[Intrathecal infusion of the antineoplastic agents for meningeal dissemination].

One of the specific forms of progression of malignant tumors of the central nervous system is meningeal dissemination. Meningeal dissemination is a condition in which tumor cells migrate to the brain surface and sub arachnoid space via cerebrospinal fluid and then infiltrate there. This condition can arise from both primary and metastatic brain tumors, with reported incidences of 4.2% for primary tumors and 5.1% for metastatic tumors. Meningeal dissemination frequently arises from germinoma, medulloblastoma, ependymoma and glioblastoma in cases of primary brain tumors and frequently arises from breast cancer, lung cancer and gastric cancer in cases of metastatic brain tumors, known as meningeal carcinomatosis. The prognosis of meningeal dissemination is poor, and conventional treatments such as systemic chemotherapy and radiation therapy are ineffective. Intrathecal infusion of anti neoplastic agents is one of the options for treatment of meningeal dissemination. The advantage of intrathecal chemotherapy is that the anti neoplastic agent is rapidly diffused in the sub arachnoid space, and its duration of activity is long due to its slow clearance and metabolism. Routes of administration include infusion into the lateral ventricle by puncture of the Ommaya reservoir, infusion into the sub arachnoid space by lumbar puncture, or both of these procedures performed alternately or simultaneously, and methods of infusion include bolus injection and ventriculo lumbar perfusion. Commonly used drugs include methotrexate (MTX), cytarabine (Ara-C), and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)- 1-nitrosourea hydrochloride (ACNU), and some new drugs have also begun to be used clinically. Although there are differences depending on the histological type of the tumor, the anti neoplastic agent administered and the method of administration, the response rate is about 40-80% and mean survival time is about 4-25 months. Although side effects of the anti neoplastic agents are not as severe as with agents used for systemic chemotherapy, specific side effects include nonspecific drug-induced meningitis or ventriculitis, transient or permanent paralysis and leukoencephalopathy. These side effects can be alleviated by reducing the dose or discontinuing the anti neoplastic agents, and a small dose of an adrenocorticosteroid is sometimes administered simultaneously. Bacterial meningitis is another complication and requires discontinuation of anti neoplastic agents, removal of the Ommaya reservoir, or systemic or intrathecal administration of antibiotic agents. Although meningeal dissemination is a rare metastatic condition with a poor prognosis, there have been some reports of successful treatment using this method, which is expected to be widely used in the future.

Anti-convulsant effect of electrical stimulation and lesioning of the anterior thalamic nucleus on kainic acid-induced focal limbic seizure in rats.

PURPOSE: We examined the effect of electrical stimulation and lesioning of the anterior nucleus of the thalamus (ANT) on focal limbic seizures induced by intraamygdaloid kainic acid (KA) injection in a rat model. To address the mechanism underlying these anti-convulsant actions, cerebral glucose metabolism following ANT electrical stimulation and lesioning was also assessed. METHODS: Wistar rats were divided into five major groups: control, unilateral and bilateral ANT electrical stimulation, and unilateral and bilateral ANT lesioning. After KA injection, average clinical-seizure frequencies in each group were measured. Local cerebral glucose utilization (LCGU) was also measured using [(14)C] 2-deoxyglucose autoradiography in three groups: control, ANT electrical stimulation and ANT lesioning. RESULTS: Animals subjected to ANT electrical stimulation and lesioning exhibited significantly decreased mean seizure frequency and secondary generalized seizure frequency, compared with control-animals. In control-group, LCGU was markedly increased at both the limbic and corticothalamic circuits sites. While in ANT stimulation or lesioning-group, there was significant reduction in LCGU at the corticothalamic circuit sites, but not so considerable decrease at the limbic structures. CONCLUSION: ANT electrical stimulation and lesioning in the focal limbic seizure model were effective on convulsive seizures and secondary generalization, specifically with respect to the severity of these seizures.

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

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. METHODS: Wistar rats were divided into five major groups: control (n = 9), unilateral (n = 9), and bilateral (n = 9) ANT electrical stimulation, and unilateral (n = 9) and bilateral (n = 9) ANT lesioning. After KA injection, average clinical-seizure frequencies in each group were measured. Electrical stimulation of ANT was introduced after induction of seizure status epilepticus. Stimulation was on for 30 min and off for 30 min per 60-min cycle. Local cerebral glucose utilization (LCGU) was also measured by using [(14)C] 2-deoxyglucose autoradiography in three groups of rats: control (n = 7), bilateral ANT stimulation (n = 7), and bilateral ANT lesioning (n = 7). RESULTS: Unilateral ANT electrical stimulation and lesioning significantly reduced clinical seizure frequency, compared with control animals. Strikingly, no animals treated with bilateral ANT procedures demonstrated any clinical seizure. LCGU was markedly increased in the sensorimotor cortex, striatum, thalamus, mammillary body, and midbrain tegmentum of control group rats after KA injection, but no increase in LCGU was noted in rats treated with bilateral ANT lesioning or stimulation. CONCLUSIONS: The electrical stimulation and lesioning of ANT suppressed focal cortical clinical seizures induced by KA injection. Additionally, an analysis of cerebral metabolic changes indicated that these procedures might suppress the function as amplifier and synchronizer of seizure activity.

Focal cortical dysplasia: pathophysiological approach.

OVERVIEW: Clinical and experimental studies on focal cortical dysplasia (FCD) were carried out. MATERIALS AND METHODS: For the experimental study, an experimental FCD model of rats was developed. Twenty Wistar rats at 0-2 days after birth were used for the study. Kainic acid (KA) solution was injected stereotaxically into medial and lateral sites of the sensori-motor cortex. Bipolar electrodes were inserted in five rats. Their behavior and electroencephalogram (EEG) were recorded using a digital-video-EEG monitoring system. After observation periods of 1, 2, and 6 months, rats were perfused for pathological study. FCD was observed adjacent to the site of KA injection in all rats more than 1 month after the injection. RESULTS AND DISCUSSIONS: EEG recording demonstrated focal spike discharges in and around the site of injection. However, clinical seizure was not observed. Pathological studies showed decrease in GABA-A receptors and increase in GABA-B receptors not only in the lesion but also in perilesional areas. Fifteen surgical cases of FCD with intractable epilepsy were subjected to the clinical study. Neuro-imaging studies including high-resolution magnetic resonance imaging and single-photon emission computed tomography were performed. Conventional EEG studies demonstrated focal EEG abnormalities with epileptic phenomena. At surgery, intraoperative electrocorticography (ECoG) was performed to localize epileptic foci under neuroleptoanalgesia. Thirteen patients showed epileptiform discharges on preresection ECoG. All foci in non-eloquent areas were resected. Pathological studies including immunohistochemical staining were performed, and the characteristics of the FCD in relation to EEG findings were analyzed. Patients in whom total lesionectomy with complete focus resection was performed had favorable postoperative courses. Nine patients (64.3%) have been seizure-free with reduced medication, and significant improvement was achieved in two patients (14.3%). Electrophysiological examination revealed epileptogenecity not only in the lesions but also in perilesional areas. The immunohistochemical studies showed a decrease in GABA-A receptors and an increase in GABA-B receptors in both the lesions and perilesional areas, but N-methyl-D: -aspartate receptors were almost negative in both areas. Glutamate R1 was decreased in both areas, but glutamate R2 was increased in both areas. These findings support the results of a electrophysiological study. CONCLUSIONS: In conclusion, not only the epileptic property of experimental focal cortical dysplasia but also perilesional epileptogenesis was demonstrated. These findings supported the results of surgery for patients with focal cortical dysplasia. In cases of FCD, total removal of the lesion and resection of the perilesional epileptic focus are needed for a good outcome.

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.

Capillary hemangioma of the central nervous system.

OBJECT: Capillary hemangiomas are benign tumors or tumorlike lesions that originate from blood vessels and have rarely been reported to develop in the brain or spinal cord. The authors summarize the clinical and histological features of capillary hemangiomas of the central nervous system (CNS). METHODS: The clinical features, imaging characteristics, and outcomes in 10 patients with CNS capillary hemangiomas were reviewed. Histological studies included immunostaining with CD31, alpha-smooth muscle actin, vascular endothelial growth factor, and Ki-67 antigen. Three patients with lesions in the brain presented with symptoms of increased intracranial pressure or seizures. Seven patients with lesions in the spinal cord presented with progressive sensorimotor disturbances of the lower limbs. Computerized tomography and magnetic resonance imaging demonstrated well-defined, enhancing lesions associated with marked perifocal edema. Angiography demonstrated hypervascular lesions, which have not recurred after resection. In two cases, multiple satellite lesions resolved after the systemic administration of steroid drugs or interferon-alpha. Histologically, all lesions were consistent with findings of capillary hemangioma of the skin or soft tissues. The CNS lesions differed significantly from other vascular neoplasms, such as hemangioendotheliomas, hemangiopericytomas, and hemangioblastomas. CONCLUSIONS: Capillary hemangiomas of the CNS are benign lesions that can be surgically removed and cured without adjuvant therapy.

Clinical and experimental studies of epilepsy associated with focal cortical dysplasia.

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.