Physiopathology of brain edema

Brain edema (BE), defined as an increase in tissue water content leading to an increase in tissue volume, is a common histopathologic response associated with a number of acute and subacute brain lesions. In some cases BE is a result of an unbalance of physical forces, hydrostatic or osmotic gradients driving the water in the tissue (hypertensive encephalopathy, hydrocephaly, plasma hypoosmolarity). In most cases however BE is associated with complex brain tissue alterations. According to Klatzo (1967) two physiopathological types can be described: vasogenic edema follows a breakdown of blood brain barrier to proteins. Edema fluid enlarges the extra-cellular space and spreads within the white matter; cytotoxic edema is an intra-cellular retention of water due to various disorders of ionic balance across the plasmic cell membrane. In both cases the hydrostatic gradient between the vascular lumen and the tissue plays a major role in the amount and spread of the edema fluid. In both cases also, toxic substances produced by tissue destruction act as factors of secondary damage causing more blood brain barrier lesions and/or cellular membrane alterations and eventually enhance edema. In various pathological conditions vasogenic and cytotoxic edema are associated: edema around circumscribed lesions such as hematomas, traumatic contusions, tumors, abscesses is basically a vasogenic edema with a secondary cytotoxic component. Ischemic edema is initially a pure cytotoxic phenomenon with a secondary osmotic edema and lately a vasogenic component. The formation of BE leads to an increase in tissue pressure which may reduce local cerebral blood flow. If blood supply is already impaired this can lead to energy shortage and further tissue destruction. If the bulk of edema is large enough intracranial pressure rises up, brain shifts and herniations may occur. Hypertonic solutions and corticoids are the more widely used drugs against brain edema. Hypertonic solutions remove water from the normal brain and hence may reduce intracranial pressure rather than treat edema. Corticoids, through various discrete mechanisms interfere with some toxic substances, enhance energetic metabolism and allow tissue restitution with a rather limited effect on edema itself.     

Expression pattern of the water channel aquaporin-4 in human gliomas is associated with blood-brain barrier disturbance but not with patient survival

Aquaporin-4 (AQP4), the most prominent CNS water channel, is restricted to the glia limitans and astrocytic endfeet. We previously showed the loss of spatial AQP4 expression in glioblastomas and a redistribution across the cell surface. However, opposing AQP4 functions have been described: protective in vasogenic but detrimental in cytotoxic brain edema. Thus, specific AQP4 induction to prevent or reduce vasogenic edema is suggested. To elucidate the AQP4 role in brain tumors, we investigated 189 WHO grade I-IV gliomas by immunohistochemistry and the prognostic significance for patients' survival. In gliomas, a remarkable de novo AQP4 redistribution was observed in comparison with normal CNS tissue. Surprisingly, the highest membraneous staining levels were seen in pilocytic astrocytomas WHO grade I and grade IV glioblastomas, both significantly higher than in WHO grade II astrocytomas. AQP4 up-regulation was associated with brain edema formation; however, no association between survival and WHO grade-dependent AQP4 expression was seen. Hence, AQP4 redistribution may go along with other tumor properties, such as vascular proliferation and resulting blood-brain barrier disturbance, features usually prominent in pilocytic astrocytomas WHO I and glioblastomas WHO grade IV. In summary, our findings question the protective role of AQP4 in vasogenic brain edema. Although AQP4 was associated with brain edema formation, one has to question the suitability of AQP4 induction as a promising approach in vasogenic brain edema prevention and treatment. In addition, our results provide unexpectedly high AQP4 levels in pilocytic astrocytomas and present AQP4 as tumor progression marker in WHO grade II-IV astrocytomas.     

Role of extracellular proteins in the dynamics of vasogenic brain edema

Summary The relationship between extravasation of protein into extracellular spaces of brain parenchyma and the water content of such regions were evaluated in an experimental model. In this model, a temporary opening of the blood-brain barrier (BBB) to proteins was produced without significant injury to the cellular elements of brain tissue. Rabbits were subjected to bolus injection of their own blood under 360–400 mm Hg pressure via the internal carotid artery. The opening of the barrier and its duration were evaluated with Evans blue (EB), horseradish peroxidase (HRP), and sodium fluorescein (NaFl) tracers. The water content of brain tissue was assessed by specific gravity (SG) measurements in 1-mm-diameter tissue samples. Quantitative evaluation of protein penetration into brain tissue was carried out using¹²⁵I bovine serum albumin (BSA). The opening of the BBB to proteins persisted up to 9 h, whereas the barrier remained permeable to small molecular NaFl for 24 h. The SG measurements indicated in the areas of EB extravasation a progressive increment in water content up to 9 h, i.e., the duration of BBB opening to proteins. Following this, there was a progressive clearance of edema in spite of the BBB remaining open for NaFl for 24 h. Quantitative evaluations of¹²⁵I-BSA and SG in the same tissue samples, supported by statistical analysis, indicated approximately linear relationship between albumin and water, implying a strong correlation between the development of vasogenic edema and extravasation of proteins into extracellular spaces.     

Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia

Summary The mechanism of exacerbation of ischemic brain edema after blood flow restoration was studied in 20 cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow was measured by the hydrogen clearance method, and the left middle cerebral artery (MCA) was occluded for 6 h in group A, and for 3 h with subsequent 3 h recirculation in group B. Severity of brain edema was assessed by specific gravity measurement of tissue samples taken from coronal brain sections at the MCA area, while severity of blood-brain barrier (BBB) disruption was determined by measuring the amount of extravasated serum albumin by using [¹²⁵I]albumin and tissue-uptake method in the same samples as those used for gravimetry. Structural and ultrastructural change was correlated with the severity of ischemic brain edema and BBB disruption. The results obtained showed that: (i) ischemic brain edema observed in group A was not associated with BBB opening to serum proteins; (ii) ischemic edema in group B was exacerbated significantly after recirculation in correlation with serum protein extravasation in most of the postischemic area; (iii) in the severely edematous area, serum protein extravasation reached a plateau and morphological examination at this type of area revealed cell membrane disruption especially of astrocytes, with leakage of intracellular substances. Our study indicated that the increase of extracellular osmotic pressure due to leakage of serum proteins via the disrupted BBB and of intracellular substances via the ischemically injured cell membrane into the extracellular space is the mechanism responsible for edema fluid accumulation in exacerbated ischemic brain edema.     

Correspondence between development of cytotoxic edema and cerebrospinal fluid volume and flow in the third ventricle after ischemic stroke

ObjectivesThe importance of monitoring cerebrospinal fluid for the development of edema in ischemic stroke has been emphasized; however, studies on the relationship between intraventricular cerebrospinal fluid behavior and edema through longitudinal observations and analysis are rare. This study aimed to investigate the correlation between the development of cytotoxic edema and cerebrospinal fluid volume and flow in the third ventricle after ischemic stroke.Materials and methodsThe ventricle and edema regions were obtained using apparent diffusion coefficients and T₂ and subdivided into lateral/ventral 3rd ventricles and cytotoxic/vasogenic (or cyst) edema, respectively. In rat models of ischemic stroke, the volume and flow (via the pseudo-diffusion coefficient [D*]) of the ventricles and edema volumes were longitudinally monitored for up to 45 days after surgery.ResultsThe volume of cytotoxic edema increased in the hyperacute and acute phases, whereas the volume (r = -0.49) and median D* values (r = -0.48 in the anterior-posterior direction) of the ventral 3rd ventricle both decreased, showing negative correlations with the volume of cytotoxic edema. In contrast, the volume of vasogenic edema/cyst was positively correlated with the volume (r = 0.73) and median D* values (r = 0.78 in the anterior-posterior direction) of the lateral ventricle in the subacute and chronic phases.ConclusionsThis study showed that the evolution of cerebrospinal fluid volume and flow in the ventricles was associated with edema progression at different time points in the ischemic stroke brain. This provides an efficient framework for monitoring and quantifying the interplay between cerebrospinal fluid and edema.     

Vasogenic Edema of the Basal Ganglia after Intra-Arterial Administration of Nimodipine for Treatment of Vasospasm

The intra-arterial administration of nimodipine (IAN) is commonly used for cerebral vasospasm refractory to medical treatments. We report two cases of vasogenic edema after IAN. Our patients with aneurismal subarachnoid hemorrhage presented with vasospasm, which was treated by IAN. Consequently, vasogenic edema developed in the basal ganglia. Reperfusion following IAN for vasospasm may have the potential for inciting vasogenic edema in the ischemic brain.     

酶屏障抑制剂LB治疗血管源性脑水肿的实验研究

目的　观察酶屏障抑制剂ＬＢ对血管源性脑水肿（ＶＢＥ）的治疗作用。方法　Ｗｉｓｔａｒ大鼠腹腔注射苯肾上腺素制成ＶＢＥ模型,分别注射ＬＢ和甘露醇,用远红外线水份分析仪分别测量灰、白质水份含量。结果　ＬＢ对脑水肿有显著脱水作用,与甘露醇比较有显著差异（Ｐ＜ ０．０１）,尤其对白质的脱水作用更显著（Ｐ＜０．０１）。结论　酶屏障抑制剂ＬＢ对脑水肿,尤其对脑白质水肿有选择性治疗作用。是治疗ＶＢＥ的新方法。     

Use of diffusion tensor imaging to assess the vasogenic edema in traumatic pericontusional tissue

Background and objectiveCerebral edema is a frequent and serious complication of traumatic brain injury (TBI). Diffusion tensor imaging (DTI) is considered a useful technique to assess white matter integrity after TBI. The objective of this prospective, observational study was to assess the characteristics of the vasogenic edema in the traumatic pericontusional tissue and compare it to the vasogenic edema found in brain tumors. We also included a control group.MethodsUsing DTI, the Apparent diffusion coefficient (ADC) and Fractional anisotropy (FA) were measured in the area of vasogenic edema in both TBI and tumor patients. The measurements in the control group were done in the gray and white matter. We included 15 TBI patients, 18 tumor patients and 15 controls.ResultsADC and FA showed no differences between TBI and tumor patients (p = 0.27 for AF; p = 0.79 for ADC). Compared to healthy controls, TBI and tumor patients presented higher ADC values and lower FA values. The differences between TBI and controls were statistically significant (p < 0.05).ConclusionsIn this prospective observational study using DTI-MRI in a selected group of mild and moderate TBI patients with vasogenic pericontusional edema we have shown that there were no significant differences of the ADC and FA values compared to brain tumor patients. Furthermore, healthy controls showed significant lower ADC values and higher FA values compared to TBI and tumor patients. Future studies, using DTI-MRI, should address whether any therapy has a favorable impact on the vasogenic edema of TBI patients with brain contusions.     

Massive Cerebral Edema After Recanalization Post-Thrombolysis

BACKGROUND: Intravenous thrombolysis with tissue plasminogen activator is an approved and effective therapy for acute ischemic stroke within the first 3 hours from onset. In addition to the risk of hemorrhage, there is a risk of postrecanalization cerebral edema. The authors present the case of a patient with an ischemic stroke treated successfully with intra-arterial thrombolysis who subsequently developed massive brain edema in the face of clinical improvement. CASE: An 81-year-old man presented within 1 hour of developing a full right middle cerebral artery (MCA) syndrome. Computed tomography (CT) was normal. A cerebral angiogram demonstrated an occlusion of the M1 segment of the right MCA. The patient was treated with intra-arterial urokinase 750,000 units. He recovered during the procedure. Serial CT scans demonstrated progressive edema with mass effect in the right MCA distribution. The patient remained asymptomatic except for a mild sensory deficit. DISCUSSION: Postrecanalization cerebral edema is an uncommon but potentially lethal complication of thrombolysis. It is postulated that the edema is due to ischemic injury aggravated by reperfusion with vasogenic edema. The presence of this massive edema is usually associated with clinical worsening. The present case illustrates that this disorder can be associated with good outcome.     

Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement

Blood–brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.     

Classification of the cerebral edemas with reference to hydrocephalus and pseudotumor cerebri

Cerebral edema is a common clinical disorder that results from an abnormal increase in water content within the extracellular (EC) compartment of the brain. It is distinguished from two other types of brain bulk enlargement: (1) vascular swelling, caused by arterial dilatation or venous obstruction; and (2) cellular swelling, caused by cytotoxic injuries or metabolic storage. Under normal conditions, the EC compartment has two fluids, the interstitial fluid (ISF) and the cerebrospinal fluid (CSF), and extends from the blood brain barrier (BBB) through a series of 100 to 150-Å-wide intercellular spaces that are anatomically continuous with the CSF spaces. There are four primary types of EC edema: (1) vasogenic edema, which results from an increase in brain capillary permeability, the most common type, in which leakage of plasma constituents into the brain follows the pathways of ISF bulk flow and is governed by the interaction of systemic arterial pressure and tissue resistance; (2) osmotic edema, which results from an unfavorable osmotic gradient between the plasma and ISF across an intact BBB; (3) compressive edema, which results from obstruction of ISF bulk flow pathways; and (4) hydrocephalic edema, which results from obstruction of CSF bulk flow pathways. In this latter type of edema, distension of the collecting channels proximal to the block leads to retrograde flooding of the EC compartment with the formation of periventricular edema. The syndrome of pseudotumor cerebri includes several different types of brain bulk enlargement.     

Protective effects of AVS 1,2-bis (nicotinamido)-propane, against cold-induced brain edema: magnetic resonance imaging and spectroscopy

It was hypothesized that AVS 1,2-bis(nicotinamide)-propane, a free radical scavenger, could potentially be useful for the treatment of brain edema. Vasogenic brain edema was produced by freezing brain regions in 36 rats that had been treated with either AVS or saline. The efficacy of treatment was analyzed using proton magnetic resonance imaging (¹H MRI) and proton magnetic resonance spectroscopy (¹H MRS) of perchloric acid tissue extracts. T2-weighted MRI was obtained at 1 and 24 h after freezing. For ¹H MRS studies, rats were killed using liquid nitrogen and the extracted metabolites from the frozen hemispheres analyzed. ¹H MRI showed the edema lesion that indicated a region of a high signal intensity gradually extended and increased in intensity. Suppression of the edema development was observed in the AVS-treated group. Shortly after injury, the levels of acetate and lactate rapidly rose. Subsequently, the amino acid of alanine was also increased and N-acetyl aspartate and glutamine were markedly depressed. In AVS-treated rats, increases of lactate and alanine, and decreases of N-acetyl aspartate were statistically significant. We concluded that AVS is valuable for the treatment of vasogenic brain edema using these MR techniques.     

Glyburide is Associated with Attenuated Vasogenic Edema in Stroke Patients

Background

Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known.

Methods

Using a case–control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the glyburide advantage in malignant edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke.

Results

We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level.

Conclusions

Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial.     

Vasogenic edema in striatum following ingestion of glufosinate-containing herbicide

Glufosinate-ammonium (GLA) is a broad-spectrum herbicide used worldwide. We report a patient who attempted suicide by ingesting a liquid herbicide containing GLA. A diffusion-weighted MRI showed cytotoxic edema in the hippocampus as well as vasogenic edema in the striata. To our knowledge, vasogenic edema caused by GLA-containing herbicide involving the striatum has not been reported in association with cytotoxic edema in the hippocampus. We assume that this herbicide affected the central nervous system via different mechanisms to produce both cytotoxic and vasogenic edema in the same patient.     

The apparent diffusion coefficient does not reflect cytotoxic edema on the uninjured side after traumatic brain injury

After traumatic brain injury, vasogenic and cytotoxic edema appear sequentially on the involved side. Neuroimaging investigations of edema on the injured side have employed apparent diffusion coefficient measurements in diffusion tensor imaging. We investigated the changes occurring on the injured and uninjured sides using diffusion tensor imaging/apparent diffusion coefficient and histological samples in rats. We found that, on the injured side, that vasogenic edema appeared at 1 hour and intracellular edema appeared at 3 hours. Mixed edema was observed at 6 hours, worsening until 12–24 hours post-injury. Simultaneously, microglial cells proliferated at the trauma site. Apparent diffusion coefficient values increased at 1 hour, decreased at 6 hours, and increased at 12 hours. The uninjured side showed no significant pathological change at 1 hour after injury. Cytotoxic edema appeared at 3 hours, and vasogenic edema was visible at 6 hours. Cytotoxic edema persisted, but vasogenic edema tended to decrease after 12–24 hours. Despite this complex edema pattern on the uninjured side with associated pathologic changes, no significant change in apparent diffusion coefficient values was detected over the first 24 hours. Apparent diffusion coefficient values accurately detected the changes on the injured side, but did not detect the changes on the uninjured side, giving a false-negative result.     

Proton NMR relaxation times in ischemic brain edema

The state of water in cerebral ischemia was studied by using the proton nuclear magnetic resonance (1H-NMR) method. Cerebral ischemia was induced experimentally in Mongolian gerbils by unilateral ligation of the common carotid artery. Longitudinal (T1) and transverse (T2) relaxation times of the ischemic brain were measured with a pulse FT-NMR spectrometer and the water content was determined by the wet/dry method. Quantitative analysis of the relaxation times was performed sequentially during the initial 7 hours following ligation and the data were compared with those of brain edema previously reported by S. Naruse in the rat. Characteristic findings in brain ischemia include prolongation of the slow component of T2 and increase in the water content. A quantitative comparison of relaxation rate and water content demonstrates that ischemic brain edema in Mongolian gerbils is different from cytotoxic and vasogenic types of brain edema. When R2 (1/T2) was plotted against the water content, the slope value of ischemia in the gerbil was between the slope values of the TET intoxication and cold injury induced edemas reported previously. From these results, it might be said that ischemic brain edema includes both the cytotoxic and vasogenic types of brain edema. Glycerol was demonstrated to affect brain ischemia by decreasing the water content and by shortening the slow component of T2. By analysis of the relaxation times and water content, we examined the pathophysiological characteristics of water molecules in ischemic brain tissue.     

Ultrasound agents may open the blood–brain barrier in rats and aggravate pathologic consequences of experimental head trauma

Unilateral intracarotid injection of contrast agents may considerably destabilize the blood–brain barrier in rats. This leads to vasogenic edema in the ipsilateral hemisphere. Mortality and extravasation increased significantly when administration of these ultrasound contrast agents was followed by mild traumatic brain injury. Direct administration to the cerebral circulation is, therefore, indicative for edema‐related pathology and may amplify the consequences of experimental neurotrauma.     

Lack of evidence for direct involvement of NMDA receptors or polyamines in blood–brain barrier injury after cerebral ischemia in rats

It is hypothesized that after various types of brain injury, blood–brain barrier (BBB) opening and vasogenic edema result from excessive neuronal release of glutamate and stimulation of capillary N-methyl-d-aspartate (NMDA) receptors linked to polyamine (putrescine) synthesis in endothelial cells. We produced cerebral ischemia in rats and measured BBB opening 6 h later as the increase in regional transfer constants (K_i) for blood to brain diffusion of []sucrose. Such BBB opening was not mitigated by drugs which block NMDA receptors (MK801 or AR-R 15896AR) or polyamine synthesis (difluoromethylornithine). These results question generality of the capillary NMDA receptor/polyamine hypothesis.     

Regional brain polyamine levels in permanent focal cerebral ischemia

Transient global cerebral ischemia has been shown to induce marked changes in the polyamine pathway with a significant increase in putrescine, the product of the ornithine decarboxylase reaction. This study examined the relationship between tissue and extracellular polyamines and regional cerebral blood flow and brain edema. Six hours of focal ischemia in cats (n=10) was produced by permanent middle cerebral artery occlusion. Extracellular polyamines were measured in extracellular fluid obtained by microdialysis. Regional cerebral blood flow using laser Doppler flowmetry and specific gravity, an indicator of brain edema, were measured in contralateral (non-ischemic), penumbra and densely ischemic brain regions. A significant increase in the tissue putrescine level was found in the penumbra but there was no difference in the putrescine levels between contralateral and densely ischemic regions. There was no significant change in the spermidine and spermine levels in the three regions. Extracellular levels of putrescine and spermidine were found to be significantly lower than the tissue levels and no change in polyamines was observed in any region. Significant edema formation was observed in densely ischemic and penumbra regions. This is the first demonstration that tissue putrescine is increased in the penumbra region, an area of incomplete ischemia that is developing brain edema.     

Role of Circulatory disturbances in the development of post-ischemic brain edema

Two post-ischemic circulatory disturbances that play a significant role in pathophysiology of an ischemic lesion are: (1) reactive hyperemia or hyperperfusion and (2) hypoperfusion. The reactive hyperemia promptly follows release of major cerebral artery occlusion, and it is associated with the opening of the blood-brain barrier to serum proteins and ensuing edema. Prevention or reduction of reactive hyperemia results in significant amelioration of edema and the resulting ischemic brain tissue injury. The post-ischemic hypoperfusion, studied in gerbils, develops soon after recirculation and usually lasts up to 6 h. Its relationship to post-ischemic edema is evident in repeated ischemic insults. In these studies, three ischemic insults of 5 min duration when applied at 1 h intervals, i.e., during the period of hypoperfusion, resulted in a cumulative effect, post-ischemic edema and tissue injury becoming considerably more pronounced that those following a single 15 min ischemia. There was no cumulative effect when the ischemic insults were spaced 3 min or longer than 6 h apart. These observations indicate that repeated ischemic insults taking place during the phase of post-ischemic hypoperfusion may significantly increase the development of edema and brain tissue injury.