David W. Beck

Treatment of Ischemic Deficits from Vasospasm with Intravascular Volume Expansion and Induced Arterial Hypertension

In 58 patients with progressive neurological deterioration from angiographically confirmed cerebral vasospasm after spontaneous subarachnoid hemorrhage, arterial hypertension was induced in an attempt to improve their deficits. The most effective regimen consisted of intravascular volume expansion, blockade of the vagal depressor response, and the administration of antidiuretics and vasopressor agents. With this protocol, arterial blood pressure could be sustained at high levels for prolonged periods. Neurological deterioration was reversed in 47 patients, transiently in 4; permanent improvement occurred in 43. Complications experienced during therapy included pulmonary edema, dilutional hyponatremia, aneurysmal rebleeding, coagulopathy, hemothorax, and myocardial infarction. Elevating systemic arterial pressure in states of cerebrovascular insufficiency resulting from vasospasm is safe if meticulous attention is paid to physiological, biochemical, and hematological parameters, with the exception that it may be hazardous in the presence of an untreated ruptured or intact aneurysm. Intravascular volume expansion and induced hypertension are effective in reversing ischemic deficits from vasospasm provided that treatment commences before cerebral infarction and that adequate pressures are maintained for a sufficient period. The production of a hypervolemic state by the use of colloid and crystalloid infusion accompanied by atropine blockade of the vagal depressor response and blunting of the diuresis with vasopressin enables arterial pressure to be elevated for longer than 1 week.

Glial Cells Influence Polarity of the Blood-Brain Barrier

Polarity has been shown to exist at the blood-brain barrier (BBB) with respect to Na+-dependent neutral amino acid transport. A situation similar to the endothelial-astrocyte relationship existing at the BBB can be produced by growing cultured cerebral endothelium on one side of a filter and C6 glial cells on the other in an enclosed double chamber. In this setting 3H-α-methylaminoisobutyric acid transport can be demonstrated and is more rapid from the glial surface across the endothelium, as compared with transport in the opposite direction. The observation supports a glial influence on BBB polarity in this system.

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.

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.

Postoperative prophylactic anticonvulsant therapy in cerebral gliomas

A retrospective study was performed to evaluate the efficacy of prophylactic anticonvulsants in preventing seizures in 68 patients with supratentorial astrocytomas who had been treated with operation and irradiation and who had no previous history of convulsions. Thirty-three patients received prophylactic anticonvulsants and 38 patients did not. The incidence of all types of seizures (generalized convulsions or partial) was lower in patients receiving anticonvulsants. No seizures with an impairment of consciousness occurred in the patients with documented therapeutic anticonvulsant blood levels. The overall incidence of seizures was 39% in untreated patients and 21% in treated patients. The incidence of major seizures including tonic/clonic or partial complex seizures with impairment of consciousness was zero in patients with therapeutic anticonvulsant levels and 18% in untreated patients. Regarding the overall incidence of seizures in both groups, there tend to be fewer seizures in older patients, females, patients with a higher grade of malignancy, and patients who had a more radical resection of the tumor. This study suggests that seizures are a frequent occurrence after operation and irradiation for supratentorial glioma and that anticonvulsants may be effective in reducing the incidence of those seizures.

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)

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)

The role of the macrophage in microvascular regeneration following brain injury.

Although macrophages are the earliest cells found in association with vessels in an area of cerebral injury, the role of this cell in the subsequent regeneration of the microvasculature is unknown. DNA synthesis in cerebral endothelial cells at the margin of injury of mouse brain was assayed by quantitation of the labeling indices from 3H-thymidine autoradiographs of normal animals and animals with X-ray-induced leukopenia. A mean endothelial cell labeling index of 10% in the irradiated animals was significantly lower than control animals (26.7%) (p < 0.01). In vitro tissue culture studies utilizing peritoneal macrophages and cerebral endothelium were then used to isolate the endothelial response to macrophages and their products. Macrophage-conditioned media did not stimulate cerebral endothelial proliferation when evaluated by a growth factor assay, although this macrophage-conditioned media did stimulate DNA synthesis in fibroblasts and bovine aortic endothelium. A migration study of the cerebral endothelial cells utilizing an agarose technique showed enhanced random migration in the presence of macrophage-conditioned media compared to controls (p < 0.01). The results indicate that macrophages do not directly stimulate proliferation of cerebral endothelial cells, but influence their migration. A loss of contact inhibition and subsequent DNA synthesis and replication may follow.

Uptake of Glucose Analogues into Cultured Cerebral Microvessel Endothelium

Tritiated glucose analogues 3-O-methylglucose (3-OMG) and 2-deoxy-glucose (2-DG) were used to study glucose uptake properties in established lines of cultured mouse cerebral microvessel endothelium. Uptake of both analogues was similar in terms of rate and absolute amount for the first two minutes. Thereafter, intracellular accumulation of 2-DG continued at a more rapid rate because of intracellular phosphorylation of this substrate. The uptake of 3-OMG uptake was temperature-dependent, independent of Na+, and not inhibited by ouabain or 2,4-dinitrophenol. Phloretin and cytochalasin B both significantly inhibited 3-OMG uptake. Other hexoses in high concentration acted as competitive inhibitors at the endothelial cell membrane. Pre-incubation of cells with 50 mM D-glucose resulted in higher levels of 3-OMG accumulation than in control cells (counter-transport phenomenon). In contrast to findings at the blood-brain barrier in vivo, insulin was found to stimulate 3-OMG uptake. Maximal stimulation of approximately 3-fold was found at ambient insulin concentrations of 1,000 ng/ml or higher. The findings provide support at the cellular level for some components of the model of carrier-mediated glucose transport across the blood-brain barrier which has been postulated to exist in vivo. The effect of insulin is discussed in the light of new data that show stimulation of glucose analogue transport into isolated cerebral capillaries.

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.