Headache in cerebral venous thrombosis associated with extracranial tumors: a clinical series.

Cerebral venous thrombosis (CVT) may represent the clinical onset of malignancies or complicate their course, also in phase of quiescence. In literature, there are several case reports on the association between CVT and tumors, but there are few articles on its clinical characteristics in cancer patients (Pts). Our aim was to analyze the clinical characteristics of CVT associated with extracranial tumors. We identified nine cases of CVT in adults affected by extracranial tumors in 6 years from six hospitals. The median age was 40 years; eight Pts were female. Associated tumors were: lymphoma (4/9); breast (2/9), rhinopharynges (1/9) and gastric (1/9) carcinomas. One patient presented a kidney tumor and a melanoma at the same time. Multiple sinuses were affected in seven Pts. MRI showed parenchymal lesions in most cases (7/9). Clinical manifestations were: focal deficits (7/9), headache (6/9), early seizures (4/9) and consciousness disorders (3/9). Headache was the onset symptom in six Pts. In four of these Pts, headache preceded the onset of the focal deficit and/or seizures than 2-15 days. The characteristics of the headache were variable in intensity, location and type but all the Pts agreed in saying that it was an unusual headache, unresponsive to common pain medications. Five of the six Pts complaining of headache in the course of CVT presented focal deficits and parenchymal lesions at admission to the emergency room. All nine Pts were anticoagulated without further haemorrhagic complications. At discharge, the Pts presented a complete recovery in four cases, mild sequelae in four and moderate sequelae in one. In conclusion, we would like to underline the importance of particular care to cancer Pts complaining of headache, since the early diagnosis and the appropriate anticoagulant treatment could prevent the appearance of parenchymal lesions and the consequent neurological deficits. Also in the cases of normal brain CT, a brain MRI/MR venography should be performed in emergency setting if CVT is suspected.

Irradiation fields and doses in glioblastoma multiforme: are current standards adequate?

AIMS AND BACKGROUND: The optimum conventional radiotherapy in glioblastoma multiforme patients has not been clearly defined by prospective trials. To better characterize a standard radiotherapy in glioblastoma multiforme, the impact on survival of different fields and doses was analyzed in a retrospective single center series. METHODS: One hundred and forty-seven patients with glioblastoma multiforme, submitted to biopsy only (n = 15), subtotal (n = 48) or total resection (n = 82) and who completed the planned postsurgical radiotherapy, were considered. The median age was 57 years, the male/female ratio 1.5/1, and the performance status > or =70 in 76%. Whole brain irradiation, followed by a boost to partial brain, was used in 75 cases with a whole brain dose of 44-50 Gy (median, 46) and a partial brain dose of 56-70 Gy (median, 60 Gy). Partial brain irradiation alone was used in 72 patients with a dose of 56-70 Gy (median, 61 Gy). Ninety-eight patients received 56-60 Gy (median, 59 Gy) to partial brain whereas 49 patients received 61-70 Gy (median, 63 Gy). RESULTS: There was an almost significantly longer survival in patients irradiated to the partial brain alone with respect to those also receiving whole brain radiotherapy (P = 0.056). Doses >60 Gy significantly prolonged survival (P = 0.006). Multivariate analysis confirmed that the impact on survival of radiation dose was independent of age, performance status, extent of surgery, field of irradiation and the use of chemotherapy. The extent of irradiation field was not independently related to improved survival. CONCLUSIONS: Our retrospective findings suggest that we reflect on the adequacy of the current standard irradiation parameters. Well-designed prospective trials are necessary to standardize the radiotherapy control group in patients with glioblastoma multiforme to be compared in phase III trials with innovative therapeutic approaches.

Alpha6 beta4 and alpha6 beta1 integrins in astrocytomas and other CNS tumors.

Laminin may alter the biological behavior of gliomas. Therefore, we investigated the expression of two laminin receptors, alpha6 beta1 and alpha6 beta4 integrins in normal brain, astrogliotic brain, and astrocytomas as compared to other central nervous system (CNS) tumors. In most CNS tumors, the expression of these integrins was unchanged in neoplastic as compared to normal counterpart cells. In contrast, increased numbers of reactive and neoplastic astrocytes expressed beta4 integrin as compared to normal astrocytes, whereas alpha6 and beta1 integrin expression did not change. Conversely, lower numbers of astrocytoma blood vessels expressed beta4, whereas all blood vessels in normal brain expressed beta4. These data suggest that the profile of laminin receptors changes in neoplastic astrocytes and in astrocytoma blood vessels; this change may play an important role in astrocytoma pathogenesis.

Pre-targeted immunodetection in glioma patients: tumour localization and single-photon emission tomography imaging of [99mTc]PnAO-biotin.

The imaging of cerebral gliomas with radiolabelled monoclonal antibodies (MoAbs) has been previously reported. However, previous studies have been hampered by the drawback of a low tumour to non-tumour ratio. In order to overcome this problem we have developed a three-step pre-targeting method using the avidin-biotin system. The rationale of this technique consists in vivo labelling of biotinylated MoAbs targeted onto tumour deposits, when most of the unbound antibodies have been cleared from the bloodstream as avidin-bound complexes. The anti-tenascin MoAb BC2, specific for the majority of gliomas, was biotinylated and 1 mg was administered i.v. in 20 patients with histologically documented cerebral lesions. After 24-36 h, 5 mg avidin was injected i.v. followed 24 h later by a third i.v. injection of 0.2 mg PnAO-biotin labelled with 15-20 mCi technetium-99m. No evidence of toxicity was observed. Whole-body biodistribution was measured at 20 min, 3 h and 5 h post-injection. [99mTc]PnAO-biotin had a fast blood clearance and was primarily excreted through the biliary system. A dedicated single-photon emission tomography system was used to acquire brain tomographic images 1-2 h after the administration of [99mTc]PnAO-biotin. Tumours were detected in 15/18 glioma patients with a tumour to non-tumour ratio of up 14:1. This three-step method, based on the sequential administration of anti-tenascin MoAb BC2, avidin and [99mTc]PnAO-biotin, can support computed tomography or magnetic resonance imaging for the diagnosis and follow-up of patients with glioma. Further studies are required to evaluate the potential of this technique for therapeutic application.

The role of transcranial Doppler in carotid artery surgery.

In order to evaluate the usefulness of transcranial Doppler (TCD) in carotid artery surgery, 90 patients who underwent carotid endarterectomy were studied. Transcranial Doppler was performed preoperatively with digital compression of the carotid artery and intraoperatively at the time of cross-clamping, together with routine EEG monitoring. The percentage residual middle cerebral artery velocity (%MCAV) during carotid artery compression or cross-clamping was considered. The intraoperative %MCAV at cross-clamping was compared with the values obtained in the preoperative examination during the compression test and with the EEG data; the EEG records were blindly reviewed by a neurologist and divided into three groups: group A, normal; group B, moderate anomalies and group C, major anomalies. There were no significant differences between preoperative %MCAV (compression test) and intraoperative %MCAV (cross-clamping) by separate analysis of the data related to systolic, diastolic and mean velocity. The systolic, diastolic, mean %MCAV and the Gosling index after cross-clamping were then compared with the EEG data: no significant differences were seen between groups A and B; on the other hand, in all patients with major EEG anomalies (group C) the %MCAV at TCD was reduced to 0. In conclusion, preoperative TCD associated with carotid artery compression appears a safe and useful way of identifying patients at risk of cerebral ischaemia during carotid artery cross-clamping. Patients with no residual flow at intraoperative TCD need to be considered as presenting a very high risk of ischaemia and in this group the use of a shunt is mandatory.

ACTH and cortisol secretion in patients with Alzheimer's disease.

The "glucocorticoid cascade hypothesis" for pathological ageing of the brain is supported by strong experimental data, but the clinical correlates are far less clear. The basal ACTH and cortisol secretion have been studied before and after the dexamethasone suppression test in patients in the early stages of clinically probable Alzheimer's disease and in controls, and the results were all normal. These findings do not support the hypothesis that the pathological brain ageing of Alzheimer's type is caused by hyperactivity of the pituitary-adrenal axis.

Fatal aplastic anemia in a patient treated with carbamazepine.

A case of fatal aplastic anemia due to carbamazepine treatment in an epileptic woman is reported. Despite concerns of fatal bone marrow toxicity due to carbamazepine, this is only the fourth documented and published report. Carbamazepine is a safe drug, but physicians and patients should be aware of the exceedingly rare but potentially fatal side effects, better prevented by clinical than by laboratory monitoring.

Effect of after-dinner administration on the pharmacokinetics of oral flunitrazepam and loprazolam.

The pharmacokinetics of two benzodiazepine hypnotics, flunitrazepam and loprazolam, was determined on two occasions in two groups of eight healthy volunteers. Single 2-mg oral doses of either drug were given in the fasting state at morning on one occasion and after a standard dinner at night on another. Compared with administration of drugs in the fasting state, administration of the drugs after dinner decreased peak plasma concentrations, delayed the time to reach maximum concentration, and prolonged the absorption half-life. The extent of absorption was reduced for flunitrazepam but not for loprazolam. The elimination half-life of both flunitrazepam and loprazolam was not changed in the two conditions. These changes may be of clinical significance because they can delay and reduce the effects of the drugs.

Effect of food on absorption of chlordemethyldiazepam.

The kinetics of a single 1-mg oral dose of chlordemethyldiazepam (CDDZ, En) was determined on two occasions in 8 healthy volunteers. CDDZ was given in the fasting state on one occasion and following a standard meal on another. Compared with the fasting state, administration of CDDZ with food prolonged the time to reach peak concentration (1.5 vs. 6.8 h after dosage, p less than 0.01) and the absorption half-life (28 vs. 231 min, p less than 0.01). Total area under the curve was not influenced, nor was CDDZ elimination half-life (84.2 vs. 88.7 h). Thus administration of CDDZ with food slows the rate of its absorption but does not alter the completeness of absorption.

Pharmacokinetics and bioavailability of intravenous and oral chlordesmethyldiazepam in humans.

Six healthy, fasting volunteers were given single doses of chlordesmethyldiazepam by 1 mg i.v., or as drops or tablets. Chlordesmethyldiazepam and its metabolite, lorazepam, in multiple plasma samples and in urine collected for 120 h after each dose were determined by electron-capture GLC. Mean kinetic variables for intravenous chlordesmethyldiazepam were: volume of distribution, 1.71 l.kg-1; elimination half-life, 113 h; total clearance, 0.21 ml.min-1.kg-1; cumulative excretion of lorazepam glucuronide 24.2% of the dose. Following a lag time of 15.5 min (tablets) and 4.2 min (drops), which were significantly different, the absorption of oral chlordesmethyldiazepam was a first order process, with apparent absorption half-life values averaging 1.5 h (tablets) and 1.1 h (drops). Bioavailability was 77% for tablets and 79% for drops.

Tuberoinfundibular dopaminergic function in Parkinson's disease.

A deficit of nigrostriatal, mesocortical and mesolimbic dopamine systems in Parkinson's disease is well known. We know less about the involvement of tuberoinfundibular dopamine (TID) systems. In untreated (naive or wash-out) men with Parkinson's disease, we studied TID function through basal and stimulated plasma levels of growth hormone, prolactin and thyrotropin. Only minor abnormalities in prolactin responses to thyrotropin-releasing hormone were found, probably reflecting denervation hypersensitivity. TID function is preserved in men with Parkinson's disease.

Plasma beta-endorphin and beta-lipotropin in patients with Parkinson's disease.

Experimental and human data in young volunteers suggest that tuberoinfundibular dopaminergic systems physiologically inhibit pituitary secretion of beta-endorphin. This hypothesis was verified in patients with Parkinson's disease, a human model of a selective deficit of dopamine. Both previously untreated patients and patients who had been without chronic treatment for 1 week showed plasma beta-endorphin levels significantly higher than those of healthy age-matched controls. Plasma beta-lipotropin levels of patients and of controls were similar. There was no correlation between plasma opioid levels and age, severity, or duration of the disease. In five patients retested during chronic treatment, plasma levels both of beta-endorphin and of beta-lipotropin significantly decreased. This decrease approximately paralleled clinical improvement. The finding that in Parkinson's disease there is a reversible disinhibition of pituitary secretion of beta-endorphin confirms that this secretion is physiologically inhibited by tuberoinfundibular dopaminergic systems.

Homovanillic acid and 5-hydroxyindoleacetic acid modifications in CSF of patients with stroke and multi-infarct dementia.

Thirty four patients who had complete ischemic stroke confirmed by neurologic examination, were divided into three groups according to the time elapsed between the first signs of stroke and lumbar puncture: group A, 22-47 h; group B, 48-71 h; group C, 72-96 h. Nineteen patients with multi-infarct dementia (MID) assessed by neurologic and neurophysiologic examinations were also studied. The severity of the neurological deficit was assessed by the Norris rating scale. Nine age-matched subjects without neurologic disease served as controls. Levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in lumbar CSF by a fluorimetric method after separation on Sephadex G-10 columns. HVA levels decreased as the length of time after stroke increased and were lower than controls in MID, while 5-HIAA levels were low in group B and MID. Our results in stroke can be interpreted as showing they are the consequence of dopamine and serotonin global depletion in the early phases of brain ischemia. In MID, the CSF changes might reflect not only tissue loss secondary to multiple infarcts but also the persistence of a state of diffuse ischemia.

Cognitive deficits and their relationship to other neurological complications in chronic alcoholic patients.

In randomly selected chronic alcoholics hospitalised for the first time for detoxification a high prevalence (68%) of cognitive deficits was found. Peripheral neuronal damage was seen in 74%, autonomic neuronal damage in 24%. Cognitive deficits were not correlated with age, daily ethanol intake, duration of alcohol abuse or severity of liver damage. There was no correlation of peripheral, autonomic and central nervous system damage. Alcohol-induced damage of the nervous system is a common complication of chronic alcoholism, whose clinical importance often obscures possible concomitant liver damage.