copper- and zinc-containing SOD, extracellular SOD, and mitochondrial manganese-containing SOD) were measured in the hippocampus, and electroencephalograms (EEGs) were used to evaluate seizure sensitivity. RESULTS Hippocampal levels of GSSG were lower in the edaravone group than in the untreated control group, and the GSH/GSSG ratio, Cu/Zn-SOD, and EC-SOD activities were higher in the edaravone group. Edaravone shortened the duration of interictal spike discharges and clinically suppressed epileptic seizures. CONCLUSION Edaravone increases antioxidant potency and reduces seizure susceptibility in EL mice, making it a promising novel antiepileptic agent.

Cerebrospinal Fluid Levels of Neopterin in Child Patients with Neurological Diseases-In Correlation with IFN-γ or TNF-α

Cerebrospinal fluid (CSF) neopterin levels were measured in child patients with neurological diseases. CSF neopterin levels on admission were significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or in those with non-pleocytotic CSF. CSF neopterin levels in patients with bacterial meningitis one day after admission were higher than those on admission and were markedly elevated with high levels of CSF IFN-γ and TNF-α. CSF neopterin levels in patients with bacterial meningitis one day after admission were related to the period of positive serum C-reactive protein. In patients with non-pleocytotic CSF, CSF neopterin and CSF IFN-y levels were higher in patients with febrile convulsion (FC) than in those with pyrexia only or convulsion (including epilepsy) only. These results suggest that elevation of CSF neopterin in bacterial meningitis results from monocytes/ macrophages costimulated with IFN-γ and TNF-α and that immunological activation in the central nervous system is one of the mechanisms of onset with FC.

A Girl with Idiopathic Epilepsy Showing Forced Normalization after Levetiracetam Administration

BACKGROUND Forced normalization has been reported in association with almost all anti-epileptic drugs. PATIENT We report on a 9-year-old girl with idiopathic epilepsy who showed forced normalization after administration of levetiracetam (LEV). She initially presented with generalized tonic-clonic seizures when she was 4 years old. Diffuse sharp and slow wave complexes (SWCs) were observed on electroencephalography (EEG). We prescribed sodium valproate (VPA) and benzodiazepines, but the seizures and EEG findings worsened gradually. Although subsequent administration of LEV stopped the seizures, the patient became subject to episodes of rage and violent behavior. Forced normalization was confirmed by the disappearance of SWCs on EEG. We reduced the dose of LEV and tried in various ways to resolve the situation, but finally we had to abandon LEV. CONCLUSIONS To the best of our knowledge, this is the first report of a patient with idiopathic epilepsy but without disabilities in everyday life showing forced normalization associated with LEV administration.

Neopterin May Enhance TNF-a-mediated Mononuclear Cell Death in the Cerebrospinal Fluid of Patients with Bacterial Meningitis

Abstract It has been reported that levels of neopterin are elevated in the cerebrospinal fluid (CSF) of patients with bacterial meningitis, and that neopterin enhances cell death induced by H2O2 in mouse monocytes and macrophages. In the present study, we examined the relationship between the disappearance of inflammatory cells in the CSF of patients with bacterial meningitis and the effects of neopterin on cell death. We hypothesized that the rapid cell death of mononuclear leukocytes (MNs) and survival of polymorphonuclear leukocytes (PMNs) brought about by high levels of tumor necrosis factor-a TNF-a may be related to the pathophysiology of PMN predominance in the CSF of patients with bacterial meningitis. Peripheral blood leukocytes separated into two fractions (MNs and PMNs) were suspended in CSF samples from patients with bacterial meningitis, and the cell death rate was determined with MTT assay. The higher the CSF TNF-a level, the higher the MN mortality rate tended to be. In contrast, PMNs were able to survive high levels of TNF-a in the CSF. For control purposes, MNs and PMNs were also suspended in various conditioned media. The same association between TNF-a levels and MN mortality was observed, as was the survival of PMNs. The addition of neopterin enhanced the cytocidal effect of TNF. The present study suggests that neopterin is related to PMN predominance in the CSF of patients with bacterial meningitis via the effect of TNF-a on cell death.