Development Of Cerebral Edema Research Articles

Perspectives on Neonatal Hypoxia/Ischemia-Induced Edema Formation

Neonatal hypoxia/ischemia (HI) is the most common cause of developmental neurological, cognitive and behavioral deficits in children, with hyperoxia (HHI) treatment being a clinical therapy for newborn resuscitation. Although cerebral edema is a common outcome after HI, the mechanisms leading to excessive fluid accumulation in the brain are poorly understood. Given the rigid nature of the bone-encased brain matter, knowledge of edema formation in the brain as a consequence of any injury, as well as the importance of water clearance mechanisms and water and ion homeostasis is important to our understanding of its detrimental effects. Knowledge of the pathological process underlying the appearance of dysfunctional outcomes after development of cerebral edema after neonatal HI in the developing brain and the molecular events triggered will allow a rational assessment of HHI therapy for neonatal HI and determine whether this treatment is beneficial or harmful to the developing infant.

The temporal relationship between glucose-corrected serum sodium and neurological status in severe diabetic ketoacidosis

ObjectiveCerebral oedema is a potentially devastating complication of diabetic ketoacidosis (DKA). The relationship between osmolar changes, acid–base changes and development of cerebral oedema during therapy is unclear.DesignRetrospective cohort study on...

Serum proinflammatory cytokines correlate with diffusion tensor imaging derived metrics and 1H-MR spectroscopy in patients with acute liver failure

Hyperammonemia and inflammation are major contributing factors in the development of cerebral edema (CE) in acute liver failure (ALF). Aim of this study was to look for the relationship between proinflammatory cytokines with diffusion tensor imaging (DTI) derived metrics and (1)H-MR spectroscopy ((1)H-MRS) derived Glutamate/Glutamine (Glx). Fourteen patients with ALF and 14 age/sex matched controls were included in this study. All subjects had undergone clinical, biochemical, MR imaging and (1)H-MRS studies. Serum proinflammatory cytokines (IL-6 and TNF-α), blood ammonia level and Glx were computed for independent t-test and Pearson correlation. Serum proinflammatory cytokines, blood ammonia level and brain Glx were significantly increased in ALF patients as compared to controls. Blood ammonia level and Glx showed significant positive correlation with proinflammatory cytokines. Spectroscopy voxel derived spherical anisotropy (CS) showed positive correlation with Glx while mean diffusivity (MD) showed negative correlation. Proinflammatory cytokines showed positive correlation with CS and negative correlation with MD in various brain regions including spectroscopy voxel. Significant correlation of Glx, CS and MD with proinflammatory cytokines suggests that both DTI derived metrics and (1)H-MRS measure the synergistic effect of hyperammonemia and proinflammatory cytokines and may be used as non-invasive tools for understanding the pathogenesis of CE in ALF.

Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction

Enhanced vascular permeability attributable to disruption of blood-brain barrier results in the development of cerebral edema after stroke. Using an in vitro model of the brain barrier composed of human brain microvascular endothelial cells and human astrocytes, this study explored whether small GTPase RhoA and its effector protein Rho kinase were involved in permeability changes mediated by oxygen-glucose deprivation (OGD), key pathological phenomena during ischemic stroke. OGD increased RhoA and Rho kinase protein expressions in human brain microvascular endothelial cells and human astrocytes while increasing or unaffecting that of endothelial nitric oxide synthase in respective cells. Reperfusion attenuated the expression and activity of RhoA and Rho kinase in both cell types compared to their counterparts exposed to equal periods of OGD alone while selectively increasing human brain microvascular endothelial cells endothelial nitric oxide synthase protein levels. OGD compromised the barrier integrity as confirmed by decreases in transendothelial electric resistance and concomitant increases in flux of permeability markers sodium fluorescein and Evan's blue albumin across cocultures. Transfection of cells with constitutively active RhoA also increased flux and reduced transendothelial electric resistance, whereas inactivation of RhoA by anti-RhoA Ig electroporation exerted opposite effects. In vitro cerebral barrier dysfunction was accompanied by myosin light chain overphosphorylation and stress fiber formation. Reperfusion and treatments with a Rho kinase inhibitor Y-27632 significantly attenuated barrier breakdown without profoundly altering actin structure. Increased RhoA/Rho kinase/myosin light chain pathway activity coupled with changes in actin cytoskeleton account for OGD-induced endothelial barrier breakdown.

Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments

Although a number of factors contribute to the high mortality and morbidity associated with traumatic brain injury (TBI), the development of cerebral edema with brain swelling remains the most significant predictor of outcome. The present review summarizes the most recent advances in the understanding of mechanisms associated with development of posttraumatic cerebral edema, and highlights areas of therapeutic promise. Despite the predominance of cytotoxic (or cellular) edema in the first week after traumatic brain injury, brain swelling can only occur with addition of water to the cranial vault from the vasculature. As such, regulation of blood-brain barrier permeability has become a focus of recent research seeking to manage brain edema. Aquaporins, matrix metalloproteinases and vasoactive inflammatory agents have emerged as potential mediators of cerebral edema following traumatic brain injury. In particular, kinins (bradykinins) and tachykinins (substance P) seem to play an active physiological role in modulating blood-brain barrier permeability after trauma. Substance P neurokinin-1 receptor antagonists show particular promise as novel therapeutic agents. Attenuating blood-brain barrier permeability has become a promising approach to managing brain edema and associated swelling given that increases in cranial water content can only be derived from the vasculature. Inflammation, both classical and neurogenic, offers a number of attractive targets.

Fluid management of hypernatraemic dehydration to prevent cerebral oedema: A retrospective case control study of 97 children in China

To compare the fluid management of hypernatraemic dehydration in acute gastroenteritis in those who developed cerebral oedema (cases) versus those who did not (controls). A retrospective study of 97 cases of hypernatraemic dehydration at a tertiary children's hospital in China over five years, in which rehydration regimes of 49 children who developed cerebral oedema were compared with 48 children who made an uneventful recovery. Risk factors for cerebral oedema (vs. no cerebral oedema) were an initial fluid bolus (29/49 vs. 15/48, P=0.006), the mean rate of bolus infusion (14.7+/-2.2 vs. 10.8+/-1.4 mL/kg/hr, P<0.001), the severity of hypernatraemia (serum sodium 167.7+/-7.8 vs. 161.3+/-7.9 mmol/L, P<0.001) and the overall rehydration rate (8.2+/-1.1 vs. 6.4+/-0.6 mL/kg/hr, P<0.001). On logistic regression, a rapid rehydration rate was the most significant contributor to cerebral oedema. From receive operating characteristic (ROC) curve analysis, the safe rate of rehydration was <6.8 mL/kg/hr. The key risk factors for the development of cerebral oedema during recovery from hypernatraemic dehydration were too rapid a rate of rehydration, an initial fluid bolus to rapidly expand plasma volume and the severity of the hypernatraemia. Thus, we conclude that a uniformly slow rate of rehydration is the best way of preventing cerebral oedema.

Life-threatening sodium valproate overdose: A comparison of two approaches to treatment*

To describe two identical cases of severe sodium valproate overdose treated with two different approaches. Case report and review of the literature. Two cases of identical life-threatening valproate (VPA) overdose with high VPA blood levels, markedly elevated ammonia levels and coma. One patient was treated with supportive therapy alone until the development of cerebral edema and seizures; the other was treated with immediate extended hemodialysis followed by high-volume hemodiafiltration. The first patient remained critically ill with elevated VPA and ammonia levels until the development of seizures and life-threatening cerebral edema. After the delayed application of hemofiltration, the patient slowly recovered to be discharged from intensive care on day 11. In contrast, the second patient's VPA and ammonia levels rapidly declined with hemodialysis and hemodiafiltration with rapid clinical improvement and intensive care discharge on day 3. In severe VPA overdose, early intervention with blood purification of suitable intensity was associated with a rapid reduction in VPA and ammonia levels and clinical improvement. This improvement was not seen with supportive therapy alone.

Paediatric diabetic ketoacidosis

Diabetic ketoacidosis (DKA) can occur with both types 1 and 2 diabetes mellitus, and is the leading cause of morbidity and mortality in children with diabetes. Unlike the adult population, paediatric mortality is mainly due to the development of cerebral oedema. This article will review the pathophysiology and complications of paediatric DKA and discuss the principles behind current treatment strategies.

Posterior Reversible Encephalopathy Syndrome and Cerebral Vasculopathy Associated With Influenza A Infection

Influenza A infection can precipitate encephalopathy, encephalitis, or Reye syndrome with the development of cerebral edema in children and is associated with an increased incidence of stroke in adults. The mechanism of these events is poorly understood. Posterior reversible encephalopathy syndrome (PRES) is seen in association with infection/sepsis, and cerebral vasculopathy has been demonstrated in PRES. We describe a case of PRES that develops in association with influenza A. A normotensive 65-year-old woman presented with altered mentation and nausea in the setting of a viral prodromal illness ultimately confirmed as influenza A. Posterior reversible encephalopathy syndrome developed on the second day after admission. Catheter cerebral angiogram documented vasculopathy in PRES-involved regions with areas of focal vessel dilatation and string-of-bead appearance. The association between influenza A and PRES with documentation of cerebral vasculopathy suggests a common systemic vascular mechanism behind PRES and influenza-related encephalopathic edema and stroke.

Extreme Hypernatremia Combined With Rhabdomyolysis and Acute Renal Failure

Rhabdomyolysis is a life-threatening condition that involves muscle cell destruction. Among its etiologies, severe hypernatremia is a less common cause. We report a teenage girl with congenital central hypoventilation syndrome and hypothalamus dysfunction syndrome who presented with extreme hypernatremia (sodium, 211 mmol/L) with rhabdomyolysis (creatine kinase, 32,850 U/L) and acute renal failure (creatinine, 6.1 mg/dL) following gastroenteritis with 7-kg weight loss. Rhabdomyolysis subsequently led to acute renal failure and hyperkalemia. Acute hemodialysis was initiated on hospital day 3 for hyperkalemia. This resulted in a 13 mmol/L fall in serum sodium in 3 hours despite using a 156 mmol/L sodium bath, but without the development of cerebral edema or neurological defect. This report highlights an unusual cause of rhabdomyolysis in children and the experience of managing such a difficult clinical situation.

Hypoplasia or Occlusion of the Ipsilateral Cranial Venous Drainage Is Associated With Early Fatal Edema of Middle Cerebral Artery Infarction

Thrombosis of the cerebral venous sinus may cause venous congestion, cerebral edema, and infarction. The role of cerebrovenous disorders in arterial ischemic stroke is unknown. The objective of this study was to examine the contribution of ipsilateral cranial venous abnormalities to the development of cerebral edema in middle cerebral artery infarction. This is a retrospective study of consecutive patients with large middle cerebral artery infarction admitted to our neurocritical care unit from January 2007 to October 2008. Medical records, laboratory data, and imaging of cerebral edema and cranial venous sinuses were analyzed. Of the 14 patients identified to have large middle cerebral artery infarction and images of cranial venous drainages, 5 (35.7%) had fatal edema with clinical signs of transtentorial herniation. Four of the 5 patients developed fatal edema within 48 hours of ictus and were found to have abnormal ipsilateral cranial venous drainage, including atresia of the transverse sinus (one), occlusion of the internal jugular vein (one), and hypoplasia of the transverse sinus and internal jugular vein (2). The fifth patient had symmetrical bilateral cranial venous drainages and fatal edema at Day 5. Of the 9 patients with nonmalignant middle cerebral artery infarction, all had ipsilateral dominant or symmetrical bilateral venous drainages. In this small case series, we demonstrated that only the patients with hypoplasia or occlusion of the ipsilateral cranial venous drainage developed early fatal edema after large middle cerebral artery infarction. Our results suggest a role of cranial venous outflow abnormalities in the development of brain edema after arterial ischemic stroke.

Microglial Low-Density Lipoprotein Receptor-Related Protein 1 Mediates the Effect of Tissue-Type Plasminogen Activator on Matrix Metalloproteinase-9 Activity in the Ischemic Brain

Studies in animal models of cerebral ischemia indicate that besides its thrombolytic effect, treatment with tissue-type plasminogen activator (tPA) also induces an increase in matrix metalloproteinase-9 (MMP-9) activity in the ischemic tissue associated with the development of cerebral edema. Earlier, we had shown that the low-density lipoprotein receptor-related protein 1 (LRP1) is a substrate for tPA in the brain. In this study, we investigated the effect of the interaction between tPA and microglial LRP1 on MMP-9 activity after middle cerebral artery occlusion (MCAO). We found that exposure to oxygen-glucose deprivation (OGD) conditions increases MMP-9 activity in wild-type (Wt) and plasminogen-deficient (Plg(-/-)) microglia, but not in tPA (tPA(-/-)) or LRP1-deficient (macLRP-) cells. Treatment with tPA increases MMP-9 expression in tPA(-/-) but not in macLRP- microglia. Middle cerebral artery occlusion increases MMP-9 expression and activity in Wt but not in tPA(-/-) or macLRP- mice, and treatment with tPA increases MMP-9 activity in tPA(-/-) mice but not in macLRP- animals. Finally, MCAO-induced ischemic edema and degradation of the interendothelial right junction protein claudin-5 were significantly attenuated in tPA(-/-) and macLRP- mice. The results of our study indicate that the interaction between tPA and microglial LRP1 increases MMP-9 expression and activity resulting in the degradation of claudin-5 and development of cerebral edema.

Temporal changes in expression of aquaporin3, -4, -5 and -8 in rat brains after permanent focal cerebral ischemia

Morbidity and mortality in stroke are attributed to cerebral edema. To date, six aquaporins (AQPs) have been found in rat brains. Whereas studies have been focused on AQP1, -4 and -9, little is known about the expression of AQP3, -5 and -8. To clarify roles of AQP3, -5 and -8 in water movement, we examined the expression patterns of AQP3, -5 and -8 in ischemic brains from the rats with permanent middle cerebral artery occlusion (pMCAO). We also investigated the expression of AQP4 after ischemia, which was used as a positive control. We found that the expression of AQP4 increased continuously until 24 h after pMCAO in both the ischemic core and the border region. The increased expression was correlated with brain swelling, whereas the expression of AQP3, -5 and -8 continued to increase until 24 h after pMCAO in the border region but decreased 6 h after pMCAO in the ischemic core. We also found AQPs were colocalized with GFAP-positive astrocytes and/or NeuN-positive neurons in rat brains. This is the first study describing the expression of AQP3, -5 and -8 in rat brains subjected to pMCAO. Our findings indicated that dynamic changes of AQP3, -4, -5 and -8 expression could contribute to the development of cerebral edema after brain ischemia. Besides, AQP3, -5 and -8 may be involved in the neuronal swelling.

Hyponatremia and Subarachnoid Hemorrhage: Will That Be One Pinch or Two of Salt?

Hyponatremia and Subarachnoid Hemorrhage: Will That Be One Pinch or Two of Salt?

Occult risk factor for the development of cerebral edema in children with diabetic ketoacidosis: possible role for stomach emptying

The incidence of cerebral edema during therapy of diabetic ketoacidosis (DKA) in children remains unacceptably high-this suggests that current treatment may not be ideal and that important risk factors for the development of cerebral edema have not been recognized. We suggest that there are two major sources for an occult generation of osmole-free water in these patients: first, fluid with a low concentration of electrolytes that was retained in the lumen of the stomach when the patient arrived in hospital; second, infusion of glucose in water at a time when this solution can be converted into water with little glucose. In a retrospective chart review of 30 patients who were admitted with a diagnosis of DKA and a blood sugar > 900 mg/dL (50 mmol/L), there were clues to suggest that some of the retained fluid in the stomach was absorbed. To minimize the likelihood of creating a dangerous degree of cerebral edema in patients with DKA, it is important to define the likely composition of fluid retained in the stomach on admission, to look for signs of absorption of some of this fluid during therapy, and to be especially vigilant once fat-derived brain fuels have disappeared, because this is the time when glucose oxidation in the brain should increase markedly, generating osmole-free water.

Exogenous Progesterone: A Potential Therapeutic Candidate in CNS Injury and Neurodegeneration

The role of progesterone (PROG) in the regulation of reproductive behavior is well understood, but a large and growing body of evidence indicates that this hormone also exerts neuroprotective effects on the central nervous system (CNS), i.e. in spinal cord injuries, traumatic brain injuries and in the age-related pathological process. Its neuroprotective actions, now well documented by experimental studies, make it a particularly promising therapeutic agent for neuroinjury and neurodegenerative diseases. The purpose of this article is to review recent preclinical and epidemiological evidences that exogenous administration of PROG or its metabolites plays an important role in the CNS. The diverse signaling mechanisms and the dose- dependent neuroprotective actions of PROG are also summarized. Awareness of the pleiotropic effects of PROG may open a novel perspective for the treatment of injuries and diseases in the nervous system. PROG could be produced in the brain by neurons and glial cells in the CNS of both male and female. Laboratories around the world have reported that administering relatively large doses of PROG during the first few hours or even days after injury significantly limits CNS damage, reduces loss of neuronal tissue and improves functional recovery. PROG appears to exert its protective effects by protecting or rebuilding the blood-brain barrier, decreasing the development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis. All these are plausible mechanisms of neuroprotection.

How rapidly does cerebral swelling follow trauma? Observations using an animal model and possible implications in infancy

To study the speed of development of cerebral edema in an animal model, five 2-year-old male anesthetized Merino sheep were impacted in the left temporal region by a humane stunner. Following the induction of blunt craniocerebral trauma a highly significant increase in intracranial pressure (ICP) values occurred relative to control animals (ANOVA, p < 0.001). An immediate increase in ICP to values over 20 mmHg occurred within the first 30 min, and by 60 min, mean ICP was over 25 mmHg ( p < 0.05 versus controls). ICP continued to increase with time such that by 4 h after injury, values were consistently greater than 30 mmHg ( p < 0.001 versus controls). The mean brain tissue oxygenation (P btO 2) in control animals over the 4 h monitoring period was 52 ± 8 mmHg with a highly significant (ANOVA, p < 0.001) and early decrease in P btO 2 recorded in impacted animals following craniocerebral trauma. By 30 min after injury, P btO 2 was approximately 35 mmHg, while by 60 min, it had decreased to 20 ± 2 mmHg ( p < 0.001 versus controls). The P btO 2 continued to decline with time such that by 4 h, the value was 14 ± 2 mmHg ( p < 0.01 versus controls), or 27% of the mean control values. These data demonstrate that vasoreactive changes with increased blood volume and interstitial transfer of fluid may occur rapidly within brain tissue after blunt trauma. Detection of cerebral swelling at autopsy may not, therefore, imply prolonged survival.

The brain in acute liver failure. A tortuous path from hyperammonemia to cerebral edema

Acute liver failure (ALF) is a condition with an unfavourable prognosis. Multiorgan failure and circulatory collapse are frequent causes of death, but cerebral edema and intracranial hypertension (ICH) are also common complications with a high risk of fatal outcome. The underlying pathogenesis has been extensively studied and although the development of cerebral edema and ICH is of a complex and multifactorial nature, it is well established that ammonia plays a pivotal role. This review will focus on the effects of hyperammonemia on neurotransmission, mitochondrial function, oxidative stress, inflammation and regulation of cerebral blood flow. Finally, potential therapeutic targets and future perspectives are briefly discussed.

Management of Diabetic Ketoacidosis in Children and Adolescents: Figure.

* Based on some research evidence, DKA is a significant contributor to morbidity and mortality in children who have type 1 diabetes, and cerebral edema is responsible for most of the deaths during DKA in children. (Dunger, 2004). * Based on strong research evidence, treatment of DKA requires replacement of water and electrolytes and correction of the insulin deficiency. (Dunger, 2004). * Based on some research data and consensus opinion, after providing initial volume expansion (if needed), fluid resuscitation of children who have DKA should be calculated to rehydrate evenly over at least 48 hours. Initial fluid resuscitation should be with an isotonic solution; subsequent fluid management should be with a solution that has a tonicity of at least 0.45% saline. (Dunger, 2004). * Based on strong research evidence, insulin treatment for DKA should begin at a dose of 0.1 units/kg per hour and generally should remain at or above this level until the ketoacidosis is resolved. (Dunger, 2004). * Based on some research evidence, risk factors for the development of cerebral edema during treatment of DKA include the severity of acidosis, greater hypocapnia (after adjusting for the degree of acidosis), higher blood urea nitrogen concentration at presentation, and treatment with bicarbonate. (Dunger, 2004; Glaser, 2002).

Tissue-type plasminogen activator and the low-density lipoprotein receptor–related protein induce Akt phosphorylation in the ischemic brain

AbstractTissue-type plasminogen activator (tPA) is found in the intravascular space and in the central nervous system. The low-density lipoprotein receptor–related protein (LRP) is expressed in neurons and in perivascular astrocytes. During cerebral ischemia, tPA induces the shedding of LRP's extracellular domain from perivascular astrocytes, and this is followed by the development of cerebral edema. Protein kinase B (Akt) is a serine/threonine kinase that plays a critical role not only in cell survival but also in the regulation of the permeability of the blood-brain barrier. We found that, in the early phases of the ischemic insult, the interaction between tPA and LRP induces Akt phosphorylation (pAkt) in perivascular astrocytes and inhibits pAkt in neurons. Coimmunoprecipitation studies indicate that pAkt and LRP's intracellular domain interact in perivascular astrocytes and that this interaction is dependent on the presence of tPA and results in the development of edema. Together, these results indicate that, in the early stages of cerebral ischemia, the interaction between tPA and LRP in perivascular astrocytes induces the activation of a cell signaling event mediated by pAkt that leads to increase in the permeability of the blood-brain barrier.