Akira Hodozuka

The effect of electrical stimulation and lesioning of the anterior thalamic nucleus on kainic acid-induced focal cortical seizure status in rats.

Summary:  Purpose: The present study aimed to clarify the effect of electrical stimulation and lesioning of the anterior nucleus of the thalamus (ANT) on kainic acid (KA)–induced focal cortical seizures in a rat model. To address the mechanism underlying these anticonvulsant actions, cerebral glucose metabolism after ANT electrical stimulation and lesioning was also examined.

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.

Clinical and experimental studies of epilepsy associated with focal cortical dysplasia

Abstract  The results of clinical and experimental studies on epilepsy associated with focal cortical dysplasia (FCD) are presented. We have been interested in the findings of abnormal increases in the numbers of small vessels in specimens of FCD resected from epilepsy patients. In the clinical study of 13 patients with epilepsy, specimens of FCD or dysembryoplastic neuroepithelial tumor (DNT) were examined using immunohistochemistry. The number of vessels in both lesions were greater than those in cortical specimens of autopsy cases without epilepsy. Because the vessels showed negative staining of VEGF, it was thought that the phenomenon of increase in the number of vessels was simply a hypervascularity, not a neovascularity. The local hypervascularity was expected to show local hyperperfusion in CBF‐SPECT study, but interictal SPECT demonstrated local hypoperfusion and ictal SPECT showed hyperperfusion. This may have been caused by a functional change in those vessels. In the experimental study, we tried to make a new animal model of FCD to study epileptogenicity of FCD. When kainic acid had been infused into the neocortex in the neonatal rats, FCD was induced in adult Wistar rats. Histopathological examination revealed cortical dyslamination and abnormal neurons. On EEG, local spike bursts were elicited from the lesions, however, clinical seizures were not detected. Although the data are preliminary and observation over a longer period is required to determine whether spontaneous seizures will occur in this model, it is expected that this new model will be useful for studying epilepsy associated with FCD.

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).

Sequential change of capillary permeability in the rat brain after surgical removal of an experimental brain tumor

SummaryExperimental brain tumors were excised from rats for sequential observation of changes in local capillary permeability during the postsurgical period. Experimental brain tumor-bearing rats were prepared by stereotaxic transplantation of cultured tumor cells and the resultant tumor was delineated by administration of a dye. Following excision of the stained tumor by craniotomy, sequential changes in local capillary permeability were quantitatively followed-up by autoradiography, using14C-amino-isobutyric acid as a tracer. Capillary permeability was enhanced following surgery, reaching a maximum both in the extent and degree on the third day. After undergoing a gradual reduction, it showed a marked increase for the second time in a very small area on the 10th postoperative day. A recurrence of the tumor was responsible for this late but marked increase. For a control group, the caudate nucleus was excised from normal rats, followed by observation of the sequential changes in the local capillary permeability. Due to surgical procedure, capillary permeability reached a maximum both in the extent and degree on the 5th postoperative day (slightly later than in the tumor group). This change in capillary permeability was less pronounced than in the tumor group. The difference in the conditions of surgery — tumor excision and partial excision of a normal brain tissue — appeared to explain this difference. The results of this study indicated that it is more desirable to give water-soluble antineoplastic agents early during the postoperative period for chemotherapy of a malignant brain tumor after surgery.