Influences of pCO2 and bicarbonate concentration on bioelectric phenomena in ischemic hippocampal ex vivo tissue.

While the vasomotor effects of pCO(2) modulation are well documented, the influence of the carbon dioxide-bicarbonate system on the ischemia tolerance of brain tissue itself is controversial. Guinea-pig hippocampal tissue was subjected to ischemia simulation in an interface environment and examined electrophysiologically. Characteristics of anoxic depolarization as well as the postischemic recovery of evoked potentials were registered. During ischemia simulation, pH was changed and afterwards restored to 7.4. pH of 7.6 (n=6), and 7.8 (n=6) were adjusted by increasing bicarbonate concentration without changing pCO(2), while pH 8.2 was reached either with normal pCO(2) (n=8) or with zero CO(2) (n=9). pH 7.1 was created by doubling pCO(2) (n=22) or reducing bicarbonate (n=21), while acid pH of 6.9 (high pCO(2) and low bicarbonate) led to erratic measurements in the interface setup. Alkalotic conditions did not improve electrophysiological stability of the tissue, and pH 8.2 impeded the recovery of evoked potentials. Hypercarbic pH 7.1 led to significantly longer latency of depolarization while the same pH with lowered bicarbonate did not. Evoked potentials, however, recovered only partially after ischemia at hypercarbic pH 7.1. Once the tissue had recovered from anoxic depolarization at control pH, hypercarbic acidosis did not have any further protective effect when ischemia simulation was repeated (n=12). These results do not strengthen the concept of hyperventilation in intensive care, while they suggest a potential of hypercarbia within broader strategies delaying the onset of secondary brain damage.

Hyperbaric oxygen in neurosurgery.

BACKGROUND: The therapeutic use of pure oxygen, even under hyperbaric conditions, has been well established for about 50 years, whereas the discovery of oxygen occurred 250 years earlier. Many neurosurgical patients suffer from brain tissue damage, due to reduced blood flow, obstructive vessel disease, or as a result of traumatic brain injury. METHODS AND RESULTS: The application of pure oxygen in these patients is the only method of increasing the O(2) concentration in tissue with impaired blood supply and can minimize secondary impairment of brain tissue. DISCUSSION: In this brief historical overview we focus on the development and evidence of hyperbaric oxygenation in this specific field of insufficient oxygen supply to the central neural tissue. CONCLUSION: With the use of modern biological methods and new study designs, HBO has a place in evidence-based treatment of patients with neural tissue damage.

[Is the Canadian CT head rule for minor head injury applicable for patients in Germany?]. / Lässt sich die Canadian CT Head Rule für das leichte Schädel-Hirn-Trauma auf Deutschland übertragen?

PURPOSE: To evaluate the applicability of the Canadian CT Head Rule (CCHR) on head trauma patients in a German university hospital. METHODS: 122 patients (m = 74; f = 48; 40 +/- 19 years) were examined with cranial CT due to minor head trauma. The need for cranial CT according to the CCHR was evaluated retrospectively. RESULTS: With a sensitivity of 98.9 % and a specificity of 46.6 % all patients with the need for neurosurgical intervention were detected by applying the major criteria of the CCHR. Also, every patient with severe brain injury was detected by the extended criteria with a sensitivity of 99.6 % and a specificity of 34.1 %. This would have led to a reduction in the rate of cranial CT examinations by 45.1 % for the major and 22.1 % for the extended criteria. No patient with severe brain injury would have been missed by application of the criteria. CONCLUSION: The Canadian CT Head Rule for patients with minor head trauma is applicable with a very high sensitivity and the potential of significantly reducing the rate of cranial CT examinations in these patients.

Spontaneous spinal epidural haematoma: a therapeutical challenge? Report of an unusual case.

We report the conservative treatment of a spontaneous spinal epidural haematoma attending with acute extensive neurological deficits, which resolved spontaneously. Spontaneous remission of spontaneous spinal epidural haematoma with severe neurological deficit is rare in the literature. An 80 year old man was admitted to our hospital presenting sciatica followed by rapid development of paraparesis and cauda equina syndrome, which represents a neurosurgical emergency. Magnetic resonance imaging revealed a multilevel epidural haematoma from L1 to L5. During the initial diagnostic procedure the symptoms started to decline unexpectedly, so the surgical intervention could be withdrawn. Twenty four hours after admission the patient was almost free of symptoms, mobile, and continent. Awareness and high index of suspicion, and a willingness to seek the prompt help of the imaging department, are crucial to successful management before the opportunity to treat is lost.

Iodine-123-alpha-methyl tyrosine in gliomas: correlation with cellular density and proliferative activity.

UNLABELLED: Amino acid transport rate in gliomas can be assessed using SPECT and the amino acid L-123I-alpha-methyl tyrosine (IMT). This study attempted to correlate the uptake of IMT by gliomas with the proliferative activity and cellular density of these neoplasms. METHODS: The study used 27 patients with gliomas, including 18 patients with high-grade tumors and nine patients with low-grade neoplasms. Amino acid transport rate was determined using IMT and the triple-headed SPECT camera. Proliferative activity was immunohistochemically assessed as the relative number of cells expressing the Ki-67 nuclear antigen; cellular density was evaluated using light microscopy. RESULTS: Relative IMT uptake correlated significantly with the proliferative fraction of tumor cells (r = 0.6, p < 0.001). There was no significant correlation between IMT uptake and cellular density (r = 0.25, p > 0.05). CONCLUSION: The uptake of the SPECT radiopharmaceutical IMT is related to proliferative activity rather than to the cellular density of gliomas.

Diagnosis of recurrent glioma with SPECT and iodine-123-alpha-methyl tyrosine.

UNLABELLED: Iodine-123-alpha-methyl tyrosine (IMT) allows the investigation of amino acid transport rate in brain neoplasms. It was the aim of this study to evaluate the potential of IMT-SPECT to diagnose the recurrence of gliomas after primary therapy. METHODS: Using a triple-headed SPECT camera, the cerebral uptake of IMT was determined in 27 patients 22 mo, on average, after surgical removal of a primary brain tumor. Eighteen patients had suffered from high-grade gliomas, and nine had suffered from low-grade tumors. Four patients were examined before and after surgical revision of a presumed tumor recurrence. A total of 31 studies were evaluated. The final diagnosis was based on prospective clinicopathological follow-up. Recurrence was diagnosed in 23 cases, with marked clinical deterioration occurring 3.1 mo, on average, after SPECT, and was confirmed by histopathology in 14 instances. Eight cases were free of recurrence, as evidenced by inconspicuous clinical follow-up, ranging from 6 mo to 17 mo after SPECT in seven cases, and by clinical course and histopathology in the remaining subject. RESULTS: Patients with recurrence had significantly higher ratios of IMT uptake in the tumor area to that in a background region than did patients without recurrence (2.27 +/- 0.59 compared to 1.47 +/- 0.29; p < 0.002). The best cutoff level of the IMT uptake ratio in the differentiation between recurrence and benign posttherapeutic lesion was 1.8. Using this study-specific discrimination threshold, the sensitivity and specificity of IMT-SPECT for detecting glioma recurrence were 18 of 23 (78%) and 8 of 8 (100%), respectively. The area under the binormal receiver operating characteristic curve, fitted to the data, was 0.90 +/- 0.06. CONCLUSION: Iodine-123-alpha-methyl tyrosine-SPECT is a promising new tool in the follow-up of patients with gliomas after primary therapy.

Optical monitoring of PO2 changes and simultaneous recording of bioelectric activity in human and animal brain slices.

For investigations of hypoxic effects in nervous tissue, brain slices are often used as a model system. This provides the advantage that parameters of the micromilieu, e.g. pH and temperature can easily be controlled and measurements of different data, e.g. bioelectric potentials, ion activities etc. can be performed. It is of special importance that the PO2 the slice preparation is exposed to is equally controlled under these conditions. Therefore, a PO2 monitoring system is needed which provides representative values for the tissue environment. This requirement is fulfilled by an optical PO2 sensing method based on phosphorescence quenching as a function of PO2. Here, the application of this method as adapted for use in in vitro models is described and compared to the polarographic oxygen-sensing method. Both the optical and polarographic methods are comparable regarding accuracy and response time of measurements. Furthermore, both the optical method and electrophysiological measurements can be combined. Lastly, under experimental conditions, neither the phosphorescent dye Palladium-meso-tetra-4-carboxyphenyl-porphine nor the illumination necessary for excitation of the dye influence bioelectric activity of neuronal tissue in vitro. In conclusion, the optical PO2 sensing method presented here provides a tool for reliable and continuous monitoring of PO2 in the immediate environment of brain slice preparations.

Changes of extracellular calcium concentration induced by application of excitatory amino acids in the human neocortex in vitro.

The influence of the glutamate subreceptor agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on cortical field potentials and on changes in extracellular free calcium concentration ([Ca2+]o) was tested on human neocortical slices (eleven from nine different patients). The tissue used was a small portion of that which is normally removed for the treatment of a brain tumor. [Ca2+]o and field potentials were measured by Ca(2+)-selective microelectrodes. Local pressure-microejection of NMDA (100 mumol/l)- and AMPA (1 mmol/l)-induced negative field potentials with maximal amplitudes of 0.9 +/- 0.1 mV (11 slices, mean +/- S.E.M.) and 1.0 +/- 0.1 mV (nine slices), respectively. The negative field potentials induced by NMDA were accompanied by monophasic decreases of [Ca2+]o (0.8 +/- 0.1 mmol/l, nine slices). AMPA elicited no (three slices) or only minor decreases of [Ca2+]o (0.2 +/- 0.1 mmol/l, five slices). The responses to the glutamate subreceptor agonists NMDA and AMPA were reversibly depressed by adding their specific antagonists DL-2-amino-5-phosphonovalerate (APV, 100 mumol/l, six slices) and 6-cyano-7-nitroquinoxalin-2,3-dion (CNQX, 5 mumol/l, four slices), respectively. The results correspond to findings in animal experiments and are consistent with the interpretation that in the human neocortex the Ca2+ permeability of channels gated by NMDA is higher than those gated by AMPA.

The effects of verapamil and flunarizine on epileptiform activity induced by bicuculline and low Mg2+ in neocortical tissue of epileptic and primary non-epileptic patients.

In human neocortical slices the specific L-type calcium channel blocker verapamil had been shown to be antiepileptic in the low Mg(2+)-model of epilepsy. The present investigation demonstrated: (1) verapamil exerted also an antiepileptic effect on epileptiform field potentials (EFP) induced by the GABAA-antagonist bicuculline. (2) The unspecific calcium channel modulator flunarizine, which in contrast to verapamil penetrates the blood-brain barrier, depressed EFP in the low Mg(2+)-model and in the bicuculline model. (3) There was no significant difference in the antiepileptic efficacy of verapamil and flunarizine in epileptic (epilepsy surgery) and primary non-epileptic (tumor surgery) neocortical slices.

Acute protective effect of nimodipine and dimethyl sulfoxide against hypoxic and ischemic damage in brain slices.

Nimodipine and dimethyl sulfoxide (DMSO) were tested (alone and in combination) regarding their ability to increase hypoxic tolerance of brain slices under 'hypoxic' (deprivation of oxygen) or 'ischemic' (hypoxia+withdrawal of glucose) conditions. Direct current (DC) and evoked potentials were recorded in the CA1 region of hippocampal slices of adult guinea pigs. After induction of hypoxia or ischemia, the latency of anoxic terminal negativity (ATN) of the DC potential was determined during superfusion with artificial cerebrospinal fluid alone (aCSF), and during superfusion with aCSF containing DMSO [0.1% (14.1 mmol/l) and 0.4% (56.3 mmol/l)] with the addition of nimodipine (40 micromol/l). Latencies of ATN with first hypoxia were 6.7+/-3.7 min in the control group, 9. 3+/-4.2 min in the 0.4% DMSO group and 12.3+/-5.5 min (P=0.007) in the nimodipine/0.4% DMSO group. Latencies of ATN with first ischemia were 2.9+/-2 min in the control group, 4.1+/-1.6 min in the 0.1% DMSO group, 7.1+/-3.9 min in the 0.4% DMSO group (P=0.006), 5.3+/-1. 5 min in the nimodipine/0.1% DMSO group and 7.6+/-3 min (P<0.001) in the nimodipine/0.4% DMSO group. DMSO (0.4%), either alone or in combination with nimodipine, increase the latency of the ATN after acute onset of hypoxia and ischemia.

Neuroprotection of mild hypothermia: differential effects.

To estimate whether mild hypothermia during repetitive hypoxia provides a neuroprotective effect on brain tissue, hippocampal slice preparations were subjected to repetitive hypoxic episodes under different temperature conditions. Slices of guinea pig hippocampus (n=40) were placed at the interface of artificial cerebrospinal fluid (aCSF) and gas (normoxia: 95% O2, 5% CO2; hypoxia: 95% N2, 5% CO2). Evoked potentials (EP) and direct current (DC) potentials were recorded from hippocampal CA1 region. Slices were subjected to two repetitive hypoxic episodes under the following temperature conditions: (A) 34 degrees C/34 degrees C, (B) 30 degrees C/30 degrees C and (C) 34 degrees C/30 degrees C. Hypoxic phases lasted until an anoxic terminal negativity (ATN) occurred. The recovery after first hypoxia lasted 30 min. Tissue function was assessed regarding the latency of ATN and the recovery of evoked potentials. The ATN latencies with protocol A (n = 25) for the first and second hypoxia were 5.9+/-1.3 min (mean+/-S.E.M., 1st hypoxia) and 2.4+/-0.9 min (2nd hypoxia), with protocol B the latencies (n = 7) were significantly longer: 25.2+/-7.1 min and 15.6+/-7.7 min. With protocol C (n=8), the latencies were 5.6+/-1.8 and 3.3+/-0.5 min. No differences were seen in the recovery of the EPs with protocols A-C. Our results suggest that a mild hypothermia is only neuroprotective if applied from an initial hypoxia onwards.

Flat and steep terminal negativity in the DC-potential after deprivation of oxygen and glucose in human neocortical slices.

The so-called terminal negativity (TN) of the DC-potential is a characteristic reaction of neuronal tissue to hypoxia or ischemia. In a previous study on human neocortical slices, two types of TN with flat and steep slopes of rise (< or >10 mV/min) were found with hypoxia. The aim of the present study was to further investigate causes underlying the occurrence of flat and steep TN. Experiments were performed on 23 human neocortical slices (500 micron) resected from 13 patients (epilepsy and tumour surgery). DC-potential and evoked potentials (white matter stimulation) were recorded in layer III. The extracellular potassium concentration ([K+]o) was measured by K+-sensitive microelectrodes. In an interface type chamber, ischemic episodes were induced by oxygen and glucose deprivation. They were terminated when TN had peaked. Both flat and steep TN also existed with ischemic conditions. There was a linear correlation between the slope of rise of TN and the associated slope of rise in [K+]o, respectively, but none regarding latencies of TN or recovery of evoked potentials. Peak levels in [K+]o were 13.9+/-0.9 mmol/l. Compared to control, the slope of rise and latency of TN were clearly increased by addition of dimethyl sulfoxide (DMSO, 0.4%) to the bath solution, whereas nimodipine (40 micromol/l) in 0.4% DMSO had neither an effect on slope of rise of TN nor on latency of TN. As a whole, our observations suggest, that the actual metabolic state determines the occurrence of flat or steep TN.

Anoxic terminal negative DC-shift in human neocortical slices in vitro.

In animal models, the hallmark of a hypoxic condition is a strong negative shift of the DC potential (anoxic terminal negativity, ATN). This DC-shift is interpreted to be primarily due to a breakdown of the membrane potential of neurons. Such massive neuronal depolarizations have not been reported for all human neocortical neurons in vitro even during prolonged hypoxic periods. This poses the question whether ATN develop also in human neocortical slices made hypoxic. ATN could be observed when human brain slice preparations (n = 15, 13 patients) were subjected to periods of hypoxia (10 to 120 min). These ATN were usually monophasic and appeared with a latency of 16 +/- 4 min (mean +/- S.E.M.). Separating the ATN according to their slopes of rise, steep (> 10 mV/min) and flat (< 10 mV/min) ATN could be distinguished. Steep and flat ATN may be regarded as two different entities of reactions since steep ATN had also greater amplitudes and slopes of decay as compared a flat ATN. With repetitive hypoxias, the latency of both the steep and flat ATN was reduced for the following hypoxic episodes. During hypoxic DC-shifts, evoked potentials were suppressed. With the 1st through 4th hypoxia, they recovered fully within 30 min after reoxygenation when hypoxia was terminated at the plateau of ATN; with extension of hypoxia, recovery was only partial. From the 5th hypoxia onwards, recovery usually did not take place or was not complete.

Dimethyl sulfoxide increases latency of anoxic terminal negativity in hippocampal slices of guinea pig in vitro.

Dimethyl sulfoxide (DMSO), which is widely used as a solvent for a variety of drugs, was used in the present study to investigate its ability to increase the hypoxic tolerance of brain tissue in vitro. DC-potentials and evoked potentials (EP, Schaffer collateral stimulation) were recorded in the CA1 region of hippocampal slices from adult guinea pigs. The latencies of the negative DC-potential shift (anoxic terminal negativity, ATN) after onset of hypoxia (95% N2, 5% CO2) were determined during superfusion with artificial cerebrospinal fluid (aCSF) or DMSO 0.4% dissolved in aCSF, respectively. The latencies of ATN were increased by DMSO application from 7.5+/-0.9 min (mean +/- SEM) under control conditions (n = 38) to 11.1+/-1.3 min with DMSO (n = 22, P < 0.01). These results demonstrate a neuroprotective effect of DMSO.

Effect of nimodipine in treatment of experimental focal cerebral ischaemia.

Despite the voluminous current literature the potential of nimodipine to modify the outcome in experimental cerebral ischaemia remains a controversial matter. The authors have evaluated in controlled double blind experiments the influence of a continuous i.v. infusion of the drug (1 microgram kg-1 min-1) upon infarct size, histopathology and neurological outcome in rats with permanent middle cerebral artery (MCA) occlusion. The infusion was started 20 min before induction of ischaemia and continued 4 hours thereafter. The nimodipine treated animals were subdivided into hypotensive (MABP lower than 85 mmHg for more than 5 min after arterial occlusion) and normotensive groups. Infarction size, documented by TTC, H&E and Nissl staining was significantly smaller (p less than 0.001) in nimodipine normotonic rats than the lesions in placebo and saline treated rats, as well compared with hypotonic nimodipine animals (largest infarction). These differences were found to be entirely at the expense of the cortical (frontoparietal) component of the lesion, suggesting 'penumbra' action of the drug. Moreover, nimodipine normotonic rats displayed lower cortical neuronal injury in the periinfarct zone. These findings were corroborated by corresponding better neurological scores. Our results indicate that nimodipine is effective in reducing focal cerebral ischaemia, provided the MABP is maintained higher than 85 mmHg.

Long term EEG analytical and neurological follow-up study in completed stroke patients after extra-intracranial vascular anastomosis.

In 33 chronic stroke patients, who had internal carotid or middle cerebral artery occlusion that resulted in neurological deficit persisting for an average of more than 10 weeks, it was possible to perform a postoperative follow-up study for a period of six to eight years after extra-intracranial vascular anastomosis. Serial neurological examinations with grading of motor deficit and EEG analyses were performed to assess the clinical course of the cerebral lesion. These long term examinations showed a postoperative continuing improvement of electrical brain activity in nearly two thirds of the patients, nine patients showed no significant changes and three worsened. The EEG analytical findings correlated well to the neurological findings. An increase of electrical brain activity was bilateral with accentuation over the affected hemisphere, a phenomenon known from follow-up nrCBF measurements after anastomosis. During the follow-up one patient died five years, one six years following stroke under signs of cardiovascular disease, and one after six years suffering from a recurrent stroke opposite to the side of anastomosis. In conclusion the findings indicate that EEG analysis is of value for assessment of long term follow-up of cerebral ischaemic lesions, chronic ischaemic alterations of the brain can be improved by anastomosis, and especially in comparison to a non-operated group of stroke patients, the course of the operated one seemed to be more advantageous, as the five-year survival rate of the Framingham study for stroke victims is 69%.

Reversible focal ischemia model in the rat: correlation of somatosensory evoked potentials and cortical neuronal injury.

Somatosensory evoked potentials (SEPs) are valuable in experimental stroke studies, but only a few reports have dealt with small rodent models. Our experiments aimed to reproduce SEP monitoring during reversible middle cerebral artery occlusion (MCAo) in a surgical model of open craniotomy and vessel manipulations in the rat. The changes of median nerve SEPs were correlated to the degree of local cortical neuronal injury in the forelimb area. Based on a pilot group (n = 11) both parameters were examined at 2 h after reperfusion in a subsequent study with increase of MCAo time from 1 (n = 7) to 2 h (n = 7); 5 rats were sham operated. A significantly delayed and incomplete recovery of SEPs, expressed as a percentage of the mean preocclusion values was observed with 2 h compared to 1 h MCAo (20.8% versus 6.0% change in the latency and 59.5% versus 2.2% in the amplitude of the primary cortical response). The functional outcome was found to correlate consistently with the degree of neuronal damage in 1 and 2 h reversible MCAo (2.5% versus 79.2% severely damaged neuronal types III and IV). Our findings suggest, that 2 h MCAo followed by 2 h reperfusion produces a submaximal neuronal injury and partial electrical recovery in the periphery of the occluded vascular territory and could be therefore used as a reliable model for assessment of cerebroprotective drug efficacy.

Hypothermia as cerebroprotective measure. Experimental hypoxic exposure of brain slices and clinical application in critically reduced cerebral perfusion pressure.

An in vitro human neocortical and rodent hippocampus brain slice technique was used under repeated hypoxia to investigate the cerebroprotective effect of hypothermia. As a hallmark of the neuronal hypoxic reaction anoxic terminal negativity (ATN) was registered to test whether hypothermia delays the onset of ATN. The experiments clearly confirm an assumed protective effect of hypothermia in vitro and in vivo and give for the first time evidence of the lack of the protective effect of hypothermia once hypoxia has occurred under normothermic conditions, probably by a critical depletion of cellular ATP-stores. In patients with severe traumatic brain injury and critically low cerebral perfusion pressure mild hypothermia is able to improve clinical outcome.

Neuroprotection by 21-aminosteroids: insights from latencies of anoxic terminal negativity in hippocampus slices of guinea pig.

The protection of neuronal function by 21-aminosteroids against a hypoxic challenge was tested in guinea pig hippocampal slices. 21-aminosteroids, which apart from a protective mechanism against membrane lipid peroxidation, provide direct membrane stabilizing effects, are reported. We tested whether the 21-aminosteroid U-74389G delays the anoxic terminal negativity (ATN) of the DC-potential during hypoxia. Hippocampal slices were placed at the interface of artificial cerebrospinal fluid (aCSF) and gaseous phase (normoxic: 95% O2, 5% CO2; hypoxic: 95% N2, 5% CO2). Population spikes obtained by stimulation of Schaffer-collaterals as well as the DC-Potential were recorded in the CA1 region. The latency of appearance of ATN after oxygen deprivation was determined. In control experiments, the latency of ATN was 12.6 +/- 3.1 min (n = 6, mean +/- SEM). With application of U-74389G, the ATN-latency was 8.8 +/- 3.2 min (n = 6). We conclude that the cerebroprotective effect of the 21-aminosteroid is not mediated via direct membrane stabilization.

Repetitive hypoxic exposure of brain slices and electrophysiological responses as an experimental model for investigation of cerebroprotective measurements.

An in vitro hippocampal (CA 1 region, guinea pig) slice technique using repeated hypoxia was employed to model electrophysiological changes (DC-potentials and evoked potentials (EP) by stimulation of Schaffer-collaterals) occurring in the hypoxic CA1 pyramidal layer. A standardized neuronal response under repeated hypoxic conditions was observed in this model, consisting of disappearance of EP and a trend towards partially reversible, but progressive synaptic failure subsequent anoxic depolarisation (AD). Slices treated with the calcium antagonist nimodipine showed a prolongation of AD latency between the first and following hypoxias. So it seems possible to simulate hypoxic lesions of the brain tissue by using this in vitro slice model.