Mitsutoshi Munakata

Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy

Two children with influenza A-related encephalopathy were treated with a combination of mild hypothermia (deep body temperature of the forehead: 35 degrees C) and anticytokine agents (high-dose methylprednisolone and ulinastatin), while receiving amantadine. One of the cases exhibited acute necrotizing encephalopathy on computed tomography (CT). Although no severe complications occurred, correctable hypokalemia and hyperglycemia occurred in both cases. Both patients recovered without any neurological sequelae. Our therapeutic protocol appears to be effective for managing influenza A-related encephalopathy.

Altered Distribution of KCC2 in Cortical Dysplasia in Patients with Intractable Epilepsy

Summary:  Purpose: To examine the distribution of KCC2, a neuron‐specific K+–Cl− cotransporter, in human cortical dysplasia (CD).

Caffeine response in pyramidal neurons freshly dissociated from rat hippocampus

The effect of caffeine on the CA1 pyramidal neurons freshly dissociated from rat hippocampus was investigated with nystatin-perforated patch technique under voltage-clamp condition. Caffeine evoked a transient outward current (Icaffeine) in a concentration-dependent manner at a holding potential of -40 mV. The activation and inactivation of Icaffeine were accelerated with increasing caffeine concentration. The reversal potential for Icaffeine was close to K+ equilibrium potential. The Icaffeine was not blocked by apamin and 4-aminopyridine but suppressed by charybdotoxin, tetraethylammonium, quinine and Ba2+. Thus, the pharmacological characteristics of Icaffeine were similar to those of Ca(2+)-activated K+ current having a large conductance (IC), which generates a fast afterhyperpolarization (a.h.p.). Icaffeine was depressed by pretreatment with a membrane-permeant Ca2+ chelator (BAPTA-AM) and by depletion of the Ca(2+)-induced Ca2+ release (CICR) pool with ryanodine. A blocker of CICR sites, procaine, potently depressed the Icaffeine. In the absence of the extracellular Ca2+, an application of 10 mM caffeine depleted the caffeine-sensitive Ca2+ pools. Icaffeine recovered in an exponential fashion in the presence of the extracellular Ca2+. It was concluded that rat hippocampal pyramidal neurons have a caffeine-sensitive Ca2+ pool. Furthermore, the Ca2+ released from the pool evokes K+ current similar to IC current and hyperpolarizes the neurons.

A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease

Alexander disease is a rare, progressive, leukoencephalopathy whose hallmark is the widespread accumulation of Rosenthal fibers. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death before adulthood. Definitive diagnosis of Alexander disease has required biopsy or autopsy to demonstrate the presence of Rosenthal fibers. However, missense mutations in the coding region of the glial fibrillary acidic protein (GFAP) gene have recently been associated with a high percentage of pathologically proven cases. Here we report that a 10-year-old Japanese patient who showed clinical signs of Alexander disease is heterozygous for a C to T transition in which predicts a novel A244V amino acid substitution in the conserved 2A alpha-helix domain of GFAP. The nucleotide change was not found in 65 normal individuals (130 alleles). These results provide further support for a causative role for GFAP mutations in Alexander disease, and suggest DNA sequencing as an alternative diagnostic to biopsy.

Heterogeneity of ictal SPECT findings in nine cases of west syndrome

Summary: We evaluated the ictal and interictal single photon emission computed tomography (SPECT) of 9 patients with West syndrome (WS). In this group, we noted two clear patterns of cortical hyperperfusion and subcortical hyperperfusion in the ictal SPECT. Both patterns were different from the previously documented ictal patterns for complex partial seizures (CPS) or secondarily generalized seizures. Our results suggest that the tonic spasms of WS do not always have a single neu‐rophysiological basis; e.g., patients with hemihypsarrhythmia and focal hypsarrhythmia did not show ictal hyperperfusion of the lesion with hypsarrhythmia. These findings indicate that the origin of hypsarrhythmia as an EEG feature and the origin of tonic spasms may be different in such patients. In particular, hypsarrhythmia appears to originate from cortical lesions, whereas the subcortical structures may be primarily responsible for the tonic spasms. Our report is the first published study of ictal SPECT in patients with WS.

Differential properties of type I and type II benzodiazepine receptors in mammalian CNS neurones

1 The effects of benzodiazepine receptor (BZR) partial agonists, Y‐23684 and CL218,872, were compared with its full agonist, diazepam, on γ‐aminobutyric acid (GABA)‐induced Cl− current (ICl) in acutely dissociated rat cerebral cortex (CTX), cerebellar Purkinje (CPJ) and spinal ventral horn (SVH) neurones, by the whole‐cell mode patch‐clamp technique. 2 The GABA‐induced responses were essentially the same in both SVH and CPJ neurones, but the KD value of the GABA response in CTX neurone was lower than those in the other two brain regions. 3 Enhancement of the GABA response by the two partial agonists was about one‐third of that by diazepam in the SVH neurones (where type II subtype of BZR, BZ2, is predominant), whereas these partial agonists potentiated the GABA response as much as diazepam in CPJ neurones (where the type I subtype of BZR, BZ1, is predominant). In CTX neurones where both type I and II variants are expressed, the augmentation ratio of the GABA response by diazepam was between the values in CPJ and SVH neurones. 4 In concentration‐response relationships of BZR partial agonists, the threshold concentrations, KD values and maximal augmentation ratio of the GABA response were similar in all CTX, CPJ and SVH neurones. Also, in all preparations, the threshold concentration and KD values of diazepam action were 10 fold less than those induced by partial agonists. 5 All BZR agonists shifted the concentration‐response relationship for GABA to the left without changing the maximum current amplitude, indicating that activation of both BZ1 and BZ2 increase the affinity of the GABAA receptor for GABA. 6 The results are important in clarifying the mechanism of anxiety and might explain the anxioselectivity of BZR partial agonists.

Dynamic cortical activity during spasms in three patients with West syndrome: A multichannel near-infrared spectroscopic topography study

Summary:  Purpose: To investigate spatial and temporal cortical activity during clusters of naturally occurring epileptic spasms in patients with West syndrome (WS) by using multichannel near‐infrared spectroscopy (mNIRS).

Mechanism of tonic spasms in West syndrome viewed from ictal SPECT findings

To clarify the pathophysiology of tonic spasms, 21 patients with West syndrome were analyzed using ictal and interictal single photon emission computed tomography (SPECT). We focused on whether ictal perfusion changes were observed in the focal cortical region. Eight of the patients studied showed definite focal cortical ictal hyperperfusion, indicating that there is a unique subset of West syndrome that can be classified as infantile localization-related epilepsy. Of those eight patients, only two showed asymmetric spasms, suggesting that seizure symptomatology in infants gives only limited information on the localization-related nature of epilepsy. Furthermore, the activation of subcortical structures by focal cortical regions might be attributable to the symmetric seizure phenomena. Thirteen patients showed a diffuse pattern in their ictal SPECTs; this probably included patients with diffuse hyperperfusion and those with no changes. The following have yet to be determined: (1) whether West syndrome is divided into subgroups based on the origin of spasms, in that some patients have the origin in the cortical hemisphere and some have the origin in structures other than the cortical hemisphere, such as the brain stem; (2) whether differences in ictal SPECT patterns reflect a unique nature of tonic spasms in West syndrome, where tonic spasms appear in clusters and the interval of each spasm is different among each patient.

The origin of hypsarrhythmia and tonic spasms in West syndrome: evidence from a case of porencephaly and hydrocephalus with focal hypsarrhythmia

We report on a 3-year-old girl with West syndrome and with focal hypsarrhythmia. The left hemisphere of the patient was virtually completely defective and continuous hypsarrhythmia was only seen in the residual right frontal cortex, where an interictal single photon emission computed tomography (SPECT) showed hyperperfusion. Despite a focal epileptic pattern, the tonic spasms were quite symmetrical. In our patient, spasms might not require the sensorimotor cortex, but the brainstem containing the descending pathways that control spinal reflexes and other infratentorial structures seem to be essential for the occurrence of spasms. This is in accordance with the result of an ictal SPECT that showed hyperperfusion of the brainstem and cerebellum. These findings suggest that hypsarrhythmia originates from cortical lesions, while subcortical structures may be primarily responsible for the tonic spasms in this patient.

Reduced levels of interleukin-1 receptor antagonist in the cerebrospinal fluid in patients with West syndrome.

We measured the levels of pro- and anti-inflammatory cytokines in the cerebrospinal fluid (CSF) of 24 patients with West syndrome to clarify whether inflammatory cytokines were involved in the pathophysiology of West syndrome. There was no significant elevation of any of the three pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, in patients with West syndrome as compared with those in controls. However, level of anti-inflammatory cytokine, IL-1 receptor antagonist was significantly decreased in the CSF of patients with West syndrome. Further study is needed to elucidate whether an immune system disturbance is involved in the pathophysiology of West syndrome.