Vasogenic edema with intraparenchymatous expanding mass lesions: A theory on its pathophysiology and mode of action of hyperventilation and corticosteroids

Vasogenic edema with expanding mass brain lesions is hypothesized to be due to an increased intracapillary pressure. The latter may be due to preferential occlusion of the venous system by the growth of the lesion but endothelila proliferation and biogenic amines may also play a part. Endocytosis appears to be a mechanical response to the increased intraluminal pressure. This is a poorly selective process which can explain the proteinaceous nature of vasogenic edema. Steroids may act by forming hydrophobic bonds in the endothelial cell membrane and making it more difficult for any membrane fission to occur. Hyperventilation can be of use in vasogenic edema by decreasing intracranial pressure, providing better oxygenation and also by diminishing the capillary head pressure.     

Edema and brain trauma

Brain edema leading to an expansion of brain volume has a crucial impact on morbidity and mortality following traumatic brain injury (TBI) as it increases intracranial pressure, impairs cerebral perfusion and oxygenation, and contributes to additional ischemic injuries. Classically, two major types of traumatic brain edema exist: "vasogenic" due to blood-brain barrier (BBB) disruption resulting in extracellular water accumulation and "cytotoxic/cellular" due to sustained intracellular water collection. A third type, "osmotic" brain edema is caused by osmotic imbalances between blood and tissue. Rarely after TBI do we encounter a "hydrocephalic edema/interstitial" brain edema related to an obstruction of cerebrospinal fluid outflow. Following TBI, various mediators are released which enhance vasogenic and/or cytotoxic brain edema. These include glutamate, lactate, H(+), K(+), Ca(2+), nitric oxide, arachidonic acid and its metabolites, free oxygen radicals, histamine, and kinins. Thus, avoiding cerebral anaerobic metabolism and acidosis is beneficial to control lactate and H(+), but no compound inhibiting mediators/mediator channels showed beneficial results in conducted clinical trials, despite successful experimental studies. Hence, anti-edematous therapy in TBI patients is still symptomatic and rather non-specific (e.g. mannitol infusion, controlled hyperventilation). For many years, vasogenic brain edema was accepted as the prevalent edema type following TBI. The development of mechanical TBI models ("weight drop," "fluid percussion injury," and "controlled cortical impact injury") and the use of magnetic resonance imaging, however, revealed that "cytotoxic" edema is of decisive pathophysiological importance following TBI as it develops early and persists while BBB integrity is gradually restored. These findings suggest that cytotoxic and vasogenic brain edema are two entities which can be targeted simultaneously or according to their temporal prevalence.     

Effects of dexamethasone on brain edema induced by kainic acid seizures

The histopathological alterations developing in the hippocampus, piriform cortex and thalamus of the rat brain, the blood-brain barrier damage, and the effects of dexamethasone pretreatment on the brain edema were investigated 4 h following intraperitoneal kainic acid administration. The most pronounced Evans Blue extravasation accompanied by increases in the water and sodium contents and a decrease in the potassium content, were observed in the thalamus. Dexamethasone, injected in a dose of 5 mg/kg 2 h before kainic acid administration, reduced considerably the vasogenic edema and neuronal damage in the thalamus, but the cytotoxic edema of the hippocampus and piriform cortex remained unaltered. Kainic acid-induced seizures lead to the development of vasogenic brain edema mainly in the thalamus, as well as to cytotoxic edema in the hippocampus and piriform cortex. The vasogenic edema seems to contribute to the cell damage in the thalamus. Dexamethasone reduces the vasogenic edema and cell damage in the thalamus, possibly by inducing the synthesis of certain protein(s) with antiphospholipase A2 activity.     

Protective effect of antihistamines on cerebral oedema induced by experimental pneumothorax in newborn piglets

As a consequence of general hypoxaemia evoked experimentally by bilateral pneumothorax, brain oedema of vasogenic type developed in newborn piglets after 4 h survival. Histamine receptor antagonists, mepyramine (H1-receptor blocker), metiamide, cimetidine and ranitidine (H2-receptor antagonists) were administered either intraperitoneally or intrathecally to check to what extent the formation of brain oedema could be reduced. Mepyramine and ranitidine decreased the accumulation of water, sodium and albumin in the parietal cortex. By measuring the concentration of histamine, the presence of a histamine pool was demonstrated in the cerebral microvessels. The results suggest that histamine, if released upon hypoxic injury from the microvascular store, can take an important part in the development of vasogenic brain oedema.     

Interactions between the brain renin-angiotensin system and brain prostanoids in the control of vasopressin secretion

Summary Experiments were carried out in conscious, unrestrained, male rats to evaluate possible interactions between brain prostanoids and the brain renin-angiotensin system in the control of vasopressin release and in cardiovascular regulation. The intracerebroventricular (icv) administration of prostaglandin D₂ (PGD₂) resulted in transient increases in the plasma vasopressin concentration (P_AVP) and heart rate and a gradual increase in mean arterial blood pressure (MABP). Pretreatment icv with saralasin, an angiotensin II-receptor antagonist, moderately attenuated the vasopressin response to PGD₂, but had no effect on the heart rate and blood pressure responses. Angiotensin II icv increased both P_AVP and MABP. This vasopressin response was almost completely prevented by prior icv meclofenamate, a cyclooxygenase inhibitor, and the blood pressure response was attenuated. These observations, combined with previous studies of the role of central angiotensin II and central prostanoids in the physiological control of vasopressin release, suggest that there may be important interactions between brain prostanoids and the brain renin-angiotensin system in this control.On leave from the Second Department of Internal Medicine, Tohoku University School of Medicine     

An energy-failure based brain edema concept

Brain edema concepts comprised interstitial, cytotoxic and vasogenic edema as three separate concepts. This is a theory of initiation of brain edema genesis arising from the neuron's cellular metabolism on the basis of energy failure by relative hyperglycolysis and resulting lactacidosis. It can describe edema genesis in trauma, hemorrhage, stroke and infections.     

The inflammatory reaction in human traumatic oedematous cerebral cortex

The inflammatory reaction surrounding hemorrhagic and perihematomal brain parenchyma has been studied by means of light and transmission electron microscopy in 12 patients with severe traumatic head injuries complicated with subdural or extradural hematoma or hygroma. Perivascular cells, ameboid phagocytic microglial cells, and infiltrated macrophage/monocyte system were observed surrounding perivascular and intraparenchymal hemorrhagic foci. They showed phagocytic activity of degenerated nerve cell processes, and organized proteinaceous edema fluid present in the enlarged extracellular space. Endocytosis by means of clathrin coated vesicles also was observed. Facultative and professional phagocytes exhibited a full repertoire of lysosomes, phagosomes containing nerve cell debris, lipid droplets, and lipofucsin granules. Phagocytic pericytes remaining within the capillary basement membrane were also observed around perivascular hemorrhages. The inflammatory reaction was examined in young and old patients with an evolution time of brain injury ranging from 1 day to 2 years. The inflammatory process developed according to the intensity of traumatic insult, patient age, associated hematoma or hygroma, severity of vasogenic and cytotoxic oedema, and anoxic-ischemic conditions of brain parenchyma.     

Up-regulation of endothelial endothelin-1 expression prior to vasogenic edema formation in the rat piriform cortex following status epilepticus

Endothelin-1 (ET-1) is one of potential factors to induce vasogenic edema formation, since exogenous ET-1 treatment decreases aquaporin 4 (AQP4) expression and increases chemokines induction. To identify the role of endogenous ET-1 in vasogenic edema formation, we examined the correlation between endogenous ET-1 expression and vasogenic edema formation in the pirifom cortex following status epilepticus (SE). In the present study, SMI-71 (a brain-blood barrier marker) immunoreactivity was significantly reduced in blood vessels at 1 day after SE when vasogenic edema and neuronal damage were observed. ET-1 expression was up-regulated in endothelial cells prior to reduction in SMI-71 immunoreactivity. Furthermore, ET-1 expressing endothelial cells showed the absence of SMI-71 immunoreactivity. Increase in ET-1 expression was followed by reduced AQP4 immunoreactivity prior to vasogenic edema formation. Only a few microglia showed monocyte chemotactic protein-1 (a chemokine induced by ET-1) outside vasogenic edema lesion. Taken together, our findings suggest that endothelial ET-1 expression may contribute to SE-induced vasogenic edema formation via brain-blood barrier disruption at AQP4/MCP-1 independent manners.     

Does edema formation occur in the rabbit brain exposed to head-down tilt?

Earlier studies showed that exposure to microgravity caused cephalad fluid shift, increased capillary pressure in the head, and produced facial edema and nasal congestion. In the present study, edema formation in the brain was investigated in rabbits exposed to simulated microgravity, head-down tilt (HDT), by measuring water content and histological examinations. Water content in the brain tissues of rabbits exposed to 2 and 8 days of HDT did not increase significantly compared with that of control animals. Neither vital staining using Evans blue nor immunohistochemical examination demonstrated extravasation of plasma constituents in the brain tissues of the HDT rabbits. Although marked congestion was noted in the brain, hematoxylin and eosin staining did not show edematous changes, such as distension of the perivascular and pericellular spaces and vacuolar appearance, in the tissues obtained from HDT rabbits. Transmission electron microscopy revealed that tight junctions of the capillary endothelium were intact in the HDT rabbits. These results suggest that either HDT up to 8 days does not cause brain edema in rabbits or it induces only a slight brain edema which is hard to be demonstrated by measurement of water content or histological examinations.     

Ontogenetic aspects of traumatic brain edema--facts and suggestions.

Diffuse brain swelling (DBS) after severe traumatic brain injury (TBI) occurs more commonly in children than adults. Most of the recent clinical studies suggest that young children are more negatively affected by DBS. Until now studies in young animals in which the pathophysiology of DBS was evaluated remained seldom. However, pathogenetic mechanisms of edema formation after TBI in the immature brain appeared to be different in comparison to adult brains. There are evidences that vasogenic as well as cytotoxic edema components may be responsible for the development of DBS. Besides mechanical disturbance, the blood-brain barrier seems to be strongly endangered by oxidative stress after TBI because regional antioxidative capacity is obviously diminished. In addition, cytotoxic components of DBS may be caused by at least two different mechanisms. First, it was shown that a sustained posttraumatic cerebral hypoperfusion occurs in the immature brain. Moreover, a transient increase of NMDA receptor expression at this period of life may be responsible for an increased threat of intracellular sodium ion accumulation in brain cells. Obviously, brain swelling can be detrimental because it can elevate intracranial pressure, impair CBF, and may represent ongoing secondary brain injury.     

Radiological and histological changes following cerebral venous sinus thrombosis in a rat model

Cerebral venous sinus thrombosis (CVST) is an important cause of stroke in young especially after pregnancy. We induced CVST in rat by topical application of ferric chloride over the exposed superior sagittal sinus (SSS) and pathological changes were monitored on days 1, 2 and 7. Thrombus weight was estimated and H&E staining was performed for comparison with MRI data. T2 weighted signal changes were present in all the study group rats. T2 hyper intensity decreased over the time. In study group, the apparent diffusion coefficient (ADC) was decreased by 31.94% on day 1 compared to the controls. There was 15.5% increase in the ADC value on day 2 compared to day 1 which reached almost equal to control value on day 7. On histological evaluation, neuronal necrosis and cellular infiltration were observed in cortical region after thrombosis. The early decrease in ADC could be attributed to cytotoxic edema that precedes vasogenic edema indicated by normalization of ADC and a decreased T2 hyper intensity. In conclusion, ferric chloride induced CVST in the rat produces cytotoxic edema in early stage followed by vasogenic edema which is related to recanalization of the superior sagittal sinus.     

Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy

Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT.     

The treatment of hyponatraemia using vasopressin antagonists

Hyponatraemia is a frequent electrolyte disorder. It is primarily attributable to vasopressin excess plus sustained fluid intake. Hyponatraemia causes CNS symptoms, especially during the first 2–4 days; these symptoms are related to brain swelling. Hyponatraemia occurs in the setting of liver cirrhosis and congestive cardiac failure, in which it is related to stimulation by low arterial blood pressure acting through baroreceptors. Hyponatraemia also occurs in the syndrome of inappropriate antidiuretic hormone secretion, usually from neoplasms releasing vasopressin. The conventional treatment of hyponatraemia used to be fluid restriction and treatment of the underlying disorder. This kind of treatment has been unreliable, cumbersome and difficult to comply with for the patient. In the future, effective vasopressin V₂ antagonists will become available for clinical use in the treatment of hyponatraemia, and are expected to improve the management of hyponatraemia. Pharmacological characteristics and observations of biological effects of three antagonists are reported in the present article.     

水通道蛋白-4在大鼠急性脑缺血再灌注脑组织中的表达

目的:探讨水通道蛋白-4(AQP4)在急性脑缺血再灌注脑组织中的表达规律。方法:线栓法建立右侧大脑中动脉栓塞(MCAO)模型,分为假手术组、栓塞组和再灌注组。对脑组织病理观察、TTC染色,免疫组织化学、原位杂交组织化学、荧光定量PCR和免疫印迹检测。结果:栓塞组在右侧基底节区见细胞器肿胀、细胞体积增大,但细胞膜和血脑屏障结构完整,TTC染色缺血面积明显增加。所有再灌注组右侧基底节区的细胞肿胀减轻,再灌注早期组可见轻度血管源性水肿,TTC染色缺血面积逐渐缩小。AQP4基因和蛋白的表达量明显下降,分别与栓塞组比较均存在显著性差异。再灌注后各组AQP4基因和蛋白表达明显下降,但均高于假手术组。结论:无论是脑缺血或是再灌注,AQP4的表达均与细胞内水肿的程度一致,再灌注早期可出现血管源性水肿,再灌注越早脑细胞越容易恢复正常。     

Pathophysiology of glioma cyst formation

Fluid filled cystic cavities are accompaniments of some cerebral gliomas. These tumoural cysts together with peritumoural vasogenic brain oedema add to the morbid effects of the gliomas in terms of mass effect and increased intracranial pressure. Although different mechanisms have been suggested as to the pathogenesis of glioma-associated cysts, it is still unclear why these cysts appear in only a limited number of cerebral gliomas while brain oedema, a probable precursor of glioma cysts, is a usual accompaniment of most gliomas. Here, the authors present a two-hit hypothesis of brain glioma cyst formation. We suggest that after the formation of vasogenic tumoural brain oedema, microvascular phenomena may lead to the formation of microcysts, which might later become confluent and grow to form macroscopic cysts. Progress in the understanding of pathogenesis of cerebral glioma cysts might set targets for treatment of brain edema and glioma cysts.     

Vasopressin- and oxytocin-induced activity in the central nervous system: electrophysiological studies using in-vitro systems

During the last two decades, it has become apparent that vasopressin and oxytocin, in addition to playing a role as peptide hormones, also act as neurotransmitters/neuromodulators. A number of arguments support this notion: (i) vasopressin and oxytocin are synthesized not only in hypothalamo-neurohypophysial cells, but also in other hypothalamic and extrahypothalamic cell bodies, whose axon projects to the limbic system, the brainstem and the spinal cord. (ii) Vasopressin and oxytocin can be shed from central axons as are classical neurotransmitters. (iii) Specific binding sites, i.e. membrane receptors having high affinity for vasopressin and oxytocin are present in the central nervous system. (iv) Vasopressin and oxytocin can alter the firing rate of selected neuronal populations. (v) In-situ injection of vasopressin and oxytocin receptor agonists and antagonists can interfere with behavior or physiological regulations. Morphological studies and electrophysiological recordings have evidenced a close anatomical correlation between the presence of vasopressin and oxytocin receptors in the brain and the neuronal responsiveness to vasopressin or oxytocin. These compounds have been found to affect membrane excitability in neurons located in the limbic system, hypothalamus, circumventricular organs, brainstem, and spinal cord. Sharp electrode intracellular recordings and whole-cell recordings, done in brainstem motoneurons or in spinal cord neurons, have revealed that vasopressin and oxytocin can directly affect neuronal excitability by opening non-specific cationic channels or by closing K(+) channels. These neuropeptides can also influence synaptic transmission, by acting either postsynaptically or upon presynaptic target neurons or axon terminals. Whereas, in cultured neurons, vasopressin and oxytocin appear to mobilize intracellular Ca(++), in brainstem slices, the action of oxytocin is mediated by a second messenger that is distinct from the second messenger activated in peripheral target cells. In this review, we will summarize studies carried out at the cellular level, i.e. we will concentrate on in-vitro approaches. Vasopressin and oxytocin will be treated together. Though acting via distinct receptors in distinct brain areas, these two neuropeptides appear to exert similar effects upon neuronal excitability.     

The pathology of cerebral edema

In a review of the literature dealing with cerebral edema the author analyzes concepts, pathogenetic mechanisms, and the recent classification into vasogenic and cytotoxic forms. The relationship between systemic and cerebral edema is discussed, as well as the effects of hydrocephalus. Among the factors with a significant relationship to cerebral edema, particular reference is given to intracranial hypertension, the cerebrospinal fluid, the blood-brain barrier, and the extracellular space.The criteria used in demonstrating the existence of edema of the brain at the gross, light microscopic, and ultrastructural levels are discussed, as well as essential biochemical alterations. The relationship of spongy encephalopathies to cerebral edema is analyzed and the conclusion drawn that at least some do indeed represent special forms of edema.The author stresses that more work on the mechanisms of resolution of cerebral edema needs to be done and concludes by outlining potentially useful avenues of investigation.     

Glycocalyx is critical for blood-brain barrier integrity by suppressing caveolin1-dependent endothelial transcytosis following ischemic stroke

The breakdown of the blood-brain barrier (BBB) is related to the occurrence and deterioration of neurological dysfunction in ischemic stroke, which leads to the extravasation of blood-borne substances, resulting in vasogenic edema and increased mortality. However, a limited understanding of the molecular mechanisms that control the restrictive properties of the BBB hinders the manipulation of the BBB in disease and treatment. Here, we found that the glycocalyx (GCX) is a critical factor in the regulation of brain endothelial barrier integrity. First, endothelial GCX displayed a biphasic change pattern, of which the timescale matched well with the biphasic evolution of BBB permeability to tracers within the first week after t-MCAO. Moreover, GCX destruction with hyaluronidase increased BBB permeability in healthy mice and aggravated BBB leakage in transient middle cerebral artery occlusion (t-MCAO) mice. Surprisingly, ultrastructural observation showed that GCX destruction was accompanied by increased endothelial transcytosis at the ischemic BBB, while the tight junctions remained morphologically and functionally intact. Knockdown of caveolin1 (Cav1) suppressed endothelial transcytosis, leading to reduced BBB permeability, and brain edema. Lastly, a coimmunoprecipitation assay showed that GCX degradation enhanced the interaction between syndecan1 and Src by promoting the binding of phosphorylated syndecan1 to the Src SH2 domain, which led to rapid modulation of cytoskeletal proteins to promote caveolae-mediated endocytosis. Overall, these findings demonstrate that the dynamic degradation and reconstruction of GCX may account for the biphasic changes in BBB permeability in ischemic stroke, and reveal an essential role of GCX in suppressing transcellular transport in brain endothelial cells to maintain BBB integrity. Targeting GCX may provide a novel strategy for managing BBB dysfunction and central nervous system drug delivery.     

Vasopressin-dependent short-term regulation of aquaporin 4 expressed in Xenopus oocytes

Aquaporin 4 (AQP4) is abundantly expressed in the perivascular glial endfeet in the central nervous system (CNS), where it is involved in the exchange of fluids between blood and brain. At this location, AQP4 contributes to the formation and/or the absorption of the brain edema that may arise following pathologies such as brain injuries, brain tumours, and cerebral ischemia. As vasopressin and its G-protein-coupled receptor (V1_aR) have been shown to affect the outcome of brain edema, we have investigated the regulatory interaction between AQP4 and V1_aR by heterologous expression in Xenopus laevis oocytes. The water permeability of AQP4/V1_aR-expressing oocytes was reduced in a vasopressin-dependent manner, as a result of V1_aR-dependent internalization of AQP4. Vasopressin-dependent internalization was not observed in AQP9/V1_aR-expressing oocytes. The regulatory interaction between AQP4 and V1_aR involves protein kinase C (PKC) activation and is reduced upon mutation of Ser¹⁸⁰ on AQP4 to an alanine. Thus, the present study demonstrates at the molecular level a functional link between the vasopressin receptor V1_aR and AQP4. This functional interaction between AQP4 and V1_aR may prove to be a potential therapeutic target in the prevention and treatment of brain edema.