One of the recent topics in neuroscience is that the major inhibitory neurotransmitter GABA necessarily evokes excitation in immature brain, in contrast to inhibition in normal adult brain. Such excitatory GABA actions may be involved in neural circuitry development promoted by neuronal differentiation, migration, and synaptogenesis. On the other hand, a conversion of GABA response from inhibition to excitation could also be induced by certain pathological condition even in adult. Since GABA_A receptor is a Cl^- channel, such a developmental or a pathological switch of GABA action between inhibition (Cl^- influx) and excitation (Cl^- efflux) is induced by changes in Cl^- gradient. We have been investigating the dynamics of neural functions modulated by such active Cl^- homeostasis in the experimental models of epilepsy.
Tetanic stimulation induced post-tetanic depolarization followed by seizure-like afterdischarge in hippocampal CA1 neurons in brain slices. Massive Cl^- influx during tetanic stimulation was responsible for [Cl^-]_i increases lasting for the period of afterdischarge. This acute postsynaptic Cl^- accumulation through GABA_A receptor channels via feed-forward inhibition resulted in reversal of its own action to excitation. This feed-forward excitation induced a seizure-like afterdischarge, implicating a relation with epileptogenesis. The neuronal Cl^- homeostasis is regulated by cation-Cl^- cotransporters, so that the active shift of Cl^- homeostasis could be generated by the dynamic balance of Cl^- importer (NKCC1) and exporter (KCC2). In a rat kindling model, there was an activity-dependent increase in NKCC1 mRNA in the dentate gyrus and the pyriform cortex. Thus an increase in [Cl^-]_i and a reduction in GABAergic inhibition may occur in those epileptic rats. In a rat neonatal cortical freeze-lesion model of human polymicrogyria, GABA-induced depolarizations associated with increases in [Cl^-]_i were observed in cortical plate neurons migrating into the dysplastic lesion. NKCC1 mRNA was upregulated whereas KCC2 mRNA was downregulated in those migrating neurons. These characteristics were similar to the known characteristics of migrating cortical plate cells. Thus, cortical plate cells locating adjacent to the necrotic center of the freeze-lesion might regain or preserve the excitatory GABA actions, so that they could migrate into the dysplastic lesion to form microgyrus. Thus a collapse of active Cl^- homeostasis may be responsible for a pathogenesis of both idiopathic and organic epilepsies.

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The diagnostic Scheme for People with Epileptic Seizures and with Epilepsy 2001 is divided into five axes. Axis 5 is recommended for use as a parameter for evaluating the impairment in patients with epilepsy on the basis of the International Classification of Functioning, Disability and Health (ICF). The impairment in 132 patients with epilepsy over 18 years old was checked according to the criteria of ICF. The subjects were divided into three groups according to the necessity of help in daily life; group I: 84 cases with full help, group II: 17 cases with some help, and group III: 31 cases with no help. The impairment in groups I and II depended on mental retardation and physical disability, and the impairment could be easily checked using the components of Body Functions (b) and Activities and Participation (d). The impairment in group III could not be easily checked, but was shown in self-care (d5), major life areas (d8), and so on. There are many patients with epilepsy who seem to exhibit no impairment in their daily lives, although they have some problems. Axis 5 is worth using for objective evaluation of such patients.

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A boy, 5 years and 5 months of age, presented to our hospital with status epilepticus and fever. His past history showed intractable generalized tonic-clonic convulsions since 1 year 3 months of age and also absence seizures after 5years of age. On admission, he showed unconsciousness and right hypotonic hemiparesis.
Convulsions of his right hand occurred intermittently for 9 days. Cranial computed tomography (CT) showed edema in the left cerebral hemisphere. One month after admission, the edema shrank. Brain magnetic resonance imaging (MRI) T1 and T2 weighted images also showed left cortical hyperintensity and swelling on admission. Two months later, the images showed atrophy of left hemisphere. ^99mTc ethylcysteinate dimmer single photon emission computed tomography (ECD-SPECT) showed an increased perfusion of the left hemisphere 1 week after admission and an decreased perfusion 2 months after admission. Eight months after admission, absence seizures recurred. EEG showed bursts of diffuse 3 c/s sp-w right hemispheral dominantly, induced by hyperventilation. Absence seizures were completely suppressed by ethosuximide. Although the cause of encephalopathy was unknown, the antiglutamate receptor ε2 antibody in the serum was positive. These findings show the possibility of the autoimmune mechanism being associated with encephalopathy. The recurrence of absence seizures despite of the excessiveness of the left cortical damage may indicate the associtation between the centrencephalic function and the occurrence of absence seizures.

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