Search

We examined the mechanism of cyst formation in extra-axial tumours in the central nervous system (CNS). Cyst fluid, cerebrospinal fluid (CSF) and blood plasma were analysed in eight patients with nine peritumoral cysts: four with meningiomas, two with intracranial and two spinal intradural schwannomas. Measuring concentrations of various proteins [albumin, immunoglobulin G (IgG), IgA, alpha(2)-macroglobulin and IgM] in cyst fluid, CSF and blood plasma provides insight into the state of the semipermeability of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier. Peritumoral cysts accompanying intra-axial brain tumours are the end result of disruption of the BBB and oedema formation. Unlike intra-axial tumours which lie embedded within nervous tissue, extra-axial tumours tend to be separated from nervous tissue by arachnoid and pia mater. High concentrations of proteins were measured in the cyst fluid, approaching blood plasma levels, suggesting a local barrier disruption, and passage across the arachnoid, pia mater and cortical/medullary layer into the CNS parenchyma, leaving the protein concentrations of CSF practically unchanged. We confirmed that very high concentrations of protein are to be found in tumour cysts, plasma proteins forming almost 90 % of the total protein in the cyst. We review current hypotheses on the pathogenesis of cysts accompanying neoplasms, particularly meningiomas and schwannomas, and conclude that the majority of proteins in cyst fluid in extra-axial, intradural meningiomas and schwannomas are plasma proteins. This provides a strong argument for pathogenesis of extra-axial intradural tumour cysts in favour of leakage of plasma proteins out of the tumour vessels into the nervous tissue.

With the introduction of new (immuno-)histochemical techniques it is now possible to assess rates of proliferation and apoptosis in brain gliomas using archival paraffin embedded material. As proliferation and apoptosis are related to tumour growth rate quantification of these processes has prognostic value and is related to tumour grading. In this study we assessed the proliferation rate by measuring the Ki-67 labelling index using the MIB-1 antibody (MIB-LI) and the apoptotic rate using the in situ labelling of DNA strand breaks with TUNEL (TUNEL-LI) in 315 supratentorial gliomas. MIB-LI and TUNEL-LI in astrocytomas (A) where significantly lower compared to anaplastic astrocytomas (AA), glioblastomas (GBM) and oligodendroglial tumours [oligodendrogliomas (O) and anaplastic oligodendrogliomas (AO)]. MIB-LI and TUNEL-LI were significantly lower in AA compared to GBM. In astrocytic tumours MIB-LI and TUNEL-LI appeared to be correlated. As the distinction between A and AA is of clinical value but can be difficult histomorphologically we analysed the prognostic value of MIB-LI and TUNEL-LI in gliomas with particular emphasis on A and AA. MIB-LI below 10% was of prognostic value in A and AA, O and AO but not in GBM on univariate survival analysis. TUNEL-LI was of no prognostic value. With multivariate survival analysis MIB-LI lost prognostic significance in O and AO. Astrocytomas with a gemistocytic component (AG) are similar to A with respect to survival and MIB-LI and TUNEL-LI. MIB-LI is of independent prognostic value in A and AA. Assessment of MIB-LI in A and AA can be used as an aid in distinguishing A and AA.

We monitored 10 patients with unresected (9) or partially resected (1) supratentorial gliomas with 11C-tyrosine position emission tomography (TYR-PET) before and after radiotherapy. TYR-PET tumour volumes were measured using a threshold technique. In seven patients the tumour volume decreased after radiotherapy, although all gliomas persisted on TYR-PET images. In eight patients the tumour protein synthesis rate (PSR) was calculated using a dynamic study protocol in combination with a PATLAK analysis. There were no changes in PSR after radiotherapy, but the PSR was calculated on the remaining tumour volume using the same threshold technique as before therapy, i.e. the decrease in tumour volume was not taken into account. In eight patients the PET data were compared with magnetic resonance spectroscopic imaging (1H-MRSI) performed simultaneously. Although there was no statistically significant correlation between TYR-PET volume changes and 1H-MRSI choline level we observed a simultaneous decrease in volume and choline in four patients.

There is a growing interest in cystic lesions of the brain. By examining the cyst content of brain tumours more insight into the pathogenesis of cyst formation has been found. In this study, 39 samples of cyst fluid of 34 patients with a cyst accompanying a brain tumour were collected and studied biochemically regarding their protein content, lactate and pH. In this study we investigated the relation between the grade of malignancy and the lactate-concentration and the discrepancy between the high levels of lactate in cysts and their alkaline environment. The results of the measurements of the concentrations of albumin, immunoglobulins (IgG, IgA, IgM) and alpha(2)-macroglobulin in cysts compared to those in sera suggest that cyst formation associated with tumour is based upon a disruption of the blood-brain barrier with exudation of plasma proteins into the brain parenchyma resulting in accumulation of fluid (oedema) and eventually in formation of a cyst. There appears to be a positive relation between the grade of malignancy and the concentration of lactate in the cysts with a significant 2-fold increase in lactate concentration in malignant tumour cysts compared to the more benign tumour cysts (p

Recent reports have suggested that cyst formation accompanying astrocytomas in the central nervous system (CNS) is due to an edematous process caused by blood-brain barrier (BBB) disruption and not a result of necrosis. This study is performed to investigate whether the hypothesis of cyst formation based on BBB disruption also applies to various pathologically different intra-axial gliomatous tumors and metastases. By chemical analysis, using immunokinetic nephelometry, isoelectric focussing, cellulose acetate electrophoresis and a biuretic method, the concentrations of albumin, immunoglobulin G (IgG), IgA, alpha2-macroglobulin, IgM and total protein were measured and proportions of concentrations of these proteins were compared in cyst fluid, blood plasma and cerebrospinal fluid (CSF). Our data, based on the chemical analysis of cyst fluid and blood plasma of 37 patients, including 2 ependymomas (one cerebral; one thoracic), 3 oligodendrogliomas, 4 hemangioblastomas, 5 cerebellar astrocytomas and 1 cervical, 1 giant astrocytoma grade one, 1 gangliocytoma, 1 neuroblastoma and 19 metastases (five lung-; two renal-; three breast-; one melanoma-; one thyroid metastasis and seven metastases of unknown origin) present high protein concentrations in the cysts with a highly similar spectrum of proteins in the tumor cyst fluid and blood plasma, suggesting a BBB disruption followed by exudation of plasma proteins into the brain parenchyma with formation of edema and transition of edematous tissue into a cyst accompanying the tumor. Although histopathologically different types of tumor tissue are involved, data suggests that the pathogenesis of cysts accompanying gliomatous tumors and metastases in the CNS is based on BBB disruption and consequent edema, as is the case in the formation of cysts in anaplastic astrocytomas.

We determined dopamine (DA), noradrenaline (NA), and adrenaline (A), as well as immunohistochemically stained tyrosine hydroxylase (TH) and DA in dissected rat ventral mesencephalon (VM) tissue from Embryonic Day (ED) 14 to Postnatal Day (P) 17. Whole VM tissue DA, NA, and A contents increased with advancing age. VRI DA/protein increased from ED15 to ED16, whereas NA/protein increased from ED15 to ED16 and from ED20 to P4. VM DA/NA ratio increased from ED14 to ED15 and decreased from ED18 to P4. VM cell suspensions exhibited higher DA/NA ratios than whole VM tissue. Washed cell suspensions had higher DA/NA than unwashed counterparts. We conclude that data from both VM immunohistochemistry and catecholamine assays relate to VRI development. VM DA is contained mainly in cells, whereas VRI NA is located in fibers that channel at the dorsal side of the VM. Determination of tissue catecholamine contents may be helpful for the biochemical characterization of tentatively identified VM grafts. (C) 1997 Academic Press.

Brain tissue of rats pretreated with methylprednisolone or with the 21-aminosteroid U74389F, and that of untreated control rats, was assessed for the expression of annexin-1 (Anx-1) and the transcription of its mRNA. For this purpose Anx-1 cDNA was amplified and simultaneously a T7-RNA-polymerase promoter was incorporated into the cDNA using a polymerase chain reaction (PCR). Then digoxigenin-11-UTP was incorporated into the transcribed cRNA with T7-RNA-polymerase. With this probein situhybridization was carried out on sections of the brain. The probe was visualized by an immunoassay using an antidigoxigenin antibody conjugate. Anx-1 protein was assessed by means of immunohistochemistry using a polyclonal antibody. The various brain areas of the control animals showed an appreciable amount of Anx-1 at mRNA or protein level; on the other hand, the animals which had been pretreated with either steroid, showed a more intense Anx-1 mRNA signal than the controls in many areas. In the pretreated animals Anx-1 immunostaining was unchanged in cortex, basal ganglia, amygdala and septum, but more intense in hippocampus, hypothalamus and thalamus. In ependyma, choroid plexus, meninges, and vascular walls there was no Anx-1 mRNA transcription detectable. An opposite profile was shown by the Anx-1 immunoreactivity, the protein was present in control animals as well as the steroid-pretreated animals, suggesting that here the protein was either from systemic origin, or has diffused from adjacent structures. The results indicated that Anx-1 mRNA transcription is upregulated by either steroid, and that in the untreated animals there is a resting level of Anx-1 mRNA transcription, presumably reflecting physiological influences on Anx-1 expression.

For the synthesis of [18F]Fluoro-Org 6141 via a nucleophilic substitution reaction with 18F-, the tosyl group was chosen as the leaving group because of its stability and excellent leaving group ability. The biodistribution of the high affinity and moderate lipophilicity (log P = 2.66, calculated value) ligand [18F]Fluoro-Org 6141 (specific activity 8.2 to 37 TBq/mmol, yield 10% at EOB) was examined in sham adrenalectomized (sADX) and adrenalectomized (ADX) male Wistar rats. Two days after ADX or sADX, the animals were anesthetized and 0.37 to 1.85 MBq of [18F]Fluoro-Org 6141 was administered intravenously. Kinetics of 18F activity uptake were monitored for 3 h using a stationary double-headed positron emission tomography (PET) camera, and the biodistribution was assessed by ex vivo determination of radioactivity in several tissues and different brain areas. One hour after injection of the radioligand, the bladder, kidney, liver, trachea, and bone of sADX animals contained more concentration on a wet weight basis than blood. Three hours post injection, radioactivity was retained in bladder, trachea, and bone. The accumulation of radioactivity in brain corresponded to the concentration of activity in the blood within the first hours after injection. ADX animals showed a higher uptake of 18F activity in spleen, testes, and brain areas (hippocampus and brainstem) but a lower uptake in bone than sADX rats. PET scans suggested that 18F activity uptake in the brain had not yet reached a maximum at this interval. Although [18F]Fluoro-Org 6141 is not useful for PET studies of glucocorticoid receptors (GRs), the results obtained with this compound indicate a synthetic strategy suitable for the synthesis of high-affinity radioligands for GRs.

In 32 patients with gliomas, one- and two-dimensional proton magnetic resonance spectroscopy (H-1-MRS) has been conducted, the latter allowing reconstruction of spectroscopic data into a spectroscopic image (MRSI), showing the distribution of the various metabolite concentrations over the cross-sectional plane. For lack of absolute concentrations, the measured concentrations of phosphocholine (CHOL), N-acetyl-L-aspartate (NAA), and lactate (LAG) were conventionally expressed in ratios relative to that of creatine (CREAT). Compared to normal brain tissue, an increased CHOL/CREAT ratio was found in all groups of tumours, in glioblastomas, high-, middle- and low-grade astrocytomas both at the margin and the core of the tumours, but in oligodendrogliomas only at the margin. This is consistent with an increased phosphocholine turnover in relation to membrane biosynthesis by the proliferating cells. The NAA/CREAT ratio was decreased in all groups of tumours, both in the centre and at the margin, reflecting replacement of functioning neurons by neoplastic cells. The LAG/CREAT ratio was elevated in the core of malignant gliomas, which may be the result of a prevailing glycolysis, characteristic of tumours, possibly in conjunction with hypoxia/ischaemia. In the perifocal oedema, there was neither elevation of the CHOL/CREAT ratio nor decrease of the NAA/CREAT ratio; an increased LAC/CREAT ratio therefore rather reflected ischaemia/hypoxia probably due to locally elevated pressure and compromised regional perfusion. In the normal brain, the metabolite ratios of grey matter did not differ from those of white matter. The frontal lobe and basal ganglia showed lower NAA/CREAT ratios than the other cerebral areas. In 7 patients positron emission tomography was also performed with [F-18] fluoro-2-deoxy-D-glucose ((18)FDG) or L-[1-C-11]-tyrosine (C-11-TYR); the latter demonstrated a pattern of C-11-TYR uptake similar to that of CHOL elevation in the MRSI.

Proton magnetic resonance spectroscopic imaging (1H-MRSI) and positron emission tomography with the tracer L-[1-11C]tyrosine (11C-TYR) were used to localize gliomas for biopsy or resection. This is especially helpful in cases of low-grade gliomas, if these lesions are not visualized by contrast-enhanced computed tomographic and magnetic resonance imaging scans. The clues to improved localization are provided by changes in tissue metabolite contents, such as elevation of phosphocholine, indicating cellular proliferation; decrease of N-acetylaspartate, denoting loss of neurons (as these are replaced by tumor cells); and elevation of lactate, pointing to the prevalence of glycolysis, as observed in many tumors. These data on tissue metabolite content have been obtained in vivo in the patient by proton magnetic resonance spectroscopy; metabolite maps derived from these data then visualize the distribution of the various metabolites over the section of the brain under investigation. Alternatively, localization of a tumor may be achieved by means of positron emission tomography depicting the pattern of uptake of the amino acid tracer 11C-TYR, as it tends to be incorporated in the process of cellular proliferation and protein biosynthesis. Five cases are presented as examples.

Lipocortin-1, lipocortin-2 and lipocortin-5 were immunohistochemically assessed in rats. Apart from animals receiving no treatment, other animals received pretreatment with methylprednisolone, or the 21-aminosteroid U-74389F. Whereas Hpocortin immunoreactivity was absent in the greater part of the brain in animals not pretreated with steroid (except in sporadic microglial cells and choroid plexus), there was obvious immunostaining of parenchymatous elements in steroid pretreated animals. In the steroid pretreated animals lipocortin immunoreactivity of the brain tissue may indicate local formation of lipocortin under the influence of steroids that had entered the tissue. The cellular elements which showed immunostaining included meningeal cells, neurones, ependyma, oligodendroglia and capillary endotheHum.

With in vivo 1H-MRS resonances of several metabolites were simultaneously measured in cerebral gliomas and adjacent normal brain. 15 patients with inoperable brain gliomas all histologically verified were monitored with 1H-MRS and MRI before and after radiotherapy. 11 patients were evaluable. 1H-MRS technique evolved from single volume measurements to one dimensional and two dimensional 1H spectroscopic imaging. In all patients N-acetyl-aspartate signals were decreased in tumour areas compared to the normal brain hemisphere. No recovery was seen after radiotherapy. Choline signals were increased in tumour margins of high grade gliomas and more diffusely in low grade gliomas. In 5 patients the choline resonance decreased after radiotherapy, accompanied by a shrinkage of tumour diameter on MRI. Lactate signals were present in high grade and unspecified astrocytomas and absent in most low grade gliomas. In 3 patients the lactate signal disappeared after radiotherapy. These observations indicate the feasibility of 1H-MRS in monitoring metabolic responses on radiotherapy of brain gliomas.

In this study we examined the efficacy of cryopreserving porcine fetal mesencephalic tissue. After microscopical dissection of the ventral mesencephalon (VM) from E28 pig fetuses, the collection of explants was randomly divided into two equal parts. One part was directly prepared as cell suspension. The other part was stored in hibernation medium for less than 2 days and then cryopreserved as tissue fragments and stored in liquid nitrogen. After 2 weeks up to 1 year, these tissue fragments were thawed and processed as cell suspensions. After cell counting and assessment of viability, these cell suspensions were used to examine survival, morphology, and neurite formation of the dopaminergic neurons in cell culture as well as after intrastriatal implantation in 6-OHDA-lesioned rats. Comparison of cryopreserved with fresh VM cell suspensions showed no significant difference with respect to cell viability and the average number of living cells per VM explant. The morphology of cultured dopaminergic neurons after cryopreservation was identical to that of fresh cells. After intrastriatal implantation, survival and outgrowth of cryopreserved dopaminergic neurons as well as functional effects did not differ from those of fresh cells. In conclusion, the cryopreservation technique we used proves to be a reliably effective method for storing porcine fetal VM tissue.

Brain tissue of rats pretreated with methylprednisolone or with the 21-aminosteroid U74389F, and that of untreated control rats, was assessed for the expression of Annexin-1 (Anx-1) and the transcription of its mRNA. For this purpose Anx-1 cDNA was amplified and simultaneously a T7-RNA-polymerase promotor was incorporated into the cDNA using Polymerase Chain Reaction (PCR). Then digoxigenin-11-UTP was incorporated into the transcribed cRNA with T7-RNA-polymerase. With this probe in situ hybridization was carried out in sections of the brain. The probe was visualized by an immunoassay using an anti-digoxigenin anti-body conjugate. Anx-1 protein was assessed by means of immune-histochemistry using a polyclonal antibody. The various brain areas of the control animals showed an appreciable amount of Anx-1 at mRNA or protein level; on the other hand, the animals which had been pretreated with either steroid, showed a more intense Anx-1 mRNA signal than the controls in many areas. In the pretreated animals Anx-1 immunostaining was unchanged in cortex, basal ganglia, amygdala and septum, but more intense in hippocampus, hypothalamus and thalamus. In ependyma, choroid plexus, meninges, and vascular walls there was no Anx-1 mRNA transcription detectable. An opposite profile was shown by the Anx-1 immunore-activity, the protein was present in control animals as well as the steroid-pretreated animals, suggesting that here the protein was either from systemic origin, or has diffused from adjacent structures. The results indicate that Anx-1 mRNA transcription is upregulated by either steroid, and that in the untreated animals there is a resting level of Anx-1 mRNA transcription, presumably reflecting physiological influences on Anx-1 expression.

The physicochemical properties of water enable it to act as a solvent for electrolytes, and to influence the molecular configuration and hence the function— enzymatic in particular—of Polypeptide chains in biological systems. The association of water with electrolytes determines the osmotic regulation of cell volume and allows the establishment of the transmembrane ion concentration gradients that underlie nerve excitation and impulse conduction.

LCT- 1, LCT-2 and LCT-5 were assessed in uninjured rats and rats subjected to a cortical freezing injury or middle cerebral artery (MCA) occlusion. Apart from animals receiving no treatment, other uninjured or injured animals received methylprednisolone (2 or 30 mg/kg) or the 21-aminosteroid U-74389F (10 mg/kg) one day and 2 hours before killing. The animals were killed by decapitation 1 hour after the freezing injury or the MCA occlusion and the area containing the lesion was removed and frozen in Freon. Frozen sections were treated with rabbit polyclonal anti-LCT antibody; binding of antibody was visualized by horseradish peroxidase-conjugated swine antirabbit antibody. Without steroid pretreatment, in the uninjured brain LCT immunoreactivity was absent in the greater part of the brain, except in sporadic microglia. In steroid-pretreated animals and in the freezing lesion of both pretreated and untreated animals there was extensive immunostaining; in the freezing lesion it may be due to passage of systemic LCT across the impaired blood-brain barrier in the lesion. The cellular elements showing immunostaining were meningeal cells, neurons, ependyma, choroid plexus, oligodendroglia and capillary endothelium. It implies that also in the brain the steroid effect is consistent with LCT formation.

A classification of the existing multitude of cystic lesions of the brain is proposed, which allows an understanding of their genesis and consequent therapeutic implications, as well as their diagnostic characteristics. Essentially, cerebral cystic lesions may be classified into the following categories: Cysts containing CSF-like fluid, which include ex vacuo type cysts, such as leptomeningeal cysts, and cysts following surgical resection; cysts with fluid secreting walls and CSF-like content, such as arachnoid cysts; cysts associated with dysgenesis, for example Dandy-Walker cysts. The ex vacuo cysts increase craniospinal compliance, whereas the other cysts with CSF-like content do not; they are not per se expansive, however, although their occasional location along CSF pathways may cause obstruction and hydrocephalus. Another category includes cysts with a lining of non-neural epithelium like colloid cysts, epidermoid cysts, or craniopharyngiomas. They may increase in size and cause symptoms by compression, although not at the rate of tumour-associated cysts. The cysts associated with gliomas and other tumours have a pathogenesis bearing upon blood-brain barrier impairment and formation of vasogenic oedema. Finally, one may distinguish a category of cysts with infectious origin, such as brain abscesses and hydatid cysts. The cysts with CSF-like contents may be recognised by their magnetic resonance characteristics resembling those of CSF, whereas cysts containing proteinaceous fluid are associated with blood-brain barrier impairment and consequent contrast enhancement. The cysts with a lining of non-neural epithelium exhibit diverse properties of attenuation on computed tomography (CT) and magnetic resonance imaging (MRI), depending on the nature of their cyst contents.

The history of our evolving knowledge of arachnoid cysts illustrates the misconceptions that have existed about their nature and pathogenesis. In the past, arachnoid cysts were confused with pockets of the true sub-arachnoid space, which have been sequestered by arachnoid adhesions following trauma or infection, and which are presently known as leptomeningeal cysts or false arachnoid cysts.1 It may presumably explain the persisting belief in the existence of arachnoid cysts that originate from trauma. Contrary to arachnoid cysts, these leptomeningeal cysts are readily accessible from the subarachnoid space, as demonstrated by radioisotope cisternography studies.2 Moreover, leptomeningeal cysts have shown a smooth wall surface when viewed by scanning electron microscopy,3 whereas the walls of arachnoid cysts tend to show fenestrations and microvilli of diverse shapes (Figure 5.1).

There are brain tumors which are associated with cysts. With respect to control of intracranial pressure, the occurrence of large cysts is of clinical significance, especially when removal of the tumor per se is not possible, since evacuation of the cyst may readily achieve considerable increase of intracranial compliance. Yet the study of the mechanism of formation of tumor cysts, and of the conditions determining their prevalence and recurrence, has generally received little attention. Tumor cysts typically contain a protein-rich fluid. It is the protein that probably maintains cyst volume by retarding its resolution, as in the case of protein-rich vasogenic edema fluid. Conceivable origins of cyst fluid are necrosis or degeneration of tumor tissue versus vasogenic edema accompanying the tumor. If the cyst fluid originates from tumor tissue, it should predominantly contain cell proteins, whereas a vasogenic origin would imply a fluid constitution in which plasma proteins prevail.

Imaging of blood-brain barrier damage by magnetic resonance was currently studied as to the potential of dextran-magnetite particles (DMP) for contrast enhancement. For that purpose, dextran T10 (average molecular weight: 10.9 Kilodalton) was complexed with magnetite (Fe3O4) in ammonia. Experimental testing of the agent was made in vivo using Wistar rats with a freezing injury to the brain. DMP was i.v. injected at a dose of 90 µM Fe/kg b.w. followed by 2% Evans blue (0.6 ml). Control animals with trauma were studied without administration of DMP. Histochemical assessments were made to analyze the tissue distribution of DMP in the brain, kidney and liver after fixation in 4% formalin. MR imaging was conducted with 1.5 Tesla field strength with a circular coil 15 min after the freezing insult and administration of DMP. T1- and T2-weighted images were obtained using spin echo sequences among others. Regression analyses indicated a 50% reduction of Ti at a DMP concentration of 48 µM Fe, while for T2 only 4 µM/ Fe(DMP) were sufficient for a 50% reduction. DMP was also accumulating in other organs, particularly in the Kupffer cells of the liver. Administration of DMP led to recognition of the freezing lesion as black area in agreement with macroscopical findings obtained by autopsy. In animals with a freezing lesion without administration of DMP, only T2-weighted images demonstrated a somewhat higher intensity attributable to the disruption of the blood-brain barrier. The present findings demonstrate the usefulness of DMP for contrast enhancement of lesions following disruption of the blood-brain barrier.

The results of 16 cases of temporal bone resection were evaluated. The resections, 12 of which were total and 4 partial, had mostly been performed for squamous cell carcinoma invading the temporal bone. Five patients in whom the intervention was considered radical and not followed by irradiation, were alive and well 9 years or more later. The significance of postoperative radiotherapy was demonstrated in 3 patients who were alive and in good health 9 years or more later, although histological examination of resection margins showed residual tumour. Eight patients died 10 months to 5 1/3 years after operation, 6 of whom from recurrence, one from radiation necrosis of the temporal lobe of the brain, and one from cerebrovascular occlusion. Histologically, squamous cell carcinoma was found significantly more among the patients who died from recurrence than among those still living.

To study the possible application of monoclonal antibody/dextranmagnetite conjugates in specific MR imaging of brain metastases, both components of these conjugates were tested for their ability to penetrate the endothelium during conditions of local blood-brain barrier (BBB) impairment.

The behavior of the BBB in cerebral ischemia was studied in symptom-positive Mongolian gerbils subjected to left common carotid artery occlusion using Evans Blue dye as indicator of BBB injury. The BBB damage was demonstrable grossly by the presence of areas of blue discoloration, and microscopically by the presence of a bright red fluorescent tracer, localized mostly in the neurons. The survey of various groups of animals revealed a direct relationship between the incidence and time of appearance of the BBB lesions and the duration of the ischemic occlusion. This relationship can be interpreted as another example of the previously described "maturation" phenomenon. A relatively late occurrence of the BBB injury in cerebral ischemia, at the time when the affected brain tissue shows severe, edematous histopathologic changes indicates that the brain edema, as the main complication of ischemia, could be regarded as being primarily of the cytotoxic type.

✓ The isolation of edema fluid from cats with cold-induced cerebral edema allowed the study of changes of Na+ and K+ content, lactate dehydrogenase and creatine phosphokinase activity, colloid osmotic pressure and the level of intravenously administered 99mTc-albumin in the edema fluid during a period of hypoxia. The changes consisted of an increase of all mentioned parameters, except Na+; and could be interpreted as a concentration of solutes (but for Na+) in the extracellular edema fluid, concomitant to a reduction of the extracellular space, as the oxygen deficiency caused improper functioning of the cellular Na+-K+ pump, with a resulting shift of fluid (including Na+) into the cellular elements.

Proton relaxation times T1 and T2 of macromolecular solutions, bovine brain tissues, and experimental cat brain edema tissues were studied as a function of water concentration, protein concentration, and temperature. A linear relation was found between the inverse of the weight fraction of tissue water and the spin-lattice relaxation rate, R1, based on a fast proton exchange model for relaxation. This correlation was also found for the spin-spin relaxation rate, R2, of gray matter samples and macromolecular solutions at low concentrations. Concentrated solutions of protein-water samples showed an enhanced relaxation due to viscosity effects. The T2 of white matter was considerably lengthened with elevated water concentration, but showed no straightforward relation with the total tissue water content. The relaxation times of all samples increased with temperature, supporting the assumption of fast proton exchange in the model for relaxation. This was not found for white matter, in which T2 decreased with increasing temperature, which indicated that intermediate or even slow exchange was present. The relation found between relaxation times and tissue water content can be used to predict the amount of and/or increase in tissue water due to water-elevating processes such as edema. © 1988 Academic Press, Inc.

Although generally benign, meningiomas may be associated with extensive peritumoral brain edema, as visualized on computed tomographic (CT) scans. An analysis of 38 meningiomas indicated that severity of edema on CT scans positively correlated with tumor size and also with evidence of disruption of the cortical layer, which initially separates the tumor from the white matter, in which edema tends to accumulate. The various histological subtypes also seemed to be distinct in their tendency to induce edema, with the transitional and meningotheliomatous subtypes associated with the more severe grades of edema. There was no correlation between grade of edema and location of the tumor. Contact of the edematous area or the tumor itself with the ventricle, which is relevant to the possibility of drainage of edema fluid into the ventricle, seemed to occur in cases of the more severe grades of edema rather than in cases showing slight or no edema.

✓ The morphological similarity of the lining of arachnoid cysts to subdural neurothelium and the mesothelium of arachnoid granulations suggested that the latter tissues might be the origin of arachnoid cysts. Transport Na+-K+-adenosine triphosphatase was shown by enzyme ultracytochemistry to be an indication of secretory activity in the lining of arachnoid cysts and in the endothelial lining of arachnoid granulations. This secretory activity suggests the existence of a biochemical mechanism for cerebrospinal fluid absorption at these granulations separate from the mechanisms already demonstrated.

Hydrocephalus was induced in rats by the injection of silicone oil or kaolin suspension into the cisterna magna. One to 5 weeks later the walls of the lateral ventricles were studied with the scanning electron microscope after killing the animals by perfusion fixation. In contrast to controls, the hydrocephalic animals killed 1 or 2 weeks after injection showed degeneration of ependymal cilia and infestation of the ependymal and choroid plexus surface with reactive cells, which presumably may be identified as Kolmer phagocytic cells by their ultrastructural features as studied by the transmission electron microscope. A coating of debris on the surface of the choroid plexus in the hydrocephalic animals possibly bears upon the ciliary degeneration with consequent deficiency of the clearing effect of ciliary movement. In the longer surviving hydrocephalic animals regeneration of cilia seemed to have occurred.

Proton spin longitudinal (T1) and transverse (T2) relaxation and proton density studies were carried out on human fatty tissue and bovine white matter, both in the native state and after immersion in D2O. It is concluded that nuclear magnetic resonance signals from fatty tissue result mainly from methyl and methylene protons of hydrocarbons. No contribution from lipid protons could be detected for white matter, although it contains a high percentage of lipids. Imaging experiments, resulting in T1, T2, and proton density maps, support the results obtained with spectroscopic relaxation studies.

Brain edema fluid was collected from cats with a freezing lesion in the left parietal cortex by the insertion into the brain of needles containing nylon wicks and connected to polyethylene tubes. The edema fluid samples which accumulated in the polyethylene tubes were regularly analyzed for Na+ and K+ content, colloid osmotic pressure, lactate dehydrogenase and creatine phosphokinase activity, and 99mTc-albumin radioactivity; the albumin tracer being introduced intravenously at the time of cold-injury. One series of cats received an intracerebral injection of ouabain solution, the control series an intracerebral injection of saline, at 100 min after the cold-injury. The ouabain injection was followed by an increase of K+ content, LDH and CPK activities but a decrease of Na+ concentration in the edema fluid, attributable to a concentration of solutes in the edema fluid as presumably water and Na+ were shifted into the cells and hence the extracellular space was reduced.

A method is described for the evaluation of the patency of ventriculoatrial shunts. It is based on local cooling of the shunt and recording of the transported cold at a site downstream, by means of a thermosensitive device connected to a Wheatstone-bridge and a recorder.

Summary An intracranial tumour is described in a 42 year old man. Histologically the tumour showed a rather heterogeneous picture with marked variation in cellularity. The most conspicuous and consistent feature was the presence throughout the tumour of elastin deposits. The tumour differs essentially from the elastofibroma dorsi. Whether it originated from the brain or from the meninges could not be established. A comparable tumour has neither been observed by the authors nor come to their notice.

The effect of hyponatraemia was studied in a series of rats loaded with salt-free solutions and in a control series, both having cold-induced cerebral oedema in one hemisphere. The loaded series showed evidence of plasma hyposmolality concomitant with hyponatraemia and osmotic oedema in the uninjured brain hemisphere, but no aggravation of cold-induced oedema. The findings were explained by the disruption of the blood-brain barrier in the cold lesion, as a result of which the hyponatraemic condition of the blood plasma was communicated to the injured brain tissue causing the rapid abolition of the gradient which is required for the development of osmotic oedema.

In the analysis of the multitude of lesions causing damage to the brain, the concept of secondary brain damage has evolved as a form of damage that is not inherent to the primary insult, although it is the consequence of a detrimental chain of events that may follow. In a follow-up study on craniocerebral trauma, it appeared that among patients with severe primary injury as indicated by the low scores on the Glasgow Coma Scale, there was a group with an initial higher score, which subsequently deteriorated and ended fatally (Minderhoud, 1977). It is tempting to assume, that the latter group represented those patients, who might have suffered from secondary brain damage in addition to their severe primary injury.

NMR spectroscopical measurements of relaxation times were conducted on muscle, intestine, fatty tissue and cerebral cortex and white matter of the rat at various time intervals following removal of the tissue. It appeared that most tissues can be stored at 4 degrees C up to 24 hours without noticeable effects on NMR relaxation parameters. Exceptions are the T2 of muscle and the T1 and T2 of intestine, which tended to change in the first hour after biopsy. Relaxation parameters change considerably after fixation of the tissues. Therefore the effects of fixation have to be taken into account when carrying out NMR measurements on fixed tissues.

As observed in a previous study (1), rises of cortical vein wedge pressure and ventricular fluid pressure concomitant to elevation of arterial blood pressure are increased after infliction of a freezing injury to the brain due to impairment of vasomotor autoregulation and consequent increased propagation of arterial blood pressure into the capillary bed of the cold-injured region. Since the impairment of vasomotor autoregulation seems to enhance the deleterious effect of the arterial blood pressure upon the development of vasogenic brain, edema, it was the aim of this study to investigate whether hyperventilation might influence vasomotor activity under the conditions of brain injury.

In cat brain with a freezing injury, the uptake of 1-11C-acetoacetate (11C-ACAC), 2-18F-fluorodeoxy-D-glucose (18FDG), and L-1-11C-tyrosine (11C-TYR) was monitored by positron emission tomography following intravenous administration of the tracers, at 1 day, and 1-3 weeks after the injury. The development and further course of the cold-induced oedema was monitored by magnetic resonance imaging. In the fresh (1 day old) lesion there was increased uptake of 11C-ACAC, probably due to release of the restrictive influence of the blood-brain barrier upon passage of the substance into brain. The uptake of 18FDG, which normally occurs by carrier-mediated transport at the barrier, was decreased in the fresh lesion, probably as a result of damage of the carrier mechanism. In the 3 week old lesion 18FDG uptake was still reduced, and 11C-ACAC uptake was still increased, although barrier function to Evans blue had recovered. It is suggested, that the increased 11C-ACAC uptake in the chronic lesion bears upon the proliferation of macrophages and reactive glial cells in the lesion. This is supported by the increased uptake of 11C-TYR in the 2 weeks old lesion, while in the fresh lesion 11C-TYR uptake was unchanged.

Protein tracer flux from brain microvessels has been studied at intervals of 10 s and 5, 15 and 60 min following hyperosmolar perfusion injury of the blood-brain barrier with 0.6 ml of a 4 M urea solution. In one group of Wistar rats 75 mg horseradish peroxidase (HRP) was given intravenously 10 min before killing as an exogenous protein tracer. In another group endogenous IgG was used as tracer; to enhance serum levels and to facilitate demonstration, the rats were immunized with HRP beforehand, resulting in high titer serum antibodies of IgG class. After perfusion fixation and tracer demonstration in Vibratome sections the localization of the tracer was studied in 1 μm Epon sections and unstained ultrathin sections. The incidence of tracer presence was estimated with quantitative and statistical methods. The results indicate that in this experimental model of blood-brain barrier damage protein tracer extravasation only occurs during the first minutes and thus may be a rapidly reversible phenomenon. The signs of endothelial activation include increased numbers of vesicles and channel-like structures. As the ratio of vesicles with and without tracer remains fairly constant, increased vesicle formation seems to occur randomly in activated endothelial cells and thus does not represent a tracer outflow mechanism by itself. Any qualitative sign of endothelial activation and protein tracer uptake may occur with or without tracer passage into the surrounding brain, actual tracer extravasation thus appearing to be an overflow mechanism in endothelial cells that can be estimated only with quantitative methods. Protein tracer extravasation may occur by random uptake in vesicular or channel-like structures or by cytoplasmic pooling in endothelial cells or cell segments; tracer extravasation through interendothelial junctional areas is not substantiated by our results. Removal of extravasated tracer may occur at least in part by local tracer backflow into the lumina of larger vessles. And finally, the differences in extravasation pathways between HRP and IgG appear to be significant, demonstrating that more than one pathway may be involved and that the predominance of a pathway may at least in part be tracer dependent.

Clamping of both common carotid arteries for 15 min in the Mongolian gerbil (Meriones unguiculatus) is a well-known model for the study of postischemic changes in the permeability of the blood-brain barrier (BBB) and in the formation of edema1,12,15. The two main characteristics of this model are the differential permeability changes of the BBB and a biphasic edema formation. The permeability of the BBB is increased for sucrose from the start onwards, while an increased permeability for 5-hydroxytryptamine, ∝-amino-isobutyric acid and norepineprhin as well as dextran occurs from 24, 36 and 72 and 144 postichemic hr onwards, respectively.

T1 and T2 relaxation times were determined in vitro at 21 MHz (0.5 T) for a variety of spinal and paraspinal tissues. Intensity formulas for spin echo and inversion recovery sequences were derived and used to calculate the intensities of these tissues as they would appear in magnetic resonance images. The intensity was calculated as a function of various repetition, echo, and inversion times. It is shown that the combination of acquiring in vitro relaxation time values and calculating intensity as a function of pulse timings is useful to predict the parameter setting for optimal contrast between certain tissues without applying series of magnetic resonance images.

Although CT scanning has considerably improved diagnostic accuracy, problems remain in establishing a precise preoperative diagnosis in cases of intracranial lesions especially when a cyst is present. Five cases of cystic lesions are presented to illustrate these problems. The CT features of cystic lesions as well as the pathophysiological processes that lead to their formation are discussed. The pertinent literature on this topic is reviewed.

Three surgically removed primary arachnoidal cysts were studied with scanning electron microscopy (SEM) and two of the cases with transmission electron microscopy (TEM). The cells lining the cyst cavity had microvilli at the surface, true cilia were absent. In the cytoplasm multivesicular bodies, many pinocytotic vesicles, some large vacuoles and strands of tonofilaments were prominent features. The cells were interconnected by desmosome-like junctions and were separated from the surrounding tissue by a distinct but sometimes incomplete basal membrane. Based on these findings it is concluded that arachnoid cysts are derived from the outer arachnoid cells (subdural neurothelium), the formation of the cysts being attributabel to secretory capacity of the subdural neurothelium.

The passage of plasma proteins into the brain is pertinent to the question of resolution of vasogenic brain edema, as the proteins give rise to the colloidosmotic pressure of brain interstitial fluid, one of the parameters in the Starling relation of transcapillary fluid exchange [6].

Cold induced brain edema fluid is thought to propagate through the white matter from the site of the lesion. In the severe cold lesion brain edema model, a large increase in white matter content occurs with hours, and edema fluid can be isolated (I). The edema fluid is driven through white matter by blood pressure and causes tissue pressure gradients to extend from the lesion to normal tissue along the edema pathway (2). As both labelled substances within edema and components of edema fluid are found in the ventricular CSF (2), clearance of edema fluid by CSF flow is thought to occur. This model was used to determine whether severe cerebral edema alters CSF formation. To eliminate individual variation, CSF formation was measured in the same animal by ventriculocisternal perfusion both before and after a cold lesion. In addition, brain water content and arterial blood pressure were measured.