Glioma cell influence on cerebral endothelial cell Na(+)-K(+)-ATPase.

Using in vitro techniques, we have shown that astrocytes do not increase the ouabain-sensitive Na(+)-K(+)-ATPase activity in cerebral endothelial cells. However, malignant astrocytoma cells when co-cultured with cerebral endothelial cells significantly enhance ouabain-sensitive Na(+)-K(+)-ATPase activity in cerebral endothelial cells. Also, Na(+)-K(+)-ATPase activity in cerebral endothelial cells co-cultured with malignant astrocytoma cells is inhibited by corticosteroids to the same degree as ouabain. These results suggest that brain edema associated with malignant glioma may in part be due to an increase in ouabain-sensitive Na(+)-K(+)-ATPase activity at the blood-brain barrier and that the antiedema effects of corticosteroids may be due to a reduction in the activity of this enzyme.

De novo aneurysm formation following carotid ligation: case report and review of the literature.

The authors report a patient with an aneurysm of the carotid siphon who underwent ligation of the cervical carotid artery. Six years after this procedure, the patient suffered a subarachnoid hemorrhage from an apparent de novo aneurysm. Pertinent literature is reviewed to determine the incidence of this occurrence, and congenital arteriosclerotic and hemodynamic factors causing aneurysm enlargement are discussed.

Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage.

A dose-escalation study of the calcium ion entry blocking drug nicardipine was performed using large dose infusions in 67 patients with recent aneurysmal subarachnoid hemorrhage (SAH). A safe, potentially therapeutic dose of the drug was determined. Patients admitted within 7 days of SAH from a documented cerebral aneurysm were entered into the study if no spasm was present on the initial angiogram. Nicardipine was administered as a continuous intravenous infusion throughout the 14-day period after SAH, regardless of the timing of surgery. To determine the safest possible dose, nicardipine was administered at seven dose levels from 0.01 to 0.15 mg/kg/hr. The total daily doses ranged from 27.7 mg to 375.0 mg. A follow-up angiogram was carried out on all 67 patients 7 to 10 days after SAH. Computerized tomography and neurological examinations were used to determine the presence of cerebral infarction. No major adverse effects, unexpected reactions, or permanent sequelae could be attributed to nicardipine. A decline in blood pressure was noted following administration of the drug. This occurred more frequently among patients given the largest dose but did not produce clinical problems or require discontinuation of the drug. Favorable outcomes were noted in 52 patients (78%). Vasospasm was found by arteriography in 31 patients (46%). A dose-related trend was noted: only eight (24%) of 33 patients treated at the highest dose level (approximately 10 mg/hr) developed arteriographic evidence of vasospasm. Symptomatic vasospasm was diagnosed in only two (6%) of 33 patients treated with this dose. Of the 34 patients receiving the lower dose levels, angiographic spasm was observed in 68% and symptomatic vasospasm in 27%. No deaths due to vasospasm occurred. Nicardipine appears to prevent both vasospasm and cerebral ischemia after SAH. A multicenter randomized double-blind trial to test this hypothesis is planned.

Androgen receptors in meningiomas.

Meningiomas have been hypothesized as being hormonally sensitive on the basis of epidemiologic, clinical, and laboratory evidence. Eight meningiomas were assayed and found to have androgen-binding protein. Three tumors were subjected to in vitro growth studies in varying concentrations of dihydrotestosterone (DHT). The growth of tumor 1 was unaltered. Tumor 2 demonstrated 9% to 10% growth (P less than 0.05) in all concentrations tested. Tumor 3 revealed an 11% stimulation, but only in the lowest concentration of DHT tested. The small quantity, saturability, and in one tumor, high binding affinity, suggest this binding protein is a receptor. The in vitro response of these meningiomas was small and was not dose-related or proportionate to receptor quantity. Androgens do not appear to play as important a role as progesterone or estrogen in meningioma growth in vitro.

Combination of aminocaproic acid and nicardipine in treatment of aneurysmal subarachnoid hemorrhage.

Antifibrinolytic drugs reduce the risk of rebleeding during the first 2 weeks after aneurysmal subarachnoid hemorrhage. However, they do not lower overall mortality, largely because of an increased incidence of cerebral ischemia. The usefulness of antifibrinolytic drugs might be increased if a method to prevent or control vasospasm in patients were to be developed. We recently completed late Phase I and Phase II studies of the calcium ion blocking drug nicardipine in 67 patients treated within 1 week of subarachnoid hemorrhage. Of these 67 patients, 42 had delayed operations and were treated concomitantly with the antifibrinolytic drug aminocaproic acid (1.5 g/hr) for an average of 6 days before surgery. The outcome of these 42 patients is the subject of this report. Fifteen of 42 patients were treated with the lower dosage levels of nicardipine (0.4-4.5 mg/m2/hr), and 27 patients were treated at the highest dosage level (6.0 mg/m2/hr). Using the World Federation of Neurological Surgeons scale for subarachnoid hemorrhage, at admission 18 patients were Grade I, 15 were Grade II, 6 were Grade III, and 3 were Grade IV. Five patients (12%) developed clinical signs of deterioration suggestive of cerebral ischemia with concomitant evidence of vasospasm on arteriography. These patients were all treated with hypervolemic hypertensive therapy. Only one patient (2%) developed an infarction from vasospasm. Two patients developed symptomatic hydrocephalus requiring ventriculoperitoneal shunting, and a third patient required a temporary ventriculostomy. The 3-month postoperative outcomes were excellent. Three patients (7%) rebled. Three patients died, two from rebleeding of the aneurysm and one who never regained consciousness from the initial hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylprednisolone reduces the bulk flow of water across an in vitro blood-brain barrier.

Cerebral water content is a variable quantity subject to the influence of hemodynamic and biochemical factors. Corticosteroids are frequently used in the therapy of cerebral edema, although their mechanisms of action in promoting the resolution of this state of pathologically increased water content remains unclear. To investigate this, a modified Ussing chamber was designed. The bulk flow of media (mainly composed of water) across a monolayer of cultured mouse cerebral endothelia was measured as a control. The same membranes were then exposed to either micromolar concentrations of hydrocortisone or methylprednisolone. The hydraulic conductivity (Lp) of each membrane before and after exposure to the corticosteroids was calculated as a reflection of membrane tightness. Methyl-prednisolone decreased the Lp of the membrane (i.e. tightened) by 36.1% compared to control. Hydrocortisone actually increased Lp (i.e. loosened the membrane) but not to a significant extent. The decrease in the bulk flow caused by methylprednisolone in vitro suggests that the mechanism of the clinically observed decrease in cerebral edema after corticosteroid administration may be due to the reduction of bulk flow across the blood-brain barrier.

Spontaneous subarachnoid hemorrhage in young adults.

We evaluated 95 hospitalized patients (50 women and 45 men) aged 15 to 45 who had nontraumatic subarachnoid hemorrhage (SAH). Aneurysmal SAH was identified in 75 patients. Other causes for SAH were ruptured arteriovenous malformations (2 cases), amphetamine arteritis (1 case), and leptomeningeal melanoma (1 case). The cause of SAH was undetermined in 16 (17%) patients. Thirteen patients had histories of hypertension, 5 used oral contraceptives, and 4 had consumed large quantities of alcohol during the day before SAH. Only 1 patient had Type I diabetes mellitus. Diagnosis was delayed in 21 patients. Operation was performed in 71 patients, with only 3 (4.2%) deaths. The overall mortality was 8.4% (8 of 95), with all deaths due to neurological causes. Our data suggest that the overall management and surgical results of treatment of ruptured aneurysms in young adults are excellent, diabetes is rare among young adults with SAH, recent alcohol consumption does not seem to be a major factor predisposing to SAH in young adults, and misinterpretation of the early symptoms of SAH continues to be a serious problem.

The role of new vessels and macrophages in the development and resolution of edema following a cortical freeze lesion in the mouse.

The role of an influx of macrophages and neovascularity in the resolution of vasogenic edema is not well defined. The inhibition of these processes with x-irradiation or parenteral corticosteroid administration was used to evaluate their contribution to the resolution of edema around a cortical freeze lesion in mice. The resorption of Evans blue, a marker of protein extravasation, was delayed in x-irradiated mice on the second day following a freeze lesion (p = 0.0075), which correlates with a delay in macrophage infiltration around the lesion. The specific gravity of the lesion and its border regions was significantly less in x-irradiated animals on day 7 than in controls (p = 0.00062), which correlates with a delay in new vessel formation around the lesion. Administration of corticosteroids from the time of production of the freeze lesion resulted in a specific gravity significantly less than control when measured eight days after the lesion (p = 0.01). Macrophages may participate by inhibiting the development of the macromolecular portion of vasogenic edema. The development of neovascularity correlates with the resorption of the aqueous portion of vasogenic edema. As with x-irradiation, corticosteroids administered from the time of freeze lesion inhibited the resorption of the aqueous portion of vasogenic edema, but they may suppress the spread of edema in this experimental model.

Lesions in Meckel's cave: variable presentation and pathology.

A series of 12 patients with mass lesions arising from Meckel's cave is presented. Patients' age on presentation ranged from 13 months to 71 years. Nine of the 12 patients had symptoms referable to the fifth cranial nerve, but only three complained of facial pain. The 12 patients presented eight different pathological entities, including meningioma, lipoma, schwannoma, malignant melanotic schwannoma, arachnoid cyst, neurofibroma, epidermoid tumor, and chordoma. Computerized tomography and magnetic resonance imaging were most useful in localizing the lesion to Meckel's cave. All 12 patients underwent a subtemporal approach to the lesion, and gross total removal was achieved in 11. Postoperative results were excellent with no increased neurological deficits seen 3 months postoperatively. Most patients had resolution of the cranial nerve deficits except for fifth nerve function, which was impaired in nine patients postoperatively. This series demonstrates that lesions in Meckel's cave can have a varied and unusual presentation, as well as an assortment of pathology. Total removal of lesions in this area resulted in relief of symptoms in most patients, with minimum morbidity.

Comparative evaluation of intracranial epidermoid tumors with computed tomography and magnetic resonance imaging.

The diagnosis of intracranial epidermoid tumors with computed tomography (CT) is often difficult because of indistinct margins, close proximity to the skull base, and a density similar to that of cerebrospinal fluid (CSF). Recent experience with six histologically confirmed epidermoid tumors served to emphasize the value of magnetic resonance (MR) imaging in studying these lesions. MR images were obtained using varying spin echo and inversion recovery techniques with a 0.5-tesla superconducting magnet. CT with and without enhancement had been performed in each case. In Case 1, CT showed an ill-defined left cerebellopontine angle hypodensity. MR imaging clearly showed the presence of abnormal tissue at that location. Case 2 showed a CSF density mass in the right upper posterior fossa. MR imaging of that area showed a variegated signal of a mass extending supratentorially. CT of Case 3 showed a left medial middle fossa hypodensity with an enhancing rim. MR imaging showed a clearly extraaxial mass in that location. In Case 4, a diffuse cerebellar hemispheric hypodensity was observed on CT and was clearly demarcated by MR studies. A huge lesion, thought initially to be an arachnoid cyst on CT of Case 5, was seen on MR imaging to be a large, extraventricular mass displacing the temporal lobe. Finally, CT in Case 6 was suggestive of a poorly demarcated right cerebellopontine angle lesion, which was seen on MR images to be extraaxial, displacing the brain stem. Various MR images more clearly demonstrate the extent of abnormal tissue than CT of epidermoid tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effect of angiographic contrast medium on cortical specific gravity after middle cerebral artery occlusion in rats.

Early angiography after cerebral arterial occlusion has been cited as potentially detrimental. This investigation evaluates the effect of acute angiographic contrast medium administration on the cortical edema induced by middle cerebral artery (MCA) occlusion. Sixteen rats underwent MCA occlusion, and after 1 hour half the rats underwent ipsilateral internal carotid injection of meglumine diatrizoate, whereas the remainder underwent cervical internal carotid exposure only. Six rats had only sham operations on the MCA and internal carotid, and 4 other rats served as normal controls. Cortical specific gravity was measured to reflect cerebral edema 4 hours after occlusion or sham operation. Specific gravity of the lateral frontal cortex in the hemisphere ipsilateral to occlusion was 1.0396 +/- 0.0011 (mean +/- SEM) when no angiographic contrast medium was administered, significantly less (p less than 0.01) than in rats exposed to contrast medium (specific gravity 1.0442 +/- 0.0005). The latter value was not significantly different from normal. Other cortical areas on the side of the contrast medium injection were also relatively dehydrated compared with normal controls. Early meglumine diatrizoate administration after MCA occlusion results in a decrease in cerebral cortical edema, possible by inducing an osmotic gradient that draws water from the extravascular space.

Effect of the antiprogesterone RU-38486 on meningioma implanted into nude mice.

Meningiomas have been shown to have steroid-binding proteins. In vitro, estradiol, progesterone, and the antiestrogen tamoxifen stimulate tumor growth. However, incubation of tumor cells with an antiprogesterone agent results in tumor inhibition. In this investigation, a human meningioma was implanted subcutaneously in athymic nude mice. Two treatment groups were established, one receiving the antiprogesterone agent RU-38486 (10 mg/kg/day in suspension) and the other receiving only vehicle. After 3 months, the tumor growth index (defined as the tumor volume at 3 months divided by the initial tumor volume) was 0.25 +/- 0.46 (mean +/- standard deviation) in the group receiving antiprogesterone and was 1.54 +/- 0.58 in the control group (p = 0.041). Further investigation of the effect of antiprogestational agents on the growth and hormone-binding proteins of other meningiomas will better define the mechanism of their effects.

Painless compressive cervical myelopathy with false localizing sensory findings.

Five patients who presented with clearly defined thoracic sensory levels were found by myelography and follow-up computed tomography (CT) to have cervical spinal cord compression. None of these patients had pain or an immediate preceding history of trauma. There is currently no satisfactory explanation for the large discrepancy between the sensory level and the level of cord compression in such patients. It is crucial that the clinician recognize the possibility of a cervical cord lesion in patients with such a presentation so that appropriate radiographic studies can be performed. Failure to appreciate this syndrome could result in failure to diagnose a treatable lesion.

Effect of heparin, heparin fragments, and corticosteroids on cerebral endothelial cell growth in vitro and in vivo.

Heparin and heparin fragments in combination with corticosteroids have been shown to markedly inhibit tumor angiogenesis. Experiments were performed to test the hypothesis that heparin, heparin fragments, and the combination of heparin and corticosteroids affect DNA synthesis and the proliferation of cerebral microvessel endothelium (ME). In vitro, methyl-3H-thymidine incorporation in the ME cells was measured after a 24 hour pulse. Our results show that heparin, hydrocortisone, and heparin in combination with hydrocortisone had a slight inhibitory effect on DNA synthesis of ME (p less than 0.05), and hydrocortisone in combination with heparin had a slight inhibitory effect on ME cell growth (p less than 0.05). The hexa-, octa-, and deca-saccharide fragments of heparin stimulated DNA synthesis in ME (p less than 0.01). In vivo, DNA synthesis in cerebral endothelial cells at the margin of a freeze lesion to mouse cerebral cortex was assayed by quantitation of labeling indexes from methyl-3H-thymidine autoradiographs in mice treated with heparin, cortisone, or a combination of heparin and cortisone. A mean endothelial cell labeling index (LI) of 6% in the cortisone-treated animals was significantly lower than controls (32%, p less than 0.01). The addition of heparin to cortisone did not significantly alter the endothelial cell LI compared to the cortisone-treated animals, and heparin alone did not significantly alter the LI compared to the controls. These results indicate that cortisone markedly reduces the endothelial proliferation around a cortical freeze lesion in vivo. This effect is independent of heparin.

Glial cells influence membrane-associated enzyme activity at the blood-brain barrier.

Glial cells have been shown to influence several cerebral endothelial cell properties in vitro. A situation similar to the endothelial-astrocyte relationship existing at the blood-brain barrier (BBB) can be produced by growing cultured cerebral endothelium on one side of a filter and glial cells on the other in an enclosed double chamber. In this setting membrane-associated reaction product on the cerebral endothelial cell for both Na+,K+-ATPase and non-specific alkaline phosphatase was markedly increased when the endothelial cells were co-cultured with glial cells. In addition, the distribution of reaction product on the cerebral endothelial cell membrane was similar to that reported in vivo. These observations support a glial influence on enzyme activity at the BBB.

Percutaneous retrogasserian glycerol rhizotomy for treatment of trigeminal neuralgia.

The treatment of trigeminal neuralgia by percutaneous retrogasserian glycerol rhizotomy was assessed in a series of 58 patients with a follow-up period ranging from 2 to 40 months postoperatively. All patients were considered medical failures prior to the procedure. Idiopathic trigeminal neuralgia was the diagnosis in 54 patients, and four patients had trigeminal neuralgia associated with multiple sclerosis. Forty-two patients (72%) reported complete relief from the procedure and are taking no medications. Four patients (7%) are much improved and require only minimal drug therapy. Twelve patients (21%) were considered treatment failures. The recurrence rate after initial relief of symptoms was 11%. Ten patients (17%) noticed a mild decrease in facial sensation following the procedure, and one additional patient had a profound sensory loss including loss of corneal reflex. The authors conclude that, while percutaneous retrogasserian glycerol rhizotomy may be useful in the treatment of trigeminal neuralgia, more clinical series and documentation of recurrence rate and complications are needed before any firm conclusions can be reached as to the efficacy of this therapy.

Hormonal manipulation of meningiomas in vitro.

Speculation that meningiomas are subject to endocrine influence is supported by their higher incidence in women, reports of exacerbation of symptoms during pregnancy, and the discovery that these tumors harbor progesterone- and estrogen-binding proteins. To evaluate if these properties could be exploited therapeutically, specimens from three convexity meningiomas were used for estrogen- and progesterone-binding protein assays and establishment of tissue cultures. Each tumor (designated A, B, and C, respectively) was grown in experimental media containing 7.5 X 10(-5) to 10(-12) M 17 beta-estradiol, 2.5 X 10(-4) to 10(-12) M progesterone, 10(-7) to 10(-9) M tamoxifen (an estrogen antagonist), and 10(-6) to 10(-10) M RU486 (a progesterone antagonist). After incubation, cell growth was compared to control preparations by counting the meningioma cells present in each medium. Tumors A, B, and C contained estrogen-binding proteins of 8.45, 13.6, and 26.9 fmol/mg cytosol protein and progesterone-binding proteins of 210, 130, and 126 fmol/mg cytosol protein, respectively. The media containing 17 beta-estradiol and progesterone caused 21% to 36% growth stimulation in Tumors A and B. In Tumor A, the addition of tamoxifen stimulated growth by 35%, while it caused only transient stimulation in Tumor B and had no effect on Tumor C. RU486, the progesterone antagonist, caused inhibition of cell growth in all three tumors, ranging from 18% to 36%. These data suggest that selected meningiomas are subject to hormonal influence in vitro. The inhibition of meningioma growth in vitro by the antiprogesterone, RU486, has not been previously reported, and serves to encourage further development of alternative modes of therapy for recurrent and unresectable meningiomas.

Insulin stimulates DNA synthesis in cerebral microvessel endothelium and smooth muscle.

Experiments were performed to test the hypothesis that insulin stimulates DNA synthesis in cerebral microvessel endothelium and smooth muscle. Cultured endothelium and smooth muscle derived from isolated mouse cerebral microvessels were exposed to insulin in serum-free medium, and [3H]-thymidine incorporation in the cells was measured. Up to 40-fold stimulation of DNA synthesis in endothelium and fourfold stimulation in smooth muscle were observed. Stimulation became maximal in both cell types at an insulin concentration of approximately 10(4) ng/ml, although an effect was observed at much lower concentrations. Similar concentrations of insulin produced a less-dramatic (approximately twofold) increase in both endothelial and smooth muscle cell numbers. This effect of insulin, observed in microvessel endothelium and smooth muscle, but not in bovine aortic endothelium, emphasizes another way in which large- and small-vessel endothelia appear to differ.