Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas.

BACKGROUND: Considerable numbers of patients with low-grade gliomas experience an early malignant course and may benefit from aggressive treatment. These patients are difficult to identify using established prognostic factors. A retrospective study was performed to determine whether the (11)C-methionine uptake in tumor is a survival factor in adult patients with supratentorial gliomas classified as World Health Organization Grade 2. METHODS: The authors identified 89 patients with histologically confirmed low-grade gliomas in whom an (11)C-methionine positron emission tomography (PET) scan had been performed as part of the diagnostic tumor investigation from 1983 to 1998. Clinical data were collected, and the PET scans were re-evaluated according to a fixed protocol. The (11)C-methionine uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analyses. RESULTS: At the end of the study, 49 patients (55.1%) had died. The median overall survival was 5.7 years. Low methionine uptake was significantly favorable in the multivariate survival analysis (P = 0.04) along with oligodendroglioma (P = 0.003). In the histologic subgroups, (11)C-methionine uptake was an important survival factor among patients with astrocytomas (P = 0.05) and oligodendrogliomas (P = 0.03). Tumor resection was a favorable prognostic factor in patients with high methionine uptake (P = 0.01) but not in patients with low uptake. CONCLUSIONS: Baseline (11)C-methionine PET is a prognostic indicator in patients with low-grade gliomas. The results imply that PET is a valuable tool in the clinical management of these patients and may assist in the selection of patients for therapy.

Screening for ventricular shunt function in children with hydrocephalus secondary to meningomyelocele.

OBJECTIVE: To evaluate the current method of using computerized tomographic (CT) scans to screen for ventricular shunt failure in children who have hydrocephalus. DESIGN: Retrospective review of 112 randomly selected charts. PATIENTS: Children diagnosed with infantile hydrocephalus secondary to meningomyelocele, who were treated at the Andrew J. Kirch Developmental Services Center since 1978. RESULTS: One hundred and twelve patients were monitored with CT scans for an average of 12.2 years. There was a total of 2,869 CT scans and an average of 2.1 CT scans per year. Shunt failure was diagnosed 76% of the time by symptoms, 15% by physical findings and 8% by routine CT scans. Sixteen patients had no shunt failure, whereas the remaining 96 had 255 shunt failures. Complications occurred during 30 of the 255 admissions. One child died due to complications directly related to shunt failure. No statistically significant correlations were found between the length of stay or complications and method of diagnosis. CONCLUSIONS: Although children in this study received frequent CT scans, 76% of the episodes of shunt failure were diagnosed because of symptoms. Children admitted to the hospital with symptomatic shunt failure did not have more complications or a longer stay than those diagnosed by routine CT scan. This study suggests that the use of routine CT scans to diagnose shunt failure while patients are asymptomatic does not lead to significantly better medical outcomes and is not cost-effective. However, before routine CT scans are eliminated, a prospective study needs to be conducted that examines outcomes such as cognitive and psychological functioning.

Conjugate chemistry, iodination and cellular binding of mEGF-dextran-tyrosine: preclinical tests in preparation for clinical trials.

A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest for clinical tests was prepared using mouse epidermal growth factor, mEGF, and dextran. The mEGF was first coupled to dextran by reductive amination in which the free amino group on the N-terminal of mEGF was reacted with the aldehyde group on the reductive end of the dextran chain. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines introduced to the dextran part of the conjugate. The mEGF-dextran-tyrosine conjugate was, with high efficiency, iodinated with the chloramine-T method. Approximately 25-35% of the radioactivity could be removed from the conjugate after exposure to protease K while 65-75% of the radioactivity could be removed after exposure to dextranase. Thus, the largest amount of the iodine was on the dextran part of the conjugate. The iodinated mEGF-dextran-tyrosine had EGFR specific binding since the binding to an EGFR rich human glioma cell line could be displaced by an excess of non-radioactive mEGF. The conjugate was to a large extent internalized in these cells and the administrated radioactivity was thereby retained inside the cells for at least up to 50 h.

MR imaging of cerebrospinal fluid dynamics in health and disease. On the vascular pathogenesis of communicating hydrocephalus and benign intracranial hypertension.

The CSF flows in the aqueduct and at the foramen magnum were examined in 5 patients with communicating hydrocephalus (HC) and in 10 with benign intracranial hypertension (BIH) as well as in 5 healthy volunteers. As compared to normal individuals, the aqueductal flow in HC was about 10 times larger and the cervical flow was half as large. In BIH the CSF flows were not different from those of normal volunteers. The decreased arterial expansion as reflected in the reduced cervical flow in HC may be due to pathologic changes in the arteries and paravascular spaces. The large aqueductal flow in HC reflects a large brain expansion, causing increased transcerebral mantle pressure gradient and ventricular dilatation. In BIH there is a normal brain expansion (aqueductal flow) and consequently no ventricular dilatation. It is argued that BIH be caused by an obstruction on the venous side, as opposed to the vascular alterations in HC, which are on the arterial side.

CT showing early ventricular dilatation after subarachnoidal hemorrhage.

We performed a retrospective analysis of 398 patients with subarachnoidal hemorrhage (SAH) confirmed by CT. On the first CT examination the temporal horns were enlarged in 84%, the frontal horns in 32%, and the third ventricle in 21% of the patients. The amount of blood in the basal cisterns was highly correlated to dilatation of the temporal horns. The temporal horns were enlarged even when small amounts of blood were found in the cisterns. The frontal and temporal horns were dilated only when moderate or large amounts of blood were present in the cisterns. In 24 patients no blood was seen in the basal cisterns on CT performed within 5 days of the hemorrhage; none of the 3 patients with aneurysms showed normal temporal horns while 18 without demonstrable aneurysms had normal, and 3 had moderately dilated, temporal horns. Because the temporal horns cannot usually be seen at CT of healthy individuals, dilatation could be a useful sign in the diagnosis of SAH.

A new method for long-term lumbar pressure monitoring with a fiber optic catheter.

A new method for long-term monitoring of cerebrospinal fluid (CSF) pressure in the spinal canal using a catheter with a fiberoptic pressure monitor is described. This method has been used in the investigation of 16 patients with communicating hydrocephalus (CH). Duration of monitoring ranged from 2-48 hours without any complications. In 6 cases the recording was interrupted prematurely. Valuable data on the patterns of pressure variation could be attained and the occurrence of B-waves showed a good correlation with the clinical outcome of shunt operation. No sign of external or internal leakage of CSF was observed during the first 24 hours of monitoring. This technique could prove to be a less invasive method for evaluation of CSF-pressure in patients with CH or other diseases where CSF-pressure in the spinal canal can have some clinical significance.

Neurotoxicity of benzylpenicillin in experimental renal failure and Enterobacter cloacae meningitis.

The neurotoxic potential of benzylpenicillin administered as a continuous intravenous infusion was studied in rabbits with intact blood-CNS barriers, experimentally established Enterobacter cloacae meningitis and experimental renal failure, secondary to cephaloridine-induced acute tubular necrosis after iv administration. The concentrations of benzylpenicillin in serum, CSF and brain tissue fluid were assayed at the onset of epileptogenic electroencephalographic activity. The brain tissue concentrations of benzylpenicillin were consistently higher than those in CSF in both infected and uninfected animals. The highest brain tissue fluid concentrations of benzylpenicillin were found in rabbits with renal failure after cephaloridine pretreatment. The brain tissue fluid concentrations of benzylpenicillin rather than the CSF concentrations were decisive for neurotoxicity. Cephaloridine-induced uraemia, but not the combination of uraemia and meningitis, resulted in a significantly increased tolerance of high intracerebral concentrations of benzylpenicillin before EEG-changes were precipitated.

Regional cerebral blood flow and histopathologic changes after middle cerebral artery occlusion in rats.

Changes in regional cerebral blood flow were correlated with the distribution of histopathologic signs of brain injury in 35 rats after middle cerebral artery occlusion. Rats were allowed to survive for periods of up to 4 weeks after the operation, and we focused particular interest on the time course of blood flow changes from the initial ischemic events to the late stage of infarction. Regional blood flow was measured using [14C]iodoantipyrine and a quantitative autoradiographic technique. Blood flow in regions with histologic signs of infarction (i.e., the lateral caudoputamen and adjacent neocortex) was below 0.238 ml/g/min, corresponding to 15% of normal values for those regions. In perifocal regions without infarction such as the medial caudoputamen and globus pallidus, cerebral blood flow was also reduced, but it never declined below 20% of its normal value. The decrease in cerebral blood flow was most marked during the first hours after occlusion. Thereafter, cerebral blood flow values gradually normalized, and at 4 weeks there were no significant differences compared with the contralateral side. The border between cortical regions with hypoperfusion and normal cerebral blood flow was rather sharp in the coronal plane, but in the sagittal plane there was a more gradual transitional region. The region with hypoperfusion, observed in the sagittal plane, was most widespread in the acute stage, and normalization of flow occurred particularly from anterior and posterior cortical regions toward the ischemic focus. The possibility for penumbral conditions in the cortex thus exists, particularly in the anterior and posterior borders of the infarction, and remains for several hours after the initial insult.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurologic and neuropathologic outcome after middle cerebral artery occlusion in rats.

Focal cerebral ischemia was produced in 45 rats by occlusion of the left middle cerebral artery. Groups of rats were investigated over a long period after occlusion, that is, from a few hours to 42 days after the production of focal ischemia. Light microscopy showed infarcts in the frontoparietal cortex and the lateral caudoputamen. The ischemic changes closely resembled those found in ischemic infarcts in humans and followed a similar pattern over time. Measurements of the sizes of the infarct, the ipsilateral (operated) hemisphere, and the contralateral hemisphere from camera lucida drawings revealed that the infarct size changed with time after occlusion. Rats killed during the first 7 days (acute phase) had the largest infarcts; in rats killed thereafter, the infarct size diminished. The size of the ipsilateral hemisphere also changed with time; during the first 7 days after occlusion this hemisphere was swollen and larger than the contralateral hemisphere. We suggest that these acute changes are caused by cerebral edema. After the first 7 days, enlargement of the ipsilateral hemisphere gave way to a significant reduction in the size of both the ipsilateral hemisphere and the infarct. We believe that the major reasons for this shift in size are resorption of fluid together with diminished production of edema and elimination of dead cells by macrophages. We suggest that the amount of tissue loss (i.e., the degree of atrophy and the remaining infarct "scar") found 21-42 days after occlusion (during the late phase) is a measure of the total amount of tissue that succumbed as a consequence of ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased extracellular levels of ascorbate in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis.

Extracellular (EC) ascorbate concentrations were measured in microdialysates from the striatum bilaterally in rats subjected to unilateral middle cerebral artery occlusion (MCAO). The focal cerebral ischemia induced a dramatic increase in ascorbate on the ipsilateral (operated) side while the levels remained at the preocclusion level in the striatum of the contralateral (control) hemisphere. The possibility that ascorbate may aggravate ischemic neuronal damage by its proposed neuromodulatory properties and/or by its ability to induce lipid peroxidation is discussed.

Neurotoxicity of benzylpenicillin in experimental Escherichia coli meningitis.

The neurotoxic potential of benzylpenicillin administered intravenously as a continuous infusion was studied in rabbits with experimental Escherichia coli meningitis. As controls a group of rabbits was injected with saline into the cisterna magna. The concentrations of benzylpenicillin in serum, CSF and brain tissue fluid were studied at onset of epileptogenic electroencephalographic activity (thirteen rabbits) or convulsions (ten rabbits), with a previously developed method for neurotoxicity studies. E. coli meningitis did not increase the neurotoxicity of benzylpenicillin, despite high concentrations of the drug in both CSF and brain tissue fluid. The intracisternal injection of saline in the control group produced slight pleocytosis in some rabbits indicating some degree of damage of the blood-CSF barrier.

Neuron-specific enolase is a marker of cerebral ischemia and infarct size in rat cerebrospinal fluid.

Neuron-specific enolase concentrations were measured in samples of rat cerebrospinal fluid obtained repeatedly before and after occlusion of the middle cerebral artery. A method for reliable, repeated sampling of cisternal cerebrospinal fluid was developed for this purpose. Occlusion of the middle cerebral artery induced cerebral infarcts of slightly variable size with good correlation to raised neuron-specific enolase concentrations. Sham operation caused only superficial cortical damage at the site of surgery and was followed by an early, slight, and transient increase in neuron-specific enolase concentration. With our technique, the development of cerebral infarcts can be studied in individual rats under experimentally controlled conditions over an extended period of time. Analysis of neuron-specific enolase can be used in trials of drugs for mitigating the effect of ischemia. Information concerning the release of neuron-specific enolase from ischemic cerebral tissue to the cerebrospinal fluid is important because neuron-specific enolase in the cerebrospinal fluid can be determined in patients suffering from cerebrovascular insult.

Nimodipine treatment of selected good-risk patients with subarachnoid hemorrhage: no significant difference between present and historical results.

Eighty-four patients were treated early with nimodipine intravenously, and thereafter orally, up to 21 days after aneurysmal subarachnoid hemorrhage. Thirty-nine patients in the nimodipine-treated group were carefully selected to be compared with similar patients from a historical control group (114 patients) conventionally treated. The causes of poor results were clinically identified as follows: delayed ischemic deterioration (DID), rebleeding, complications of surgery, or not defined. There was no significant difference in the distribution of DID or outcome at follow-up examination (at least 6 months later) between the nimodipine-treated group and the control group.

Acute tolerance to and distribution of hexobarbital in relation to depth and duration of anaesthesia in rats.

The development of acute tolerance to hexobarbital was investigated with an EEG-threshold method in rats. Hexobarbital was infused in a tail vein and the effect was monitored either by continuous EEG-recording (using the criterion "silent second") or by continuous observation. Anaesthesia was maintained at the level of "the silent second" for periods of up to 120 min. After different time intervals the last infusion period to the EEG-criterion was followed by decapitation and samples from blood, brain, muscle and fat were analysed for hexobarbital content. Brain concentrations at the EEG criterion increased and were notable after 10 min. but statistically significant at 30 min. when a 40% increase in concentration was needed to reach the criterion. Another group of rats kept at a lower level of anaesthesia (i.e. the righting reflex) showed a slight but not always significant increase in concentration when measured in different parts of the brain at "silent second". The dose of hexobarbital needed to maintain anaesthesia for intervals up to 120 min. increased almost linearly with time. Analysis of serum, muscle and fat tissue showed that concentration in fat tissue increased linearly during this whole interval and served as the final depot in redistribution. Muscle tissue shows an increase up to 60 min. but a very small increase thereafter, which is consistent with a function as temporary storage compartment.

Neurotoxicity of benzylpenicillin: correlation to concentrations in serum, cerebrospinal fluid and brain tissue fluid in rabbits.

The neurotoxic potential of benzylpenicillin, administered as continuous intravenous infusion, was studied in rabbits. Thirteen animals were killed at the onset of epileptogenic EEG activity (seven) or convulsions (six). Benzylpenicillin levels were determined in serum, cerebrospinal fluid (CSF) and brain tissue fluid. High doses of benzylpenicillin were required to induce neurotoxicity; epileptogenic (EEG) changes were seen at serum levels of 510-960 mg/l and convulsions at 920-1902 mg/l. Neurotoxicity correlated well with levels of benzylpenicillin in brain tissue fluid, calculated as 10 x the concentration in whole brain tissue. The correlation of neurotoxic reactions to levels of benzylpenicillin in CSF was poor and the CSF levels were consistently lower than those in brain tissue fluid. The technique used was found to be a satisfactory, though laborious, way to study neurotoxicity of drugs.

Effects of castration and testosterone treatment on the hexobarbital sensitivity in male rats.

Castration increases the central nervous system (CNS) sensitivity to hexobarbital as measured by an EEG-threshold method. Testosterone treatment in doses from 1 to 5 mg/kg/day decreases CNS-sensitivity and restores threshold values in castrated rats to a level found in normal young adult male rats.

Dynamic aspects on acute tolerance to hexobarbital evaluated with an anesthesia threshold.

Induction of acute tolerance was studied with hexobarbital in male rats. A threshold technique utilizing an EEG-criterion consisting of a burst suppression of 1 second or more (the SS) was used both to induce and maintain anesthesia. Hexobarbital was infused with an optimal dose rate of 15 mg/kg/min. The infusion was stopped at the criterion and restarted when no SS had been seen for 1 min. The doses of hexobarbital needed to maintain anesthesia were fairly constant around 3.5 mg/kg/min up to durations of 120 min which indicates that redistribution of hexobarbital is of minor importance in the present experiments. After different predetermined times of this fairly stable anesthesia, the rats were sacrificed, and concentrations in the cortex of the brain were determined with a HPLC-method. Maximal induction of acute tolerance was seen as a 45 percent increase in cortex concentration after 60 min of anesthesia, but already after 10 min a slight acute tolerance was recorded.

Interaction between probenecid and two lipid-soluble barbiturates in the rat.

The effect of pretreatment with probenecid (200 mg/kg, i.p.) on the sensitivity of the central nervous system (CNS) to thiopental and hexobarbital was investigated with an EEG-threshold method. The threshold dose was significantly decreased by pretreatment with probenecid for thiopental but not for hexobarbital. This was due to an increased penetration of thiopental into the CNS, but for hexobarbital an increase in penetration could also be demonstrated by analysis of brain and serum concentrations after infusion of an equal dose of barbiturate. The concentrations in brain at the EEG-threshold were not influenced by pretreatment with probenecid for either of these barbiturates, which shows that there was no synergism between these barbiturates and probenecid due to the depressant effect of probenecid on the CNS.

The interaction between atropine and some lipid-soluble barbiturates in rats.

The effect of atropine pretreatment on the CNS sensitivity to five lipid-soluble barbiturates was studied in rats. Atropine in a dose of 8 mg/kg intraperitoneally or saline was given 1.5 hr before an EEG-threshold determination with the tested barbiturates. The barbiturate was infused by constant rate through a tail vein. The dose of barbiturate needed to induce a burst suppression period in the EEG which is one second or longer was used as the threshold dose. Atropine pretreatment decreased the threshold dose significantly for two N-methylated barbiturates, hexobarbital (enhexymalum NFN) and methohexital (enallynymalum NFN), but not for thiopental (thiomebumalum NFN), pentobarbital (mebumalum NFN) or amobarbital (pentymalum NFN). No clear effects of atropine pretreatment could be found in the ensuing anaesthesia times after threshold determinations. These results indicate that there are differences in mechanisms of action between barbiturates. One of these mechanisms is related to the cholinergic system in the CNS.