Brain edema is a clinical problem seen in trauma, tumors, ischaemia, infections and other inflammatory problems. The term edema was first used to describe the wet and soft appearance of cut brain at autopsy. The tough and dry appearance was called brain swelling. The fluid can accumulate either inside the cells or extracellularly. 

Types of brain edema: 

Vasogenic type is due to BBB (blood brain barrier) changes and increased cell permeability. It is seen in trauma, tumors, inflammation and late ischemia. The extracellular space is enlarged; later stages the cells swell as well.

The CSF formation is not increased. Both the white and the grey matter are affected. 

Cytotoxic (brain swelling) type is an intracellular swelling due to derangement of Na+/K+ pump in the glial membrane and cell metabolism resulting in Na+ and H2O accumulation. This is seen in early ischaemia, and medical conditions such as Reye’s syndrome, intoxication etc.

The BBB is not disturbed. The CSF formation is not increased. Both the white and the grey matter are involved. 

Osmotic type is due to accumulation of excess water in the brain in response to an unfavorable osmotic gradient as in water intoxication. The chemical potential of the plasma increases and water enters the brain due abnormal gradient.

The BBB is intact. The CSF formation is increased. Both intra and extracellular compartments are affected. 

Hydrostatic type is due to movement of protein-free transudate into the extracellular space due to capillary dilatation as a result of elevated transcapillary pressure. Acute arterial hypertension is the usual cause.

The BBB is intact and the CSF formation is not increased. The edema is confined to the white matter.

Interstitial type is due to acute elevation of CSF pressure, resulting in periventricular (extracellular) seepage of water as in acute hydrocephalus. 

This is confined to the white matter. The BBB is undisturbed and the CSF formation is increased.

The differentiation among the above types is artifactual; one type will eventually lead to another, and considerable overlapping occurs. However, it helps for better understanding.

Pathophysiology: 

The breakdown of the BBB is a central prerequisite to the development of brain edema. Another basic element associated with brain edema is energy depletion.

Hydrostatic and osmotic forces encourage the movement of fluid out of the vascular compartment and into the parenchyma resulting in mass effect. This compromises the CBF, and the CPP. The ICP increases.

There is abnormal diffusion of nutrients with consequent acidosis, hypoxia, and inflammatory changes.

Any brain injury initiate a response characterized by recruitment of inflammatory cells and activation of endogenous substances also plays a part.

Histamine opens the BBB with dilatation of pial arterioles.

Bradykinin increases BBB permeability and enhances blood pressure in the microcirculation.

Excitatory aminoacids (EAA), glutamate activates many enzyme systems and Ca++ influx, which can result in acute cytotoxic lesions.

Arachidonic acid is released from brain tissue in response to neuronal injury. It is the precursor of important highly vasoactive prostanoid and leukotriene compounds. Its metabolism through cyclooxygenase pathway generates free radicals. These radicals induce vasoconstriction of the pial arterioles band venules without an effect on BBB permeability.

Superoxide radical, hydrogen peroxide, and hydroxyl radicals are formed from activated neutrophils and metabolites of arachidonic acid. They cause endothelial lesions with an increase in the ionic permeability. The radical initiate lipid peroxidation of glial, neuronal, and vascular cell membranes and myelin is catalyzed. If severe enough, it causes impairment of phospholipid dependent enzymes and membrane lysis.

Free calcium is released from its source by a variety of messenger systems. Glutamate opens the receptor gated Ca++ channels. Selective neuronal vulnerability in nonvascular brain lesions, hypoglycemic coma, epileptic seizures, or following brief periods of ischaemia is calcium related. Infarction is related to free radicals and acidosis, and the vascular lesions in stroke are the result of inflammatory reactions involving calcium, free radicals, and lipid mediators. 

Intracellular accumulation of calcium is accompanied by a loss of free intracellular Mg++, which may directly relate to the extent of cellular damage, which contributes to secondary injury. Mg++ is essential for membrane integrity, normal cell respiration, mRNA transcription, protein synthesis, and also plays a role in glucose utilization and energy metabolism.

Lactic acidosis due to lactic acid accumulation and increased pCO2 can denature the proteins and alter the activities of ph dependent enzymes. Lactate enhances brain edema.

Clinical features: 

Brain edema alone will not produce symptoms until the ICP reaches a level that produces local ischemia with or without mass effect.

The symptoms and signs are related to the lesion. 

Imaging: 

CT: Edema appears as a low-density area caused by dilution of all constituents of white matter by water. The decreased amount of lipids, increased proteins and electrolytes leads to underestimation of the amount of edema fluid based on the Hounsfield number printout. There is no contrast uptake. Edema is almost always visible in acute brain abscesses, but rarely in acute intracerebral hemorrhage. Finger-like projections of low-density areas are characteristic of a tuberculous abscess. The edema associated with intracerebral hematoma is located in the cortex and the underlying white matter whilst in acute subdural hematoma affects CT  MRI-T1  MRI-T2  CSF seepage in Hydrocephalus

both the white and grey matter. Extensive edema suggests highly malignant tumors.  MRI: It is very sensitive but not necessarily specific method for detecting lesions in cerebral white matter and thus brain edema; this is particularly relevant in tumoral perifocal edema. Prolongation of T2 can be a reflection of a pathological increase in tissue water and/or demyelination processes.  Post-traumatic perifocal edema is seen early on T2. 25% of single photon emission computer tomography (SPECT) scans fail to show alterations in BBB permeability.  Treatment:  The treatment has three objectives:  edema - pyogenic abscess Finger-like projections in Tb.ab  Minimal edema -Ac. hge.  extensive edema-high grade glioma

1) Surgical evacuation of masses or CSF diversion provides an immediate decompression of the intracranial space, helps to establish a favorable gradient between swollen tissue and CSF cavities, and washes proinflammatory agents.

Surgery for contusions is controversial. 

2) ICP Control

3) Brain protection:  

Energy failure, acidosis, alterations in calcium, cytotoxic and later vasogenic edema, free radical formation and excitotoxicity are the events that may lead to irreversible damage in a cerebral insult.

Brain protective measures aim at increasing the CBF (triple H therapy), providing adequate blood substrates such as oxygen, and glucose, and restoration of blood brain interface integrity. 

a) CBF augmentation: 

Triple-H therapy consists of augmentation of CBF by means of blood volume expansion, hemodilution, and pharmacologically induced hypertension. 

Hypervolaemic hemodilution is the first step. The blood viscosity should be maintained between 0.3 and 0.34 hematocrit. If the hematocrit falls below 0.3, packed cells should be given. Preferred solutions (5% or 20% albumin or fresh frozen plasma) are those that expand the intravascular space with less extracellular distribution. It is given in 4-6 divided doses/day, each administered over 30-60 minutes. Crystalloids remain in the intravascular space for only 60-90 minutes. 

If hemodilution does not produce the desired result, cardiac output may be enhanced with dobutamine before trying pharmacologically induced hypertension, which is associated with dangerous side effects. 

Pharmacologically induced hypertension may be instituted only after optimal intravascular volume and cardiac output enhancement. The systolic blood pressure may be elevated to160mm Hg in a previously normotensive patient and 180 in previously hypertensive patients. 

The triple H therapy is withdrawn gradually starting with hypertension and later the hypervolaemia once the desired result is achieved. Dopamine or epinephrine is commonly used. 

The hyperperfusion state of this therapy should be monitored by the patient's cardiac output through a pulmonary artery catheter. The CPP can best be monitored with an ICP monitor and concomitant use of arterial pressure monitor. Frequent laboratory analyses of the patient's hematocrit provide information on the hemodilution component of therapy. Often, the patient requires sedation and may also need endotracheal intubation and mechanical ventilation.  

The aim is to keep the hematocrit between 0.3 and 0.34, hemoglobin to 10-12 gm/dl, serum sodium at 135-145 mmol/l, serum osmolality at 290-300mOsm/l, and pulmonary wedge pressure at 14-18mm Hg. The CPP is to be maintained over 70mmHg.  

Tripe H therapy is an effective therapy for reversing the neurological deficit, especially in vasospasm associated with SAH and aneurismal surgery; it is potentially dangerous to other bodily systems. There is a 25% risk of pulmonary edema and 30% of the patients show aggravation of brain edema. Anemia and decreased oxygen carrying capacity are other undesirable side effects. 

This therapy is contraindicated in established infarction and severe brain or pulmonary edema and in anemic patients.  

A new strategy aiming to reduce the hydrostatic capillary pressure using dihydro-ergotamine combined with a b1-antagonist (metoprolol) and a2-agonist (clonidine) has recently been described. 

b) Attention to energy requirements: 

Hyperbaric oxygen therapy has been used in some centers. This increases O2 concentration in the inspired air and provides increased O2 to the injured brain. 100% O2 is used widely in pneumocephalus.

Long-term use of O2 therapy may result in acute respiratory distress syndrome (ARDS).

The blood glucose should be maintained at normal levels. Tissue acidosis as a result of lactic acid accumulation (due to anaerobic utilization of glucose), may affect the metabolic recovery. Ideally the glucose should be maintained at the normal level. There is no definite evidence to suggest hypoglycemia helps the recovery.   

Strict attention to fluid and electrolytes is mandatory. Sodium is the most important one.

Barbiturates, by depressing neuronal function, reduce CMR, CBF, and ICP. It has been found effective if given within 4 hours of the insult. They have profound cardiovascular depressive effect, which should be monitored. 

Etomidate, a short acting anesthetic, produces similar effects as barbiturates with minimal cardiovascular depressive effects. 

Hypothermia, by reducing CMR, the release of glutamate and other excitatory neurotransmitters, Ca++ influx, help edema formation. Profound hypothermia (22-24 degrees C) is associated with cardiac irritability, ventricular fibrillation, metabolic disturbances, coagulopathy etc. Mild hypothermia has been found useful. 

c) Restoration of blood brain interface integrity: 

Many compounds, most of them currently on trial, are claimed to stabilize BBB at the endothelial level. 

Steroids can inhibit lipid peroxidation and stabilize lysosomal membrane. Their effectiveness in post-traumatic and ischaemic edema is not proven; newly developed synthetic 21-aminosteroids (lazaroids) lack glucocorticoid and mineralocorticoid activity and are potent inhibitors of iron dependent lipid peroxidation. Alpha-21-aminosteroids (U-74006F) appears to have great potentials. 

Antioxidants, free radical scavengers, phospholipase inhibitors have been reported to increase oxygen consumption, glucose incorporation into amino acids, and phospholipid and GABA synthesis. Alpha-tocopherol (vitamin E) has beneficial effects on brain edema and ischaemia. It inhibits both fatty acid release and lipooxygenase activity and plays a fundamental role in the stabilization of polyunsaturated fatty acids in membrane phospholipids. It may also interact with cellular membrane and prevent peroxide formation by acting as hydrogen donor. Dimethylsulphoxide (DMSO) combined with mannitol possibly act as specific scavenger for hydroxyl radicals as can ascorbic acid (vitamin C), glutathione, catalase, superoxide dismutase (SOD). 

Indomethacin induces cylooxygenase inhibition, modulates arachidonic acid metabolism, and reduces peptidoleukotrienes, which are responsible for increased vascular permeability leading to edema. 

Nimodipine reduces calcium influx through voltage-sensitive channels; but has the hazard of producing hypotension. In high doses (60mgm every 4 hour), it is reported  to have beneficial effect on injured brain. Some studies  lately have found no benefit. Among other compounds trifluoperazine inhibits calcium binding to calmodulin and inhibits Ca++ mediated K+ efflux at synaptic membranes.

Beta adrenergic antagonists such as propanolol decrease lactic acid production and reduce edema. The adrenal response can be reduced by alpha-2- agonist clonidine. 

NMDA (N-Methyl-D-Aspartate) antagonists have shown the greatest neuro protective efficacy of any drug in ischaemia. Continuing clinical trials are on.