INTRODUCTION
Posttraumatic cerebral edema is a complex process. In 1905, Reichardt coined the word “brain edema” and described the difference from “brain swelling.”[1] The incidence is around 60% in trauma-related hematoma or mass lesion and around 15% without mass lesions.[2] Pappius and McCann[3] described cerebral edema as a special condition of the brain with excessive tissue volume due to the increase water content in the brain. The excessive tissue volume leads to increase in intracranial pressure (ICP) and decrease cerebral perfusion pressure (CPP), which eventually increases the mortality after traumatic brain injury (TBI). Cerebral edema is an independent predictor of increased mortality and morbidity after TBI.[4] In one study, the presence of cerebral edema was associated with in-hospital mortality rate of 63.8%. In the same study, the cerebral edema itself caused an eight-fold increase in mortality among all severity of TBI and a five-fold increase in mortality in mild TBI group.[5] In cases of TBI, early removal of contused brain tissue or hematoma reduces cerebral edema as the presence of contusion or hematoma releases various mediators of cerebral edema.
BACKGROUND AND PATHOPHYSIOLOGY
Diverse pathways are involved in the development of cerebral edema after brain injury. Mainly two types cerebral edema occur after TBI-vasogenic edema and cytotoxic edema. Vasogenic edema is the fluid accumulation in interstitial space, and cytotoxic edema is swelling of the cells. Cytotoxic edema occurs due to the involvement of different pathways or ionic channels and correlates with the secondary type of brain injury.[6] Vasogenic edema develops due to disruption of the blood-brain barrier (BBB) or altered permeability of BBB and correlates with the level of impact and activation of molecular pathways related with neuroinflammation. Occasionally, mixed type of cerebral edema exits due combination of the vasogenic and cytotoxic component.
CYTOTOXIC BRAIN EDEMA
Cytotoxic cerebral edema is due to the accumulation of water in the intracellular space and a complex process.[7] Various intracellular organelles are involved in the process at different stages. Mitochondria play a major role in cellular energy management through the regulation of adenosine triphosphate. Mitochondria mainly cause cytotoxic edema due to the involvement of oxidative metabolism. Mitochondrial damage causes neuronal swelling: cell body as well as axon.[8]
Aquaporin
Mainly two molecular types of aquaporin is present in the brain: Aquaporin type 1 and type 4 and it controls the bi-directional water movement across the cell.[9] Aquaporin type 4 is involved in both vasogenic and cytotoxic brain edema and present at the astrocyte foot process.[10] The definite role of AQP-4 in both type cerebral edemas is still controversial. In general, aquaporin 4 eliminate the water from the cell. There is down-regulation of AQP-4 after TBI. Hence, a smaller number of channels are available to eliminate intracellular water, resulting in vasogenic cerebral edema. Few studies revealed up-regulation of aquaporin 4 after 72 h of head injury causing severe cytotoxic edema.[11][12][13][14] In a study by Ke et al.,[15] down-regulation of AQP4 was noted in contused part of brain parenchyma after 1 day without any AQP4 expression change in remote part of the brain (ipsilateral basal ganglia and contralateral cortex). Conversely, Zhao et al.[16] found reduced AQP4 in the injured brain parenchyma and more expression in the surrounding (penumbra).
Sulfonylurea-receptor 1-transient receptor potential member 4
Sulfonylurea-receptor 1 is a hetero-octameric channel. Normally absent in brain and potentially up-regulated in astrocyte, neurons, and endothelial capillary cells after head injury.[17][18]
Glutamate
Glutamate is mainly responsible for cytotoxic edema.[19] After the TBI, the concentration of glutamate will increase in brain and cause cytotoxic edema through EAAT1/2 channels along with co-transport of sodium and water.[20] The other mechanism is via the NMDA receptor. Ionotropic NMDA receptor will increase the intracellular influx of sodium and calcium leading to more edema.[7]
Na+-K+-2Cl− cotransporter (NKCC1)
NKCC1 is a special type ion channel present in brain and uses an ionic gradient for transport of Na+, K+, and Cal- across the neural membrane.[21] In the early phase after TBI, NKCC1 channel is increased in number leading to more K + in the extracellular space along with water.[22] All contribute to the formation of cytotoxic edema. For the progression of edema, NKCC1 channel uses the mitogen-activated protein kinase pathway after TBI.[23]
Arginine vasopressin
Arginine vasopressin is the type of protein present in astrocyte, neural cell, and endothelial cell.[24] Arginine vasopressin cause more cytotoxic edema around the lesion and through the up-regulation of the AQP4-related pathway.[25]
Histamine
Histamine is a potent neurotransmitter for BBB disruption. The common H2 receptor is present in vascular endothelium and involved in the regulation of nitric oxide. After brain injury, histamine via H2 receptor usually causes BBB break-down and release of nitric oxide. Overall, all contribute to brain edema.[1][26][27]
Erythropoietin
Erythropoietin is the type of neuroprotector after brain injury. It acts through AQP4 subtype of receptor. In experimental head injury model,[28] erythropoietin showed restoration of BBB and reduction of vasogenic brain edema. Erythropoietin preserves the tight junction protein zona occludens 1 (ZO-1) in BBB and start as early as 1 h after administration and persist for 4 days. Erythropoietin also restores the expression of AQP4 receptor in animal TBI model and reduced cytotoxic edema via clearance of water.
VASOGENIC CEREBRAL EDEMA
The BBB is the key structure related to vasogenic edema. Principally, two mechanisms are involved in vasogenic edema either disruption of BBB or alteration of permeability of BBB.[7] After disruption of BBB due to direct mechanical trauma, K+ ion enters the brain from blood causing increased K+ ion concentration in the brain. The high K+ ion concentration disturbs the osmotic gradient across blood and brain leading to an influx of more water inside the brain. Due to direct trauma, the cellular destruction will happen, and intracellular protein concentration will increase. The high protein concentration can alter the osmotic gradient across brain and blood resulting in the excessive influx of water inside the cell.[29][30][31] The additional molecular pathway involved in distortion of BBB is the release of metalloproteinases (MMP) after head injury. The MMPs are endopeptidases and cause the degradation of zona occludens of tight junction of BBB after brain injury. The MMP-2, -3, -9 expressions are elevated after TBI. The MMP-2,-9 can cause damage of Z-1, claudin-5, and occludin of BBB leading to increased permeability of BBB.[29] Few studies reported up-regulation of MMP-2 after 72 h of injury-related disruption of the BBB.[7][32][33]
Neuroinflammation also plays a role in vasogenic edema after head injury. After brain insult, astrocyte, neuron and endothelial cell release various inflammatory markers such as tumor necrosis factor (TNF), interleukins (IL) 6 and I beta. All these proinflammatory markers damage the BBB either directly or indirectly.[34][35] Laird et al. reported that high mobility group box protein-1 act on toll-like receptor-4 and induce IL-6 up-regulation leading to recruitment of more AQP4 and vasogenic edema.[36] TNF also acts on BBB and cause actin stress fiber formation as well as down-regulation of occludin protein. The actin fiber stress fiber formation causes the endothelial cell retraction and intercellular gap by the myosin light chain kinase.[37][38] The above said mechanism needs further proof in animal head injury model. Vascular endothelial growth factor A (VEGF-A) is a glycoprotein and upregulated significantly in astrocyte and endothelial cell, in animal TBI model. The VEGF acts on VEGF receptor 1 and down regulates occludin and claudin-5 protein at the tight junction of BBB.[39][40] Intercellular adhesion molecule-1 (ICAM-1) is the other adhesion molecule release from vascular endothelium within 4 h from injury and allow the peripheral immune cells (neutrophil, monocyte, and lymphocyte) enter the BBB leading to more inflammation and edema.[7][19]
The other predominant mechanism of vasogenic edema is change in the BBB permeability. Two types of protein cause the change: tachykinin and bradykinin.
Substance P
Substance P is a type of tachykinin present in sensory C fibers around the blood vessels inside the brain.[41] It helps in neurogenic inflammation and altered vascular permeability and increases the cerebral edema.[42][43] High serum level of substance P was related to more mortality.[44] The substance P acts through neurokinin-1 receptor and after TBI there is increased expression of neurokinin-1 receptor. Activation of neurokinin-1 receptor cause stimulation of astrocytic cell.[45] Stimulation of astrocytic cell leads to more proinflammatory mediators and increased cerebral edema.
2/Bradykinin
Bradykinin is a peptide that acts through two types of receptors B1 and B2. Both the receptors are upregulated after TBI within 24 h, and bradykinin acts through the B2 type receptor. The B2 type receptor causes cerebral edema.[46][47][48] In an animal study, bradykinin level was measured in tissue and noted maximum after 2 h of injury and up-regulation of B1 and B2 receptor after 24 h of injury. On the contrary, in B2 knock out animal (mice) model, the amount of cerebral edema was less.[47] Kunz et al.[48] in their study reported in an animal study that serum bradykinin level peak within 24 h and normalize with 96 h after head injury. Deltibant (Bradycor™) a selective B2 receptor blocker was used in patients with TBI and was found to have a positive correlation with clinical outcome and ICP.[49] The role of bradykinin and its receptor in cerebral edema formation and progression has been investigated and established in various studies.[47][48][49]
MANAGEMENT AND FUTURE RESEARCH DIRECTION
As the posttraumatic cerebral edema is a multi-pathway phenomenon, the aim of treatment should be in a phased manner. As the cerebral edema increases ICP and decreases the CPP, priority should be control of ICP by curtailing the progression of cerebral edema.[50]
Management of increased increase intracranial pressure
According to the pressure-volume curve of ICP, minimal increase in intracranial volume leads to an exponential increase in ICP after reaching the threshold level. Hence, after TBI, minimal increase in water content in brain parenchyma either by vasogenic edema or cytotoxic contributes to substantial increase in the ICP and decrease in the CPP.[51]
Management of cerebral edema constitutes of medical and surgical intervention. The basic therapeutic measures start with head end elevation, hyperventilation, sedation, CSF drainage and hyperosmolar therapy or osmotic diuresis. Hyperosmolar therapy[52] in the form hypertonic saline is mainly used for the cerebral edema and mannitol for osmotic diuresis. Mannitol acts as an osmotic agent but also help to improve the regional cerebral blood flow and CPP. Hypertonic saline is the other alternative agent and usefulness in comparison to mannitol is debatable. Hypertonic saline causes the osmotic gradient across the BBB and draws water from intracellular or interstitial space. Another action is an expansion of vascular volume and mean arterial pressure (MAP). The high MAP will cause vasoconstriction in cerebral blood vessels and decrease in the brain blood volume and ICP. Hypertonic saline also causes the alteration of arginine vasopressin levels in plasma, thus indirectly reduces the cytotoxic edema. The advantages of hypertonic saline over mannitol are the longer duration of action and consistent reduction ICP and improvement in CPP. The complication associated with mannitol therapy is rebound cerebral edema and electrolyte disturbance. Hypertonic saline also has a similar problem and strict electrolyte monitoring in mandatory with hypertonic saline therapy.[53]
Surgical intervention is an option for the treatment of the refractory cerebral edema. Qiu et al.[54] reported unilateral decompressive craniectomy had superior outcome and control of ICP in posttraumatic cerebral edema with midline shift >5 mm. Polin et al.[55] reported a study of bifrontal decompressive craniectomy for posttraumatic cerebral edema and 37% of patients had good recovery or moderate disability outcome. They also found that children had a superior outcome in comparison to an adult patient. Schneider et al.[56] reported 22.5% mortality, and good recovery or moderate disability in 77.4% of patients. Aarabi et al.[57] published a better outcome with decompressive craniectomy for intractable cerebral edema with 28% mortality and 40% good recovery. They also reported a systemic review of decompressive craniectomy for posttraumatic cerebral edema, a total of 323 patients were included in the analysis. The mortality rate was 22.3%, superior outcome in 48.3%, and vegetative state in 29.4.
Agent blocking the progression of cerebral edema
AQP-4 antagonist used in the animal model has shown a reduction of ICP without alteration of brain water content.[2][58] Glibenclamide[59] is a sulfonylurea-receptor 1-transient receptor potential member 4 channel blocker and reduced the regional edema, ICP and BBB disruption in the preclinical study. SR49059 and V1880 are the V1a and V1 receptor blocker and useful in the reduction of brain water content and ICP in the preclinical study.[24][60] Bumetanide is an NKCC1 receptor blocker and in TBI model (in vivo) showed a reduction in astrocyte swelling, cellular swelling, and BBB disruption.[21][58]
Maintenance of BBB permeability is another aspect of control of cerebral edema. ML-7 is an MLCK blocker and reduces the myosin mediated contraction of endothelial cell of BBB and reduces permeability. In an animal model ML-7 showed a reduction of cytotoxic edema and improved neurological outcome.[61][62] MMP-9 inhibition is an important step in controlling the progression of edema. SB-3CT is an active inhibitor of MMP-2 and MMP-9 and has been used in a preclinical model of head injury. Study result showed reduced MMP-9 activity, microglial activation, and protection from hippocampal and cortical damage.[63][64] Curcumin is an anti-inflammatory and neuroprotective agent and acts through AQP-4 down-regulation, inhibition of ICAM-1, vascular cell adhesion molecule-1, and protects the tight junction protein (ZO-1, occludin, and claudin-5). In a preclinical study, curcumin showed a significant reduction in brain water content and AQP-4 expression.[65][66] N-acetyl-L tryptophan (NAT) is NK1 tachykinin receptor blocker and reduces the BBB permeability. In an animal model, NAT was administered 30 min after injury and significantly reduced the ICP.[67][68] No proper human trial is available with the above-mentioned agent. A study by Soltani et al.[69] found that estrogen or progesterone when used alone reduce cerebral edema via reduced expression of AQP4 and IL-6 but when used in combination the beneficial effect was attenuated. Adjudin is a male contraceptive used in the head injury animal model and found to be effective in cerebral edema. It acts on the NF-kB pathway and reduces neuroinflammation. It also causes the reduction of gene expression of AQP-4 and has a protective effect on BBB.[70]
CONCLUSION
Posttraumatic cerebral is a complex phenomenon and involves multiple cellular pathways. Cytotoxic and vasogenic cerebral edema are grossly two types, but mixed features are also found. The various substances are involved in the formation of either type of cerebral edema and can be targeted for management of the progression of cerebral edema. Medical management (osmotic diuresis or hyperosmolar therapy) is the initial step to control the edema and ICP. In refractory cases, surgical intervention (decompressive craniectomy) has shown superior control of ICP.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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