Cerebrospinal fluid production: stimulation by cholera toxin.

Large increases in the production of cerebrospinal fluid have been observed after the intraventricular administration of cholera toxin. Because cholera toxin stimulates adenylate cyclase, the data suggest that adenosine 3',5'-monophosphate plays a role in cerebrospinal fluid production.

Expression pattern of alpha-protein kinase C in human astrocytomas indicates a role in malignant progression.

Protein kinase C (PKC) is a family of isoenzymes which play an important role in regulating cell proliferation and differentiation. Constitutive activation of PKC, either by phorbol esters or overexpression of specific isoenzymes, leads to growth abnormalities in vitro and tumor promotion in vivo. Since stimulation of PKC in cultured astrocytes results in biochemical and morphological alterations associated with the transformed phenotype, we wanted to determine whether abnormal expression of specific isoenzymes of PKC was important in development of human astrocytomas in vivo. We have detected a specific pattern of alpha-PKC expression in human astrocytomas which is noteworthy because the highest transcript levels were detected in well-differentiated (Grade 1) tumors, with intermediate expression in anaplastic (Grade 2) astrocytomas and low or nondetectable levels in glioblastomas (Grade 3 astrocytomas) and normal controls. In comparison, the beta-PKC transcript was not detected in any of the tumors, while the gamma-PKC transcript was present in only one Grade 2 tumor. Immunohistochemistry, using a monoclonal antibody to alpha-PKC, revealed diffuse, positive cytoplasmic signals in most cells of the Grade 1 tumors. Grade 2 tumors exhibited heterogeneity of alpha-PKC expression, although a significant percentage of cells showed positivity. In contrast, only a small number of differentiated cells within Grade 3 tumors were positive for alpha-PKC expression, with the more malignant, dedifferentiated cells uniformly negative. Throughout all tumor grades, the staining pattern of alpha-PKC closely paralleled that of glial fibrillary acidic protein. Taken in conjunction with the established role of PKC in tumor promotion, these results suggest that the alpha-PKC isoenzyme plays a specific role in facilitating clonal expansion of transformed astrocytes in low-grade astrocytomas. Analysis of alpha-PKC may therefore serve as a direct biological marker of malignancy which may serve to enhance the current histopathological grading system.

The role of angiotensin II in the regulation of blood flow to choroid plexuses and cerebrospinal fluid formation in the rat.

The effect of peripherally administered angiotensin II (AII) on blood flow to choroid plexuses was examined in pentobarbital-anesthetized rats. The indicator fractionation method with 123I- or 125I-N-isopropyl-p-iodoamphetamine as the marker was employed to measure blood flow. Basal blood flow to choroid plexus of the lateral cerebral ventricle (LVCP) (3.19 +/- 0.23 ml g-1 min-1) was lower than that to choroid plexuses of the third (3VCP) and fourth (4VCP) ventricles (3.90 +/- 0.38 and 3.95 +/- 0.36 ml g-1 min-1, respectively). The effect of AII on choroidal blood flow varied depending on peptide dose and anatomical location of the choroidal tissue. AII infused intravenously at rates of 30 and 50 ng kg-1 min-1 decreased blood flow to both LVCP and 4VCP by 12-20%. Both lower (10 ng kg-1 min-1) and higher (100 and 300 ng kg-1 min-1) AII doses did not alter blood flow to LVCP and 4VCP. Blood flow to the 3VCP was not affected by any dose of the peptide used. In comparison, blood flow to cerebral cortex increased by 33% during intravenous AII infusion at a rate of 300 ng kg-1 min-1. The choroidal blood flow-lowering effect of moderate AII doses was abolished by both AT1 (losartan) and AT2 (PD 123319) receptor subtype antagonists (3 mg kg-1 i.v.). To determine whether the hemodynamic changes observed in choroid plexuses with moderate AII doses influence CSF formation, the ventriculocisternal perfusion was performed in rats (under the experimental conditions described) with Blue Dextran 2000 as the indicator.(ABSTRACT TRUNCATED AT 250 WORDS)

Dibutyryl cyclic adenosine 3',5'-monophosphate: its role in regulation of cat brain extracellular fluid.

The role of dibutyryl cyclic adenosine 3',5'-monophosphate (db cAMP) in influencing the water content of the cat's gray and white matter was evaluated by intracoritcal injection of 20 micrio L of 2 x 10(-1) to 2 x 10(-6)M solution of db cAMP. Cholera toxin, a stimulator of adenylate cyclase, also was tested. Concentrations of db cAMP less than 10(-3)M failed to produce significant change in brain water content, while concentrations greater than 10(-2)M produced 31.5% +/- 8% and 17.3% +/- 3.6% increases in white matter volume, respectively (P less than .05). Cholera toxin did not increase brain water levels. These results are discussed in relation to the pathophysiology of brain edema.

Long-term outcome of children with severe head trauma and prolonged coma.

Forty-six children with significant head trauma who remained in coma more than 24 hours were the subjects of this long-term outcome study. Twelve (38%) died. The average length of coma in the 34 survivors was 15.5 days. Follow-up ranged from 9 months to 4 years (mean 21 months). Twenty-nine percent of the survivors were normal at follow-up. An additional 53% had mild cognitive or behavioral problems, but 61% of these had evidence of similar problems prior to the injury. Nine percent of survivors had motor residua but normal intellect. Nine percent had severe intellectual and motor problems. Children less than 2 years of age had a worse outcome. Despite severe injury and prolonged coma after head trauma, most children do well. Intensive medical and surgical care increases the rate of survival and does not result in a large number of severely disabled survivors.

In vitro measurement of respiration of choroid plexus cells in communicating hydrocephalus.

Communicating hydrocephalus occurs as a result of inappropriate CSF production in the circumstance of diminished absorption. Ventricular enlargement does not progress as rapidly as the measured normal production of CSF would suggest. Thus, compensatory mechanisms must exist to respond in some manner to the altered pathophysiology. In this experiment the metabolic activity (O2 consumption) of the choroid plexus cells in animals with communicating hydrocephalus was compared with that of normals. The modified Cartesian diver technique of Zeuthen13 was employed. These preliminary measurements show that the metabolic activity of the choroid plexus cells was the same in hydrocephalic animals and normals. Response to experimentally induced increased CSF pressure also showed no difference.

AT1 receptor subtype mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation in the rat.

The effect of central administration of angiotensin II (AII) on cerebrospinal fluid (CSF) formation was studied in pentobarbital-anesthetized, artificially-ventilated rats. CSF production was measured by the ventriculocisternal perfusion method with Blue Dextran 2000 as the indicator. Baseline value of CSF production was 3.35 +/- 0.08 microliters/min. Intracerebroventricular (i.c.v.) infusion of AII at rates of 0.5 and 5 pg/min significantly lowered (P < 0.01) CSF formation by 23% and 16%, respectively. In comparison, high peptide doses (50 and 500 pg/min) did not alter this parameter. The inhibitory effect of low AII doses on CSF formation was blocked by the i.c.v. AT1 receptor subtype antagonists, losartan and SK&F 108566 (2.4 and 2.7 ng/min, respectively), but not by the AT2 receptor subtype-specific agent, PD 123319 (3.8 ng/min). Peptide AII antagonists, [Sar1,Ile8]AII (5 ng/min), which binds to both AT1 and AT2 receptors, had a similar effect to those of AT1-specific blockers. It is concluded that AII, by controlling CSF formation, may influence the water and electrolyte balance in the brain.

Effect of cholera toxin and prostaglandins on the rat choroid plexus in vitro.

The present study was performed to measure the effects of cholera toxin (CT) and prostaglandins (PG) on choroid plexus cyclic AMP accumulation. Choroid plexuses, isolated from Sprague-Dawley rats, were incubated in Krebs-Ringer bicarbonate buffer containing either CT (10 microgram/ml), heat inactivated CT, prostaglandins, or appropriate controls. After a minimum incubation period of 60 min with CT, cyclic AMP accumulation (pmol/mg protein) in treated incubates (58.10 +/- 6.43, n = 6) was 4 times that in controls (14.-5 +/- 1.4, n = 6). This large increase was only seen when theophylline (10 mM) was in the incubation mixture 3--10 min prior to the end of the incubation period. The increase in cyclic AMP accumulation was dose responsive and was irreversible after 5 min of incubation. Of the 5 prostaglandins studied, only PGE2 resulted in an increase in cyclic AMP accumulation. Cyclic AMP levels were 29.64 +/- 2.5 in controls and 57.57 +/- 3.5 in plexus which had been incubated with PGE2 (20 microgram/ml) for 1 min, and this increase was dose responsive.

Hydrocephalus decreases chloride efflux from the choroid plexus epithelium.

To explore the novel concept of intrinsic brain regulation of the choroid plexus (CP), we studied the function of the CP exposed to increased intracranial pressure (ICP). The function of the CP was evaluated by in vitro chloride (Cl-) efflux from isolated CP 21 days after kaolin induced hydrocephalus. The Cl- efflux was significantly decreased in animals with elevated intracranial pressure (rate constant, K = 0.024 +/- 0.001 s-1) and enlarged ventricles (K = 0.023 +/- 0.001 s-1) compared to sham animals (K = 0.031 +/- 0.001 s-1). In contrast, the Cl- efflux of CP from animals with normal ICP and ventricular size did not differ from sham animals. These results illustrate the first demonstration of regulation of the CP epithelial function with elevated ICP; they also suggest a brain-CP regulatory mechanism that alters CP function.

Comparison of clinical result between microsurgical and direct visual intracranial aneurysm surgery.

A retrospective study of 119 operative procedures for intracranial aneurysm was performed to compare the clinical result with microsurgical technique vs. that with standard instruments and without magnification; the operative technique was the major variable. The study demonstrated more normal patients, less intraoperative aneurysm rupture, and a greater capacity to isolate the aneurysm definitively with microsurgical technique. Anatomically and pathologically more difficult aneurysms had an even greater percentage of good clinical results when treated microsurgically. Familiarity and experience with microsurgical technique was associated with better clinical results, whereas the results with direct vision remained static.

Intracranial and spinal meningiomas in patients with breast carcinoma: case reports.

Breast carcinoma has a high predisposition to metastasize to the brain parenchyma or spinal epidural space with development of progressive neurological symptoms and signs and frequently death of the patient. We report 8 patients with known breast cancer who developed neurological symptoms attributable to an intracranial meningioma and 1 patient who developed spinal cord dysfunction resulting from a thoracic meningioma. The removal of the meningiomas resulted in return of normal neurological function in all patients. At follow-up, all our patients are alive without evidence of meningioma or breast carcinoma recurrence, except 1 patient who died of a metastatic malignant melanoma. This clinical association requires repeated emphasis because of the potential benefit in management of patients with suspected metastatic disease. We have reviewed and summarized the reported literature and added our 8 cases. The mean age of presentation before the second tumor was 6 years. Breast carcinoma was diagnosed first in 85% of cases. The clinical symptoms of the meningiomas were focal neurological signs in 50% of the patients, raised intracranial pressure in 40%, and a seizure in 10%.

Distal anterior choroidal artery aneurysm: intraoperative localization and treatment.

Distal anterior choroidal artery aneurysms with intraventricular hemorrhage are rare and difficult to treat. We report the case of a 46-year-old woman with a left distal anterior choroidal artery aneurysm presenting as a typical subarachnoid hemorrhage from which she had no focal neurological signs. Because the aneurysm was located within the dominant deep temporal lobe, we used intraoperative computed tomography to guide a probe to the aneurysm to allow minimal dissection. This is the first report of a successfully treated distal anterior choroidal artery aneurysm. Reports of this unusual aneurysm and methods of approaching deep temporal lesions are reviewed.

Intramedullary epidermoid associated with an intramedullary spinal abscess secondary to a dermal sinus.

Intramedullary spinal abscesses are rare and potentially devastating lesions. A heightened clinical awareness of patients at risk is essential for an early diagnosis and intervention to improve the prognosis of these patients. The first case of spinal abscess was described in 1830, and only 63 cases have been reported subsequently. Intraspinal epidermoids also are unusual lesions. These tumors were reported first in 1829 and represent less than 1% of all intraspinal tumors. We present a case of a 2-year-old girl who had rapidly progressive paraplegia with urinary and bowel retention and was found to have an intramedullary epidermoid and an intramedullary abscess as a result of a dermal sinus. The association of an intramedullary abscess and epidermoid tumor, two rare lesions, has not been reported previously. We also review the literature related to both intramedullary epidermoids and intramedullary abscesses of the spinal cord. Advances in sectional imaging as described should help lead to an early and safe diagnosis of these rare but often debilitating lesions. This case illustrates the importance of a complete neurological assessment of all patients with a congenital dermal sinus because of the potential for intradural extension and the frequent association with other dysraphic abnormalities. Prophylactic surgery is indicated in many cases to prevent dangerous and recurrent infections of the central nervous system.

Prognostic implications of p53 overexpression in supratentorial astrocytic tumors.

The wild-type p53 gene is thought to play a critical role in tumor suppression and has been shown to reverse the transformed phenotype of tumor cells in vitro. Mutational inactivation of this aspect of p53 activity occurs frequently in many human neoplasms, including astrocytomas, and is thought to represent a critical step in tumor progression. We have found previously that the presence of p53 immunoreactivity was significantly associated with malignant astrocytomas arising in younger patients, although occurring infrequently in tumors in older patients. Given that young age is the most consistent clinical factor predictive of longer survival in patients with astrocytomas, this suggested that p53 protein accumulation might be a molecular predictor of enhanced survival. To test this hypothesis, we retrospectively studied the association of p53 overexpression with survival in 149 patients with astrocytomas, using univariate and multivariate analysis to determine its value in predicting survival. Although our analysis reaffirmed the strong association between young age and increased survival, we were unable to demonstrate any difference in survival between patients with Grade III and IV tumors with p53 immunoreactivity compared with those without. Presumably, once a tumor has progressed to high grade, the relative importance of p53 status as a predictor of survival is low, probably because of the large number of accumulated genetic alterations associated with malignant tumors. In contrast, the presence of p53 overexpression in Grade II astrocytomas seemed from survival curves to indicate shorter survival compared with patients who had no p53 immunoreactivity. However, this variable did not quite reach statistical significance (P = 0.08) as an independent predictive variable in multivariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The management of "asymptomatic" epidural hematomas. A prospective study.

Standard neurosurgical management mandates prompt evacuation of all epidural hematomas to obtain a low incidence of mortality and morbidity. This dogma has recently been challenged. A number of authors have suggested that in selected cases small and moderate epidural hematomas may be managed conservatively with a normal outcome and without risk to the patient. The goal of this study was to define the clinical parameters that may aide in the management of patients with small epidural hematomas who were clinically asymptomatic at initial presentation because there was no clinical evidence of raised intracranial pressure or focal compression. A prospective study was conducted of 22 patients (17 males and five females) aged from 1 to 71 years, who had a small epidural hematoma diagnosed within 24 hours of trauma and were managed expectantly. Of these, 32% subsequently required evacuation of the epidural hematoma 1 to 10 days after the initial trauma. Analysis of the patients revealed that age, sex, Glasgow Coma Scale score, and initial size of the hematoma are not risk factors for deterioration. However, deterioration was seen in 55% of patients with a skull fracture transversing a meningeal artery, vein, or major sinus, and in 43% of those undergoing computerized tomography (CT) within 6 hours of trauma. In contrast, only 13% of patients in whom the diagnosis of a small epidural hematoma was delayed over 6 hours subsequently required evacuation of the epidural collection. Of patients with both risk factors, 71% required evacuation of the epidural hematoma. None of the patients suffered neurological sequelae attributable to this management protocol. It was concluded that patients with a small epidural hematoma, a fracture overlaying a major vessel or major sinus, and/or who are diagnosed less than 6 hours after trauma are at risk of subsequent deterioration and may require evacuation. Conversely, patients without these risk factors may be managed conservatively with repeat CT and careful neurological observation, because of the low risk of delayed deterioration.

Thrombosis of difficult intracranial aneurysms by the endovascular placement of platinum-Dacron microcoils.

Patients with symptomatic aneurysms that are not excluded from the cerebral circulation have a poor prognosis. Standard treatment is surgical exploration with direct clipping of the aneurysm. Because of their large size or relationship to the base of the skull, some aneurysms may not be suitable for direct surgical clipping and may require alternative treatment modalities. A prospective clinical and radiological study of seven patients treated with the endovascular placement of platinum-Dacron microcoils to exclude the aneurysm from the cerebral circulation is reported. The seven patients ranged in age from 37 to 63 years; four were women. At completion of the endovascular procedure, total occlusion of the aneurysm with preservation of the parent artery had been achieved in four patients and 90% occlusion of the aneurysm in two. In the seventh patient, occlusion of the internal carotid artery resulted in the patient's death. At the 6-month follow-up review, both patients with an aneurysm less than 20 mm in size had persistent aneurysm thrombosis; however, the two patients with giant aneurysms had partial recanalization. Both required repeat thrombosis of their aneurysm with the placement of additional microcoils, one at 6 weeks and one at 6 months. These two patients have persistent aneurysm thrombosis at 12 months following their second procedure. The patient mortality rate for this study was 14%, while the procedure mortality/morbidity rate was 9%. It is concluded that thrombotic aneurysm therapy of difficult aneurysms is a safe procedure and will have a place in the treatment of selected aneurysms.

Cisterna magna microdialysis of 22Na to evaluate ion transport and cerebrospinal fluid dynamics.

Microdialysis is used in vivo for measuring compounds in brain interstitial fluid. The authors describe another application of this technique to the central nervous system, namely microprobe dialysis in the cisterna magna to study the dynamics of ion transport and cerebrospinal fluid (CSF) formation in the rat. The choroid plexus is the major source of CSF, which is produced by active transport of Na from blood into the cerebral ventricles. Formation of CSF is directly proportional to the blood-to-CSF transport of Na. By injecting 22Na into the systemic circulation and quantifying its movement into CSF by microdialysis, one can reliably estimate alterations in the rate of CSF formation. The sensitivity of this system was determined by administering acetazolamide, a standard inhibitor of CSF production. Because acetazolamide is known to decrease CSF formation by 40% to 50%, the cisternal microdialysis system in animals treated with this drug should detect a corresponding decrease in the amount of 22Na dialyzed. This hypothesis is supported by the 22Na uptake curves for control versus treated animals: that is, by the acetazolamide-induced average diminution of about 45% in both the rate and extent of tracer accession to dialysate. Bumetanide, a loop diuretic, reduced by 30% the 22Na entry into dialysate. Microprobe dialysis of fluid in the cisterna magna is thus a minimally invasive and economical method for evaluating effects of drugs and hormones on the choroid plexus-CSF system.

Gamma knife surgery for treatment of central neurocytomas. Report of four cases.

The authors investigated the use of gamma knife surgery (GKS) in the treatment of central neurocytoma, a usually benign primary brain tumor of the lateral and third ventricles. Four patients with subtotally resected or recurrent central neurocytomas were retrospectively studied. The prescription isodose was 9 to 13 Gy to the 30 to 50% peripheral isodose line. Pre- and postoperative magnetic resonance (MR) images were compared to determine the volume reduction following GKS. Follow-up review included annual MR imaging and clinical evaluation by a neurosurgeon. Follow-up periods ranged from 12 to 99 months. Marked reduction in tumor size was seen in all four patients; the decrease in tumor volume for each was 48%, 72%, 81%, and 77%, respectively, at the last follow-up review. None of the four patients required additional treatment and none experienced a decline in neurological function during the follow-up period. No complications have been noted in any of these patients to date. Even though there have been few observations and follow-up time has been limited, because of the consistency of the response and the lack of observed side effects, GKS may be the treatment of choice for subtotally resected and recurrent central neurocytomas.

Stereotactic radiosurgery for trigeminal neuralgia: a multiinstitutional study using the gamma unit.

A multiinstitutional study was conducted to evaluate the technique, dose-selection parameters, and results of gamma knife stereotactic radiosurgery in the management of trigeminal neuralgia. Fifty patients at five centers underwent radio-surgery performed with a single 4-mm isocenter targeted at the nerve root entry zone. Thirty-two patients had undergone prior surgery, and the mean number of procedures that had been performed was 2.8 (range 1-7). The target dose of the radiosurgery used in the current study varied from 60 to 90 Gy. The median follow-up period after radiosurgery was 18 months (range 11-36 months). Twenty-nine patients (58%) responded with excellent control (pain free), 18 (36%) obtained good control (50%-90% relief), and three (6%) experienced treatment failure. The median time to pain relief was 1 month (range 1 day-6.7 months). Responses remained consistent for up to 3 years postradiosurgery in all cases except three (6%) in which the patients had pain recurrence at 5, 7, and 10 months. At 2 years, 54% of patients were pain free and 88% had 50% to 100% relief. A maximum radiosurgical dose of 70 Gy or greater was associated with a significantly greater chance of complete pain relief (72% vs. 9%, p = 0.0003). Three patients (6%) developed increased facial paresthesia after radiosurgery, which resolved totally in one case and improved in another. No patient developed other deficits or deafferentation pain. The proximal trigeminal nerve and root entry zone, which is well defined on magnetic resonance imaging, is an appropriate anatomical target for radiosurgery. Radiosurgery using the gamma unit is an additional effective surgical approach for the management of medically or surgically refractory trigeminal neuralgia. A longer-term follow-up review is warranted.

The association of normal-pressure hydrocephalus with obstructive sleep apnea.

This report describes a 70-year-old man with obstructive sleep apnea who deteriorated rapidly when nasal continuous positive airway pressure was begun. The patient was found to have normal-pressure hydrocephalus, which was possibly exacerbated by the nasal continuous positive airway pressure. A review of the literature indicates several significant associations between apnea, normal-pressure hydrocephalus, and increased intracranial pressure and suggests that the association of obstructive sleep apnea and hydrocephalus might not be rare. Implications for diagnosis and treatment are discussed.