Etoposide induced blood-brain barrier disruption in rats: duration of opening and histological sequelae.

The intracarotid infusion of the antineoplastic compound etoposide enhances blood-brain barrier (BBB) permeability. In a rat model system, the functional reversibility and anatomic sequelae of etoposide induced BBB disruption were investigated. Etoposide, in a dose range from 3.0 to 22.5 mg/kg, was infused into the left internal carotid artery of Sprague-Dawley rats. BBB disruption was evaluated by the appearance in the infused hemisphere of systemically administered Evans blue dye and quantitatively by the ratio of counts of the technetium labeled chelate of diethylenetriaminepentaacetic acid in the infused to the noninfused hemisphere. Functional reversibility of altered BBB permeability was investigated at three dose levels of etoposide (3.0, 15.0, and 22.5 mg/kg) by the administration of Evans blue dye at the time of etoposide infusion and the administration of the technetium labeled chelate of diethylenetriamine-pentaacetic acid at varying time intervals after etoposide infusion. Fourteen groups of 12 rats each were studied to define the time course of altered BBB permeability at these three doses. The anatomic sequelae of etoposide induced BBB disruption were investigated at varying time intervals (up to 3 weeks) after intracarotid etoposide infusion. Nineteen rats were examined after sacrifice by intracardiac fixation perfusion with 10% formalin. Each brain was sectioned coronally and examined under light microscopy after hematoxylin and eosin staining. Evidence of BBB disruption was seen at all dose levels of etoposide. The degree of BBB disruption increased with increasing doses of etoposide. The duration of altered BBB permeability increased from less than 1 day at 3.0 mg/kg to between 3 and 4 days at 22.5 mg/kg. Histological studies revealed no evidence of parenchymal damage, although at 4 days postdisruption, a mild perivascular lymphocytic infiltration was noted in the infused hemisphere. Etoposide infusion and subsequent BBB disruption were well tolerated by all test animals. In a rat model system the intracarotid infusion of etoposide is capable of producing prolonged reversible BBB disruption.

Cerebral effects of low-flow cardiopulmonary bypass and hypothermic circulatory arrest.

Although both hypothermic circulatory arrest (HCA) and low-flow cardiopulmonary bypass (CPB) are accepted techniques for the operative management of complex cardiovascular pathology, the potential for neurologic sequelae is still a concern. To assess the relative safety of these techniques, we compared cerebral hemodynamics and clinical outcome in two groups of puppies. Sixteen puppies underwent 45 minutes of either HCA or low-flow CPB (25 mL.kg-1.min-1) after cooling to 13 degrees C. Methodology included radioactive microsphere determination of cerebral blood flow; calculation of cerebral oxygen extraction (arteriovenous oxygen content difference) and consumption; measurement of glucose consumption, and determination of cerebrovascular resistance. Measurements were obtained at baseline (37 degrees C), 13 degrees C, and 30 degrees C and at 2, 4, and 8 hours after HCA or low-flow CPB. No neurologic deficits were observed in any of the survivors (15/16). In both groups, cerebral metabolic rate of oxygen was maintained at baseline or greater levels postoperatively. Cerebrovascular resistance rose slightly in the low-flow CPB group postoperatively in contrast to a marked elevation in the HCA group. During the period of high cerebrovascular resistance after HCA, cerebral metabolic rate of oxygen was maintained by increased oxygen extraction. After low-flow CPB, oxygen extraction was not significantly different from baseline, presumably because of less severe changes in cerebrovascular resistance. Glucose metabolism followed the same trends as oxygen metabolism in both groups. These data suggest that after HCA there is a vulnerable interval, lasting as late as 8 hours postoperatively, in which cerebrovascular resistance remains high and cerebral metabolism is maintained primarily by high oxygen and glucose extraction. Any additional stress during this interval (a decrease in arterial oxygen content or perfusion pressure) could result in cerebral injury.

Pathogenesis of spinal cord injury during simulated aneurysm repair in a chronic animal model.

The pathogenesis of paraplegia after repair of thoracic aortic aneurysms is controversial. Using direct spinal cord evoked potential monitoring, critical intercostal arteries (CICA) were identified to evaluate the impact of backbleeding and ligation versus that of preservation during simulated aneurysm repair. Thirty pigs (40 kg) were randomly assigned to one of five groups. In groups 1 through 4, a thoracic segment containing CICA was cross-clamped for 60 minutes and distal aortic perfusion was provided by a centrifugal pump. In groups 1 and 2, the thoracic segment was vented, maintaining segment pressure at 0 mm Hg; CICA were ligated in group 1 and preserved in group 2. Thoracic segment was perfused at 70 mm Hg in groups 3 and 4; CICA were ligated in group 3 and preserved in group 4. Critical intercostal artery ligations were performed at the end of the cross-clamp period. In group 5 simple cross-clamping at the left subclavian artery was performed as a control. The combination of venting and ligation of CICA correlated with impaired neurologic outcome according to Tarlov's score (median, 1.5 in group 1 versus 3 in group 2; p = 0.015), indicated by a significant difference in median values of direct spinal cord evoked potential amplitude (expressed as a fraction of baseline values) at 120 minutes after cross-clamping (0.76 in group 1 versus 0.98 in group 2; p = 0.0082).(ABSTRACT TRUNCATED AT 250 WORDS)

Spectral modulation of cortical connections measured by EEG coherence in humans.

OBJECTIVE: Description of coherence patterns of cortical EEG. METHODS: EEG recordings were collected from 9 subdural electrode grids implanted in 6 patients undergoing EEG monitoring for refractory epilepsy. RESULTS: Coherence decreased with increasing inter-electrode distance and exhibited considerable variability at the same inter-electrode distances. Analysis of variance demonstrated that both spatial and temporal factors contributed significantly (P < 0.01) to this variability. The spatial factor contributed the largest portion (up to 90%) of the variability, and was modulated by frequency and inter-electrode distance. CONCLUSION: The finding that the mean frequency modulation was consistent over time for the same pair of electrodes and was different between different pairs of electrodes indicated a spatial-spectral pattern of cortical synchrony. The connections (pairs of electrodes) could be accordingly predicted from their spatial-spectral pattern, which suggested that the spatial heterogeneity of neuronal synchrony was expressed not only by the degree of synchrony, but also by distinct spectral channels of synchrony. A model based on neuronal connection and activation is proposed to account for the observations.

Three-dimensional data visualization and biomedical applications.

Three-dimensional data visualization is an important tool in several medical, scientific, and engineering areas. Visualization methods are based on a primitive representational element: contour, surface, or volume. Methods often incorporate options to cut open, see around, or see through structures, and form images in multiple windows or with animation. To visualize and interpret two or three related 3D data sets, composite imaging methods are required. The appropriate method depends on the user needs, application area, and available hardware. Visualization of 3D medical data is described for cranium/face, musculoskeletal systems, spine, intracranial structures, cardiovascular system, and radiation therapy.

The effects of spinal gray activation by strychnine on the motor evoked potential in the rat.

Spinal motor evoked potentials were elicited by electrical stimulation of the motor cortex in 14 rats before and after the application of strychnine to the surface of the spinal cord. Strychnine applied to the high cervical cord resulted in the emergence of additional peaks at the site of application and in electrodes positioned distally on the middle and lower thoracic cord. The strychnine-induced peaks occurred earlier and were larger in amplitude (P less than 0.01) in the distal spinal cord. Strychnine applied to the lower thoracic cord resulted in similar peak generation in the lower thoracic cord and in the spinal cord proximal to the application of strychnine. These findings demonstrate that strychnine-induced motor evoked potential changes arise from spinal gray activity induced by efferent pathways activated during transcortical stimulation. The role of the propriospinal tract in mediating the distal effects of strychnine is discussed. In conclusion, the strychnine-induced peaks of the motor evoked potential may be used as a measure of spinal gray integrity in experimental spinal cord injury models.

Prediction of cerebellopontine angle tumors based on discriminant analysis of brain stem auditory evoked responses.

Multivariate discriminant analysis of brain stem auditory evoked response component latency intervals in patients with cerebellopontine angle tumors allowed accurate detection of 90% (35 of 39) of the tumor population with response data recordable from at least one ear. Eight-five per cent (23 of 27) of these could be detected by using information from the unaffected ear. One of 21 normal subjects was misclassified. Tumors significantly increased the I-III and III-V intervals on the side of the tumor. Increases in III-V interval latency were also observed on the unaffected side. The size of the tumor was significantly correlated with both discriminant scores derived from the analysis of the unaffected ear and delays in the III-V intervals from either the affected or the unaffected ear. These results were attributed to physiological factors and mechanical distortions of the brain stem. Regression equations derived from linear discriminant analysis for cerebellopontine angle tumors are presented and discussed in terms of their predictive validity.

The effect of graded spinal cord injury on the extrapyramidal and pyramidal motor evoked potentials of the rat.

This study investigated the differential effects of graded spinal cord injury on the rat extrapyramidal motor evoked potential (exp-MEP) and pyramidal motor evoked potential (pyr-MEP) and the prognostic value of these effects in predicting postinjury motor performance in the rat model. In 20 rats subjected to graded spinal injury (10-100 g-cm), there was a differential injury threshold for ablation of exp-MEP and pyr-MEP. All peaks of the pyr-MEP were extinguished in the animals subjected to impact forces of 50 g-cm and above (n = 12). In contrast, the exp-MEP was completely abolished in only two animals at injuries of 80 g-cm or above. A residual exp-MEP response persisted in the remaining 18 animals. Motor performance was monitored in 16 additional animals for up to 1 week after spinal injury. The pyr-MEP was abolished in 100% of the rats subjected to a 50-g cm injury (n = 7), whereas the exp-MEP persisted up to the highest impact forces (80 g-cm). Hind leg paralysis was present in the five rats where the pyr-MEP was extinguished but with persistence of the exp-MEP. An 80% reduction in the amplitude of the pyr-MEP in four animals resulted in mild ataxia with motor improvement at the end of a week. An increase or a 70% loss in pyr-MEP peak amplitude resulted in no clinical motor deficits (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: report of a case and review of the literature.

Although systemic metastases from transitional cell carcinoma of the bladder occur frequently, involvement of the central nervous system is uncommon. We describe a patient with an isolated cerebral metastasis who had previously undergone resection of a Grade III, Stage B2 carcinoma of the bladder. We have been able to find only one previous case report of a solitary intracerebral metastasis from transitional cell carcinoma of the bladder without evidence of primary recurrence or additional sites of spread. Central nervous system metastasis from bladder carcinoma must be considered in the differential diagnosis of solitary intracerebral lesions.

Intracarotid dehydrocholate infusion: a new method for prolonged reversible blood-brain barrier disruption.

An animal model for prolonged reversible blood-brain barrier (BBB) disruption has been developed. The external carotid arteries of Osborn-Mendel rats were catheterized in a retrograde manner. Varying concentrations of sodium dehydrocholate were infused into the internal carotid artery by this technique. BBB disruption was evaluated qualitatively by the appearance in the infused hemisphere of the systemically administered dyes Evans blue and sodium fluorescein and quantitatively by the ratio of counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the infused to the noninfused hemisphere. The ability of sodium dehydrocholate to disrupt the BBB was documented with all three markers. As the concentration of the infused dehydrocholate was increased, both the incidence and the degree of BBB disruption increased. Reversibility of BBB disruption was evaluated by the administration of sodium fluorescein and 99mTc-DTPA at varying times after BBB disruption. Depending on the concentration of the infused sodium dehydrocholate, altered BBB permeability can be maintained for over 3 days. This new model of prolonged reversible BBB disruption deserves further investigation both for basic studies of the BBB and for therapeutic studies of drug delivery into the central nervous system.

Noncortical origins of the spinal motor evoked potential in rats.

Motor evoked potentials (MEPs) were recorded from the spinal cord, sciatic nerve, or both during transcortical electrical stimulation in the rat. Four peaks could be consistently identified in the spinal MEP. The latency and amplitude of the peaks varied differentially with intensity and polarity of stimulation. Conduction velocity for Peak 1 of the MEP was 43 m/sec. Bilateral sciatic nerve MEPs were present after unilateral cortical stimulation. The spinal MEP was elicited by stimulation of areas outside the motor cortex, and the response persisted during subcortical stimulation and after motor cortex ablation. We present evidence suggesting that components of the spinal MEP in rats arise from pathways outside the motor cortex.

Electroencephalographic consequences of sodium dehydrocholate-induced blood-brain barrier disruption: Part 1. Acute and chronic effects of intracarotid sodium dehydrocholate.

Prior work has shown that the intracarotid infusion of sodium dehydrocholate can produce prolonged reversible blood-brain barrier (BBB) disruption. Associated with barrier disruption is the occasional presence of behavioral seizure activity. Electroencephalographic changes were monitored in 32 rats after BBB disruption by the left internal carotid artery infusion of sodium dehydrocholate. The electroencephalogram (EEG) was monitored for 3 hours after disruption in 20 animals, and the remaining 12 animals were followed for 24 hours. The EEG was also monitored in 8 additional control animals: 4 had undergone carotid artery infusion with normal saline, and 4 had received sodium dehydrocholate intravenously. The 20 rats monitored for up to 3 hours postinfusion were found to have varying grades of BBB disruption as measured by the presence of Evans blue staining of the brain. EEG alterations in this group included decreased amplitude and slowing as well as the presence of spike activity over the disrupted and the nondisrupted hemispheres. The more extensive the disruption, the more severe the EEG changes. In animals with minimal to moderate disruption, the EEG usually returned to base line levels within 3 hours after infusion. Animals with marked disruption usually had bilaterally flat EEGs before the end of the observation period. The remaining 12 animals were followed for 24 hours postinfusion. Of 9 animals surviving 24 hours, 1 animal had a decrease in amplitude over the disrupted hemisphere; in the remaining 8 animals, the spontaneous EEG was unchanged from predisruption levels except for occasional spikes in 2 animals. Animals infused with intracarotid saline or intravenous sodium dehydrocholate demonstrated no EEG changes or Evans blue staining.(ABSTRACT TRUNCATED AT 250 WORDS)

Electroencephalographic consequences of sodium dehydrocholate-induced blood-brain barrier disruption: Part 2. Generation and propagation of spike activity after the topical application of sodium dehydrocholate.

Sodium dehydrocholate was applied topically to the right hemispheric cortex of eight rats and the electrocorticogram was monitored from both the treated cortex and the homotopic cortex of the contralateral hemisphere. All animals developed blood-brain barrier (BBB) disruption in the treated cortex as evidenced by cortical staining with systemically administered Evans blue dye. Spike activity developed in three of eight animals after the topical application of dehydrocholate. The subsequent intravenous injection of sodium dehydrocholate provoked spike activity in both hemispheres in all eight animals. Dependent and independent spike activity was recorded in the nondisrupted hemisphere. The intravenous administration of gamma-aminobutyric acid (GABA) resulted in alterations in spike activity in four of five animals because of penetration of the GABA through the altered BBB. These findings demonstrate that sodium dehydrocholate can result in increased BBB permeability when applied directly to the cortical surface. Spike activity subsequent to the topical application of dehydrocholate can be enhanced by systemic loading with dehydrocholate. Spike activity occurring over the nontreated cortex (secondary focus) represents interhemispheric propagation of spike activity from the disrupted hemisphere (primary focus). The lack of Evans blue staining in the actively discharging secondary focus suggests that spike activity does not account for the increases in BBB permeability observed with dehydrocholate treatment.

Physiological and electrophysiological consequences of etoposide-induced blood-brain barrier disruption.

The present study investigates the effects of etoposide-induced blood-brain barrier (BBB) disruption on systemic blood pressure (SBP), intracranial pressure (ICP), and electroencephalographic (EEG) activity. A total of 29 rats were divided into two groups. In Group 1, 8 control animals received intracarotid normal saline; in Group 2, 21 animals received intracarotid etoposide. SBP, ICP, and EEG were monitored continuously under general anesthesia and controlled ventilation after tracheostomy. Intravenous Evans blue dye was used for determination of BBB disruption. Although none of the Group 1 animals showed BBB disruption, 57% of the animals in Group 2 showed marked BBB disruption (3+). A slight but statistically significant increase in ICP was noted in the Group 2 animals with 3+ BBB disruption, although lesser degrees of barrier disruption (1+ or 2+) resulted in no significant alteration in ICP. The amplitude and frequency of the EEG decreased significantly ipsilateral to the side of intracarotid infusion in all animals with 3+ barrier disruption with a tendency to return toward normal within 2 hours. The degree of transient EEG change observed correlates well with the degree of barrier disruption, potentially allowing clinical determination of BBB disruption by this method.

Neurological deterioration after lumbar puncture below complete spinal subarachnoid block.

The risk of neurological deterioration after removal of cerebrospinal fluid below the level of a complete spinal subarachnoid block is generally accepted. The actual incidence of deterioration after lumbar puncture in the presence of a complete block remains unknown. The present retrospective case analysis includes a review of 100 patients found to have complete block on myelography: 50 cases with a lumbar puncture and 50 cases with a C1-2 puncture. Each group consisted of a similar age range, neurological status prior to myelography, level of block, and nature of disease. Seven patients (14%) had significant neurological deterioration after lumbar puncture, while no deterioration was seen after a C1-2 puncture. A summary of those cases in which deterioration followed lumbar puncture is presented and the possible pathophysiology is discussed. From this analysis, the estimated risk of downward spinal coning after lumbar puncture below a complete spinal subarachnoid block caused by a mass lesion is at least 14%.

Changes in contralateral brain-stem auditory evoked responses to cerebellopontine angle compression in rats.

Eleven rats were subjected to graded compression of the brain stem at the cerebellopontine angle (CPA) following craniectomy and cerebellectomy. Clicks were delivered to the ear contralateral to the compression site, and brain-stem auditory evoked responses (BAER's) were collected before and during compression. With increasing compression, there was an increase in the latency and a decrease in the amplitude of the peaks of the BAER. The later peaks of the BAER (V and VI) demonstrated changes with minimal compression that progressed as compression increased, while changes in the amplitude and latency of the earlier peaks (II, III, and IV) occurred at the higher grades of compression. Following decompression of the brain stem, there was a decrease in the latencies of most of the BAER peaks. Peak amplitude remained depressed following brain-stem decompression. These experimental findings corroborate clinical reports of abnormal BAER's elicited from stimulation of the ear contralateral to a CPA tumor. The relative sensitivity of the later peaks of the BAER to even minimal brain-stem compression explains the prolonged III to V interpeak latency reported in the literature in patients with brain-stem compression from a CPA lesion. The possible mechanisms for the BAER changes that were observed contralateral to compression are discussed.

Brain-stem auditory evoked responses in 56 patients with acoustic neurinoma.

The brain-stem auditory evoked responses (BAER's) recorded from 56 patients with acoustic neurinomas were analyzed. Ten of the patients had intracanalicular tumors and 46 had extracanalicular tumors. It was possible to obtain BAER's following stimulation of the affected side in 28 patients and after stimulation of the unaffected side in all 56. Five patients (11%) had normal BAER's following stimulation of both sides; three of these patients had intracanalicular tumors. Among BAER's obtained following stimulation of the affected ear, the mean interpeak latency (IPL) for peaks I to III associated with extracanalicular tumors was significantly prolonged relative to controls (p less than 0.001), and linear regression analysis revealed a significant positive correlation between tumor size and IPL of peaks I to III (p less than 0.05). Analysis of the 56 BAER's recorded after stimulation of the unaffected side revealed a significant positive correlation between the IPL's of peaks III to V and tumor size (p less than 0.001). This correlation was not strengthened when accounting for the degree of brain-stem compression. Finally, evidence of preserved function within the auditory pathway, even in the presence of partial hearing loss, is presented. This finding suggests that more patients might benefit from surgical procedures that spare the eighth cranial nerve.

Angiographic changes to induced hypertension in cerebral vasospasm. Case report.

A case of cerebral vasospasm complicating intracranial aneurysm surgery is presented. Angiographic findings under hypertension and normotension revealed a paradoxical response of involved vessels suggesting that normal autoregulation is either lost or overcome by spasm.

Etoposide-induced blood-brain barrier disruption. Effect of drug compared with that of solvents.

The intracarotid infusion of the anti-neoplastic compound, etoposide, has been shown to exert a dose-dependent effect on blood-brain barrier (BBB) permeability. Etoposide, however, is formulated in a complex solvent solution containing alcohol, Tween 80, polyethylene glycol 300, and citric acid. To investigate the contribution of the solvent solution to BBB disruption, the authors studied Sprague-Dawley rats after the internal carotid artery infusion of the solvent solution with and without the addition of etoposide. Experiments were performed at four doses of drug and/or solvent. Disruption of the BBB was evaluated qualitatively by the appearance of the systemically administered dye, Evans blue, in the cerebral hemispheres and quantitatively by the ratio of gamma counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the ipsilateral:contralateral hemisphere. Significant barrier opening was obtained in all four groups of animals infused with solvent plus etoposide. In the corresponding groups of rats infused with the solvent solution alone, BBB disruption was markedly lower. Only in the group infused with the largest dose of solvent was the hemispheric ratio of 99mTc-DTPA significantly different from saline-infused animals. Each of the groups with solvent plus etoposide had 99mTc-DTPA ratios significantly different from the control group. Intracarotid infusion and subsequent BBB disruption were well tolerated by the animals receiving either solvent alone or solvent and etoposide. Disruption of the BBB secondary to the intracarotid infusion of etoposide is primarily caused by the drug itself and not by the solvent solution.

Learning disability assessed through audiologic and physiologic measures: a case study.

This report describes a child with central auditory dysfunction. Audiologic tests (Willeford Battery and Staggered Spondaic Word Test) indicate a brain-stem dysfunction but normal cortical functioning. Electrophysiologic tests corroborated these results. Brain-stem auditory-evoked responses (BAERs) indicated an absent contralateral peak III bilaterally when stimulating each ear separately. This is the first reported case where brain-stem dysfunction on audiologic tests were associated with specific electrophysiologic changes in the BAER.