Hirofumi Nakai

Zonisamide: electrophysiological and metabolic changes in kainic acid-induced limbic seizures in rats.

Summary: We studied the pharmacological mechanism of zonisamide (ZNS) using an electrophysiological and autoradiographical method in a limbic seizure model in rats. Limbic seizure status epilepticus was induced by a unilateral microinjection of kainic acid (KA) into the amygdala. Initially, observed seizures were limited to the side of the injected amygdala and then propagated to bilateral sensorimotor cortex. Eighty minutes after injection, secondarily generalized seizure status epilepticus was induced, with each seizure lasting ∼30 s and recurring every 5 min. ZNS 100 mg/kg was administered intravenously (i.v.) during the generalized seizure. Forty minutes after ZNS administration, epileptic activity was observed only at the KA‐injected amygdalar site and spikes were not observed in the bilateral sensorimotor cortex. We studied local cerebral glucose utilization (LCGU) after ZNS or saline administration using an autoradiographical method in the same limbic seizure preparation. In the ZNS group, LCGU decreased in the ipsilateral sensorimotor cortex and hippocampus, whereas in the controls LCGU increased in these structures. On the other hand, ZNS did not suppress the epileptic activity of the primary focus and no decrease in LCGU was observed in the KA‐injected amygdala. ZNS inhibited seizure propagation from the epileptogenic focus but did not suppress the epileptic activity of the focus. Our results suggest that ZNS is effective for the treatment of secondarily generalized seizure.

Quisqualic acid-induced hippocampal seizures in unanesthetized cats

An intrahippocampal injection of quisqualic acid (QA) was made in chronically implanted freely moving unanesthetized cats and electrographic and clinical observations were made. Fourteen to 40 micrograms of QA injection resulted in a mild limbic seizure within 24 h after QA injection. Some cats demonstrated a pure hippocampal seizure on an electroencephalogram. Electrographic changes and clinical manifestations were less prominent as compared with those of kainic acid. Histopathological examination showed a selective loss of pyramidal cell layer of the CA3 portion in the injected side of the dorsal hippocampus. A mild but constant epileptogenic potency of QA has an advantage for an experimental model of temporal lobe epilepsy in man.

A case of intracranial arteriovenous fistula in an infant with neurofibromatosis type 1

Abstract.Introduction: Reported cases of arteriovenous fistula (AVF) with neurofibromatosis type1 (NF1) are rare. Case report: In this paper we report the first case of intracranial AVF in an NF1 infant who developed heart failure. Endovascular treatment using coils successfully obliterated the AVF. The mechanism underlying the AVF in this case was believed to be a congenital mesenchymal abnormality of the intracranial vessels. Discussion: The mechanism underlying the development of heart failure in this case is also discussed.

Basic Science and Epilepsy: Experimental Epilepsy Surgery

Epilepsy surgery, as is employed for the management of intractable seizures, was performed in animals harboring a seizure focus induced by a local application of kainic acid (KA). Amygdalo-hippocampectomy failed to stop spontaneous seizures in the contralateral hippocampus. Callosotomy inhibited seizure propagation to the contralateral sensori-motor cortex. However, epileptic activity ipsilateral to the focus, including subcortical structures, persisted even after the callosotomy. Multiple subpial transection (MST) around the epileptic cortical focus suppressed the seizure activity of the cortex. However, seizure propagations in subcortical structures remained, even after MST. Niferacetam (a new nootropic agent) was tested in these models, and its promising effect on the intractable extratemporal epilepsy is reported.

Vascular abnormalities in surgical specimens obtained from the resected focus of intractable epilepsy.

The histopathological features, particularly hypervascularity, were examined in specimens resected from 21 patients, 15 with intractable epilepsy accompanying cortical dysplasia or dysembryoplastic neuroepithelial tumor (DNT), and 6 with benign brain tumors, such as ganglioglioma and low-grade glioma. Hypervascularity was found in resected specimens from 15 of the 21 patients (71.4%) and in 10 of the 12 patients (83.3%) who had double pathology. Counting of numbers of vessels by CD31 immunohistochemistry revealed that hypervascularity was prominent, especially in cases of vascular malformation or cortical dysplasia. However, almost all cases were negative for vascular endothelial growth factor (VEGF) staining, except for some cases of benign brain tumors. Moreover, all cases showed low or no proliferative potential in MIB-1 immunohistochemistry. These results suggest that the etiology of hypervascularity in the dysplastic lesions is one of a variety of cerebral malformations, as is the case with abnormal maturation and differentiation in neuroglial elements.

Delivery of a novel nitrosourea, MCNU, to the brain tissue in glioma-bearing rats

SummaryWe observed the tissue delivery of a novel water-soluble nitrosourea, 1-(2-chloroethyl)-3-(methyl-α-D-glucopyranos-6-yl)-1-nitrosourea (MCNU) in rats bearing experimental brain tumors by conducting autoradiography on all. Prior to this study, the development of a streaming phenomenon was ascertained (and thus finding the optimum velocity for intra-arterial infusion) by14C-iodoantipyrine (IAP) autoradiography. Furthermore, a single pass extraction value of MCNU was measured. At an arterial infusion rate of 0.2 ml/min., the streaming phenomenon was recognized but the tracer was fairly evenly distributed at a rate of 1.0 ml/min. On the other hand, the single pass extraction value for MCNU was 0.18 ± 0.036 (mean ±S.D., n=3, under pentobarbital anesthesia). It was suggested that MCNU is very unlikely to be transported into the normal rat brain. We conducted14C-MCNU autoradiography to observe tissue distribution of MCNU following its intra-arterial and intravenous infusions in a brain tumor model using rats. The normal side (the side where no infusions were given) and the cerebral cortex at the side affected by the tumor (the side where the infusion was given) showed hardly any uptake of14C-MCNU in both the intra-arterial and intravenous infusion groups. The tumorous section was divided into the periphery and the center to measure tissue concentration of the tracer in each section. Compared against the cortical section, the periphery and the center showed significant increases in the concentration (approximately 11 to 15 times and 3 to 7 times, respectively, the figure for the cortical region) for both the intra-arterial and intravenous groups. When compared against the intravenous infusion group, the arterial infusion group showed a significantly high rate of accumulation (1.3 to 3.9 times).

Clinical Application of Experimental Cortical Dysplasia in Rats

This report details clinical and experimental studies of focal cortical dysplasia. The first part deals with 14 surgical cases of children with intractable epilepsy. At surgery, intraoperative electrocorticography was performed to localize the epileptic foci under neuroleptanalgesia. Thirteen patients showed epileptiform discharges on this preresection electrocorticography. All foci in noneloquent areas were resected. Patients who had undergone total lesionectomy with complete focus resection showed the most favorable postoperative results. However, the positive correlation between the intraoperative electrocorticographic findings and the pathologic classification of cortical dysplasia was not found in the present study. Nine patients have been seizure free with reduced medication and two patients have achieved worthwhile improvement. We conclude that intraoperative electrocorticography can improve the surgical outcome for intractable epilepsy by localizing epileptic foci for resection. The second part describes a kainic acid—induced experimental model of focal cortical dysplasia, which demonstrated not only the epileptic properties of the dysplasia but also the perilesional epileptogenicity. The findings supported the surgical results for the patients with focal cortical dysplasia. (J Child Neurol 2005;20:351—356).

Correct localization of epileptogenic focus with I-123 iomazenil cerebral benzodiazepine receptor imaging: a case report of temporal lobe epilepsy with discordant ictal cerebral blood flow SPECT

A 26-year-old female with intractable epileptic seizures was studied with 1-123 iomazenil cerebral benzodiazepine receptor, 1-123 IMP inter-ictal and Tc-99m ECD ictal cerebral blood flow SPECT. The ictal cerebral blood flow SPECT indicated the location of the seizures to be in the left temporal lobe, where increased regional cerebral blood flow was noted in marked contrast to the inter-ictal SPECT. Ictal electroencephalograms (EEGs) recorded with scalp and sphenoidal electrodes also suggested the left temporal lobe as the location of the seizures. On 1-123 iomazenil SPECT, however, decreased benzodiazepine receptor density was demonstrated in the right temporal lobe. MRI showed mild atrophy and abnormal signal intensity in the right temporal lobe. Ictal EEGs recorded with intracranial electrodes revealed that abnormal electrical activity of the brain always emerged from the right temporal lobe and then propagated to the contralateral side. Based on the findings of intracranial EEGs, partial resection of the right anterior temporal lobe including hippocampus was performed. After the surgery, no seizure occurred. Pathological examination of the surgical specimens revealed hippocampal sclerosis. This case suggested that cerebral benzodiazepine receptor imaging with 1–123 iomazenil can be helpful for correct localization of epileptogenic foci.