Basic science and clinical aspects of procaine HCl as a limbic system excitant.

The literature in animals and humans which indicate that systemic procaine HCl activates limbic tissue is reviewed. Studies in cats which suggest that procaine excites limbic cells by reducing neural inhibition are then described. Evidence that power spectral analysis of high frequency EEG bands (omega or 31-55 cps) in the temporal cortical EEG reflects degree of limbic (amygdala) excitation in animals and humans is reviewed. Studies in cats are described which show that procaine selectively increases omega band activity in the amygdala and temporal cortex in a dose related fashion which parallels dose related increases in amygdaloid neural activity. Preliminary results of combining intravenous procaine and omega band analysis of scalp EEG in humans to predict therapeutic response to carbamazepine in borderline personality and affective disorder patients are then described. The effects of procaine on omega are compared to the effects of direct electrical stimulation of human limbic system in complex partial seizure patients undergoing assessment for temporal lobectomy. The results tentatively support the hypothesis that some psychiatric patients have hyperexcitable limbic systems, and those that do, show a positive behavioural response to carbamazepine.

Enhancement of 3H-phenytoin binding by diazepam and (+)bicuculline.

3H-Phenytoin binding to the particulate fraction of rat wholebrain homogenate was studied using the filter assay technique. It was found that diazepam and (+)bicuculline methobromide caused a concentration-dependent enhancement of the total binding of 3H-phenytoin, whereas GABA and (-)bicuculline methobromide (the inactive bicuculline isomer) had no effect. In subsequent competition experiments (labelled versus unlabelled phenytoin), it was found that the presence of a potentiating concentration of diazepam transformed the biphasic phenytoin competition isotherm into a simple curve with a Hill coefficient of approximately one, and a Ki of 110 nM.

Intradural extramedullary spinal metastasis. A report of 10 cases.

The management of 10 patients with symptomatic localized intradural extramedullary spinal metastasis is reviewed. The single most common primary source was carcinoma of the breast (four cases). The initial symptom in nine patients was pain, with five patients reporting a characteristically severe cramping discomfort with radicular distribution. All patients underwent laminectomy decompression. At the time of surgery, six of the patients were weak but ambulatory and four were bedridden. Following surgery, four patients enjoyed some measure of pain relief, seven patients became ambulatory, and three remained bedridden. Two patients achieved a "satisfactory" result, and were walking and continent 6 months after surgery. Secondary brain tumors were demonstrated or implicated in nine patients, supporting the concept that the spinal metastases represented tertiary deposits following dissemination via the cerebrospinal fluid. Symptomatic intradural extramedullary spinal metastasis causes a virulent clinical syndrome with poor prognosis and disappointing outcome after treatment. Given the high incidence of associated cerebral metastatic involvement, total neuraxis radiation and/or chemotherapy should be considered when symptomatic spinal metastasis is discovered to be intradural and extramedullary.

Pharmacological investigation of gamma-aminobutyric acid (GABA) and fully-developed generalized seizures in the amygdala-kindled rat.

The effects of GABA-modulating drugs were assessed in a pharmacological study of amygdala-kindled seizures in the rat. Fully-kindled subjects were tested with a randomized dose regimen, including drug vehicle, for each of seven drugs. Afterdischarge duration, motor seizure latency, motor seizure duration and motor seizure stage were scored. The GABA synthesis inhibitor, 3-mercaptopropionic acid, the GABA antagonist, bicuculline, and the chloride ionophore blocker, picrotoxin, all decreased motor seizure latency, but did not otherwise alter the kindled seizure duration or seizure stage. The inhibitor of GABA metabolism, gamma-vinyl-GABA, and pentobarbital, which competes for the picrotoxin binding site, both antagonized kindled seizures. Gamma-vinyl-GABA, however, did not appear to antagonize kindled seizures by a specific effect on GABA neurotransmission. The GABA agonists, imidazole acetic acid and [alpha-(chloro-4'phenyl)fluoro-5-hydroxy-2-benzylidene-amino]-4-butyramide (SL 76-002), did not alter the kindled seizures. The results of these experiments are not consistent with the hypothesis that kindled seizures result from a loss of GABA-mediated inhibition; however, GABA may have a role in the modulation of kindled seizure activity.

Analysis of facial displays and verbal report to assess subjective state in the non-invasive detection of limbic system activation by procaine hydrochloride.

The problem of scalp EEG as a measure of cortical or subcortical activity is particularly relevant to complex partial seizures as the abnormal discharging is frequently limbic in origin [14, 30]. Livingston [38] has suggested that administration of intravenous procaine as a limbic activator and cortical suppressor would be of utility in diagnosing limbic involvement in complex partial seizures. While there is considerable evidence derived from experimental animal models that procaine hydrochloride is a limbic system activator that acts preferentially on subcortical epileptic foci at lower doses than on less active epileptic foci or non-epileptic tissue [2, 4], it was necessary to demonstrate that procaine activates the human limbic system. The non-invasive approach taken in the present study was to compare the published effects of direct electrical stimulation of the human limbic system [31] to the behavioural and subjects effects of intravenous procaine administration. The areas in which we obtained the most robust procaine effects (hallucinations, emotions and alimentary sensations) were also Halgren et al.'s [31] most repeatable effects. The correspondence between electrical stimulation effects and procaine administration effects was striking - with verbal report by patients matching exactly in many instances. Furthermore, analysis of facial displays proved useful in providing access to subjects state fluctuations which would otherwise have gone undetected. The data provide strong evidence that procaine hydrochloride can be used as a human limbic system activator. Future research will investigate the clinical and diagnostic significance of differential response to procaine.

Power spectral analysis of EEG drug response in the kindled rat brain.

The specificity of procaine as a limbic epileptic focus activator was investigated in rats kindled in the amygdala. Power spectral analysis of spontaneous EEG was employed to assess the effects of two doses of procaine HCl (60 and 100 mg/kg) on the kindled and unkindled amygdala. Analysis revealed a dose-dependent increase in power in the 1--15 c/sec frequency band of the EEG. Power increases were greater in the kindled than in the unkindled amygdala of the same rat, and exceeded power changes induced in unkindled controls. The effects of procaine on the EEG persisted past the day of injection, but returned to baseline by the fifth day. Changes in power over days following an injection of procaine differed in the kindled and unkindled amygdala amygdala of the same rat. The kindled amygdala showed an increase on the day of injection, followed by a steady decline to baseline. The unkindled amygdala showed a delayed rise in power on day 2 and then a decline to baseline levels over days. Comparison of spectral changes induced by drug and by electrically triggered seizures suggested that procaine induces EEG patterns which are seizure-like in the absence of seizures. The data are consistent with the view that procaine may be a useful focus specific activator in the detection of limbic epilepsy.

Effects of diazepam on hippocampal excitability in the rat: action in the dentate area.

Acute and chronic experiments were performed on rats to examine the effects of diazepam (Valium) on recurrent inhibition in the monosynaptic perforant path-dentate synapse of the dentate area of the dorsal hippocampus. Evidence was obtained which indicated that diazepam facilitated a presumably GABA mediated post synaptic recurrent inhibition in both acute and chronic preparations at 1 and 2 mg/kg doses (IP). Acute studies also revealed that diazepam prolonged recurrent inhibition, possibly by lengthening the IPSP. An effect of the drug on cholinergically mediated positive feedback from the septum could not be ruled out, however. Taken together, this study extends the evidence that diazepam acts centrally on GABA mediated inhibition in the limbic system. Furthermore, the limbic action of diazepam revealed here suggests a mechanism for the anticonvulsant properties of diazepam in epilepsy involving subcortical (limbic) circuitry.

Dissecting aneurysm of the cerebral arteries. Case report.

A spontaneous dissecting aneurysm of the left middle cerebral artery with extension into its major branches is reported in a 23-year-old man. The characteristic pathological and angiographic findings are demonstrated, including the rarely documented progression of this lesion. The etiological factors, the early recognition by the neuroradiologist, and the possibility of immediate treatment are briefly discussed in this report.

Flash-evoked afterdischarge in rat as a model of the absence seizure: dose-response studies with therapeutic drugs.

The flash-evoked afterdischarge (FEAD) is a self-sustained burst of wave-and-spike complexes recorded from occipital cortex in the rat and other animals in response to a single light flash. On the basis of behavioral experiments and studies employing single doses of antiepileptic drugs, FEAD has been proposed as a model of the absence seizure. In order to test the validity of FEAD as an absence seizure model, the present experiments determined dose-response relationships for the suppression of FEAD by six antiepileptic drugs with established clinical profiles. It was found that phenobarbital, ethosuximide, and trimethadione suppressed FEAD in a dose-related manner, and that ethosuximide was approximately three times as potent as trimethadione. Mephenytoin produced a maximal reduction of FEAD of only 30 to 40%, which was not dose-related. Neither phenytoin nor acetazolamide suppressed FEAD. The results obtained with ethosuximide, trimethadione, and phenytoin are qualitatively similar to their therapeutic effects in absence epilepsy. The FEAD model failed, however, to unequivocally predict the therapeutic efficacy of mephenytoin or acetazolamide. In this respect, it is similar to the metrazol seizure model. It is concluded that FEAD is a valid absence seizure model with a pharmacological predictive value that is at least as good as the metrazol model.

The neurosurgical management of spinal metastases causing cord and cauda equina compression.

The authors report a series of 100 consecutive patients with spinal metastases causing cord or cauda equine compression, who were treated with surgical decompression. Of these, 30% (all women) had breast cancer. The most common primary neoplasm in man was prostatic carcinoma. Pain was the earliest and most prominant symptom, followed by weakness. Bladder dysfunction was recorded in 40 patients. The thoracic region was the most common site of cord compression (76 patients). Surgical treatment involved urgent and extensive laminectomy decompression. Concomitant spinal stabilization was required in 10 cases, involving posterior rib graft fusion in seven and Harrington rod instrumentation in three. At last follow-up review, 29 of these patients were living with an average postoperative survival of 2.3 years; 71 patients had died with an average survival of 8.8 months. Surgical decompression produced effective pain relief in 70% of the patients. Postoperatively, 58 patients could walk; of these, 40 were walking and continent of urine 6 months following surgery (including five patients who were totally paraplegic on admission). Positive approach and aggressive management in this problem can achieve results superior to those generally reflected in the literature.

Hemangiopericytoma of the spinal canal. Report of three cases.

Hemangiopericytoma is a vascular neoplasm consisting of capillaries outlined by an intact basement membrane that separates the endothelial cells of the capillaries from the spindle-shaped tumor cells in the extravascular area. These neoplasms are found in soft tissues but have rarely been shown to involve the spinal canal. This is a report of three such cases. Surgical removal of the tumor from the spinal canal was technically difficult. A high risk of recurrence has been reported but in these three cases adjunctive radiotherapy appeared to be of benefit in controlling the progression of the disease. These cases, added to the six cases in the literature, confirm the existence of hemangiopericytoma involving the vertebral column with extension into the spinal canal. This entity should be included in the differential diagnosis of lesions of the spinal canal. The risk of intraoperative hemorrhage should be anticipated.

Electroencephalographic signs of ethanol tolerance and physical dependence in the cat.

Spontaneous electrical activity was recorded from three cortical and five subcortical sites, via permanently implanted electrodes, in five conscious, freely-moving adult cats. Initial observations were made during and after an intravenous infusion of ethanol, 1 g/kg. The animals then received ethanol by gastric intubation, in doses of 1.5 g/kg every 8, 12 or 24 h, for a period of 5 weeks. Electrical and behavioral observations were repeated on the day following the last gavage, before and during another intravenous infusion of ethanol 1 g/kg. All animals showed EEG changes which are interpreted as signs of tolerance to and dependence on alcohol. EEG changes appeared up to a day earlier than gross behavioral signs of alcohol withdrawal.