Presented by Dr Mohammed atif

CEREBRAL EDEMA
Cerebral edema or cerebral oedema is an excess

accumulation of water in the intracellular and/or extra cellular spaces of the brain. In fact cerebral edema is the main cause of morbidity in patients who have had brain injuries due to head trauma, stroke and other conditions. Patient who are brought for head injury are tested and observed immediately for the possibility of CEREBRAL EDEMA. Since it is a serious and early detection could make a big difference, doctors would not want to take any chances in spotting this ailment.

Pathophysiology of cerebral edema at cellular PATHOPHYSIOLOGY level is complex. Damaged cells swell, injured blood vessels

leak and blocked absorption pathways force fluid to enter brain tissues. Cellular and blood vessel damage follows activation of an injury cascade. The cascade begins with glutamate release into the extra cellular space . Calcium and sodium entry channels on cell membranes are opened by glutamate stimulation. Membrane ATPase pumps extrude one calcium ion exchange for 3 sodium ions. Sodium builds up within the cell creating an osmotic gradient and increasing cell volume by entry of water. Increase in water causes dysfunction but not necessarily permanent damage. Finally, hypoxia depletes the cells energy stores disabling the sodium - potassium ATPase and reducing calcium exchange [2].

Because of failure of the energy-dependent sodium pump in the cellular membrane, sodium accumulates intracellularly and water moves from the extra cellular to the intracellular space to maintain osmotic equilibrium [3]. Calcium accumulates inside the cell activating intracellular cytotoxic processes. An inflammatory response is initiated by the formation of immediate early genes such as c-foc and c-jun and cytokines and other intermediary substances. Microglial cells are activated and release free radicals and proteases which contribute to the attack on cell membranes and capillaries. Once the membranes are disrupted recovery of the cells is impossible [2].

Free radicals are toxic to cells. Reactive oxygen species such as super oxide ion, hydrogen peroxide and hydroxyl ion are produced by the arachidonic acid cascade. Release of fatty acids such as arachidonic acid provides a supply of damaging molecules [2]. Nitric oxide (NO) is also a source of free radicals. Macrophages and activated Microglial cells form NO through the action of inducible or immunological NO synthetase (iNOS) [2].

To explain the consequences of cerebral edema in the simplest terminology, it is best to take the help of Monro-Kelie hypothesis, which says that the total bulk of three elements (inside the skull) i.e. brain - 1400 ml, cerebral spinal fluid (CSF) 150 ml and blood 150 ml is at all times constant. Since skull is like a rigid box which cannot be stretched - if the volume of one of these components increases, it will force the reduction of volume of the other components. So if there is excessive water, the volume of brain as well as blood inside the skull is compressed. Conversely, primary blood flow disturbances also lead to brain edema [6]. As the brain, blood or CSF volumes continue to increase, the accommodative mechanisms fail and intracranial pressure (ICP) then rises exponentially. Greatly raised ICP eventually causes a reduction in cerebral blood flow throughout the brain. In its most severe form the widespread ischemia produces brain death.

ETIOLOGY in following neurological Cerebral edema is seen

1.NEUROLOGICAL CONDITIONS: Ischemic stroke and intra cerebral hemorrhage

Brain tumors Meningitis and encephalitis of all etiologies Other brain infections like TB ,Cysticercosis, and toxoplasma

2. NON NEUROLOGICAL CONDITIONS Diabetic ketoacidosis, lactic acidotic coma Malignant hypertension, hypertensive encephalopathy Fulminant viral hepatitis. Hepatic encephalopathy

Reyes syndrome Systemic poisoning ( carbon mono oxide and lead ) Hyponatremia SIADH Opoid drug abuse and dependence Bites of certain reptiles and mammals High altitude cerebral edema

TYPES
1.

Vasogenic cerebral edema

2. 3. 4.

Cytotoxic cerebral edema Osmotic cerebral edema Interstitial cerebral edema

1. Vasogenic cerebral edema

Due to a breakdown of tight endothelial junctions which make up the blood-brain barrier (BBB). This allows normally excluded intravascular proteins and fluid to penetrate into cerebral parenchymal extra cellular space. Once plasma constituents cross the BBB, the edema spreads; this may be quite fast and widespread. As water enters white matter it moves extracellularly along fiber tracts and can also affect the gray matter. This type of edema is seen in response to trauma, tumors, focal inflammation, late stages of cerebral ischemia and hypertensive encephalopathy.

Some of the mechanisms contributing to BBB dysfunction are: physical disruption by arterial hypertension or trauma, tumorfacilitated release of vasoactive and endothelial destructive compounds (e.g. arachidonic acid, excitatory neurotransmitters, eicosanoids, bradykinin, histamine and free radicals). Some of the special subcategories of Vasogenic edema include:

 Hydrostatic cerebral edema

This form of cerebral edema is seen in acute, malignant hypertension. It is thought to result from direct transmission of pressure to cerebral capillary with transudation of fluid into the ECF from the capillaries. Cancerous glial cells (glioma) of the brain can increase secretion of vascular endothelial growth factor (VEGF) which weakens the junctions of the blood-brain barrier. Dexamethasone can be of benefit in reducing VEGF secretion[2].

Cerebral edema from brain cancer

 High Altitude Cerebral Edema

High altitude cerebral edema (or HACE) is a severe form of (sometimes fatal) altitude sickness. HACE is the result of swelling of brain tissue from leakage of fluids from the capillaries due to the effects of hypoxia on the mitochondria-rich endothelial cells of the blood-brain barrier[3]. Symptoms can include headache, loss of coordination (ataxia), weakness, and decreasing levels of consciousness including disorientation, loss of memory, hallucinations, psychotic behavior, and coma. It generally occurs after a week or more at high altitude. Severe instances can lead to death if not treated quickly. Immediate descent is a necessary life-saving measure (2,000 4,000 feet). There are some medications (e.g. Dexamethasone) that may be prescribed for treatment in the field, but these require proper medical training in their use. Anyone suffering from HACE must be evacuated to a medical facility for proper follow-up treatment. A gamow bag can sometimes be used to stabilize the sufferer before transport or descending. Climbers may also suffer high altitude pulmonary edema (HAPE), which affects the lungs. While not as life threatening as HACE in the initial stages, failure to descend to lower altitudes or receive medical treatment can also lead to death.

2. Cytotoxic cerebral edema

edema is due to the derangement in cellular metabolism resulting in inadequate functioning of the sodium and potassium pump in the glial cell membrane. As a result there is cellular retention of sodium and water. There are swollen astrocytes in gray and white matter. Cytotoxic edema is seen with various intoxications (dinitrophenol, , hexachlorophene, isoniazid), in Reye's syndrome, severe hypothermia, early ischemia, encephalopathy, early stroke or hypoxia, cardiac arrest, pseudo tumor cerebri, and cerebral toxins.

3. Osmotic cerebral edema

fluid (ECF) osmolality of the brain is slightly greater than that of plasma. When plasma is diluted by excessive water intake (or Hyponatremia), syndrome of inappropriate antidiuretic hormone secretion (SIADH), hemodialysis, or rapid reduction of blood glucose in hyperosmolar hyperglycemic state (HHS), formerly (HONK), the brain osmolality will then exceed the serum osmolality creating an abnormal pressure gradient down which water will flow into the brain causing edema.

4. Interstitial cerebral edema

Occurs in obstructive hydrocephalus. This form of edema is due to rupture of CSF-brain barrier resulting in trans-ependymal flow of CSF; this permits CSF to penetrate brain and spread in the extra cellular space of white matter. Differentiated from Vasogenic edema

in that fluid contains almost no protein.

CLINICAL FEATURES
A high index of suspicion is very important. The

features of cerebral edema add on to and often complicate the clinical features of primary underlying conditions. In a given clinical setting alteration in level of consciousness, appearance of bradycardia, rise in blood pressure, abnormal breathing patterns, evidence of extra ocular movement abnormalities, alteration and in equality of pupillary size, and extensor plantar response on the side of lesion should raise the suspicion of cerebral edema.

Symptoms and Signs of Elevated ICP

Cranial nerve palsies

Papilledema
Vital sign changes
Cushings

Arterial hypertension and bradycardia Respiratory changes

Papilledema
Swelling of the optic nerve

head with engorgement of the retinal veins May be accompanied by hemorrhages into the nerve and adjacent retina Presence almost always indicates raised intracranial pressure.

CLINICAL FEATURES
Know what to look for
Altered mental status/ severe headache Recurrence of vomiting Changes in pupil size, seizures, bradycardia Clinical worsening despite improving lab values CT/ MRI changes may not be seen in early cerebral

edema

Cerebral Edema Bedside Score

Caveat note that patient needs to be significantly Muir Diab affected to meet diagnostic criteria Care 2004 27:1541-46

INVESTIGATIONS CT scan can provide an excellent tool for

determination of abnormalities of brain water content. The area of edema appear as low density on unenhanced scan. This is due to dilution of all the constituents of white matter. The anatomical specificity of CT permits detection of not only the presence but also the type of brain edema. CT is also an excellent method for following the resolution of brain edema following therapeutic intervention. MRI appears to be more sensitive than CT at detecting brain abscess in the ceribritis phase of its development as well as at detecting associated cerebral edema

 ICP monitoring is an important tool to monitor

cases where cerebral edema is present or anticipated and is routinely done in all Neurology and Neurosurgery ICUs. Unfortunately the direct measurement of ICP and aggressive measure to counteract high pressure have not yielded uniformly beneficial results, and after two decades of popularity the routine use of ICP remains contaversial. EEG is not very helpful in the management of cerebral edema, because the changes which are noted are the sum total of changes due to cerebral edema, raised ICP and primary lesion superimposed upon each other.

TREATMENT
Treatment for cerebral edema involves relieving the

pressure, getting rid of the water, and getting to the root cause of the problem to see if recurrence can be prevented. The use of corticosteroids can help bring the swelling down, while diuretics will help the body express the excess water, which will further reduce the swelling. Sometimes surgical means are used to relieve pressure on the brain as well, although this can be dangerous.

 MEDICAL TREATMENT:
1.OSMOTHERAPY;
The most rapid and effective mean of decreasing tissue water and brain bulk is osmotherapy. Osmotic therapy is intended to draw water out of the brain by an osmotic gradient and to decrease blood viscosity. These changes would decrease ICP and increase cerebral blood flow. Mannitol is most popular osmotic agent. It is an organic compound with formula ( C6H8 (OH)6. It is an osmotic diuretic agent and a weak renal vasodilator. It was originally isolated from secretions of flowering ASH, called MANNA after their resemblance to biblical food and also referred as MANNITE and MANNA sugar.

Mannitol is thought to decrease brain volume by decreasing overall water content, to reduce blood volume by vasoconstriction, to reduce CSF volume by decreasing water content. Mannitol may also improve cerebral perfusion by decreasing viscosity or altering red cell rheology. Lastly , Mannitol may exert a protective effect against biochemical injury. There is some evidence that lower dosage is quite effective with less chances of inducing hyperosmolar problems that have been noted with frequent high dose therapy. It is given in a dose of 1g/kg ,then 50 g every 2-3 hrs. When Mannitol is used one should aim for plasma osmolality 300- 310 m Osm /L with maintenance of adequate plasma volume. Prolonged ad of Mannitol results in an electrolyte imbalance that may override its benefits and that must be carefully monitored.

 OTHER USESU
Medical applications

Mannitol is used clinically to reduce acutely raised

intracranial pressure until more definitive treatment can be applied, e.g., after head trauma. This use is controversial, though reference to it is still made in texts published as recently as 2009. .It is administered intravenously, and is filtered by the glomeruli of the kidney, but is incapable of being resorbed from the renal tubule, resulting in decreased water and Na+ reabsorption via its osmotic effect. Consequently, Mannitol increases water and Na+ excretion, thereby decreasing extra cellular fluid volume.

 Mannitol can also be used to open the blood-brain

barrier by temporarily shrinking the tightly coupled endothelial cells that make up the barrier. This makes mannitol indispensable for delivering various drugs directly to the brain (e.g., in the treatment of Alzheimer's disease). Mannitol is commonly used in the circuit prime of a heart lung machine during cardiopulmonary bypass. The presence of mannitol preserves renal function during the times of low blood flow and pressure, while the patient is on bypass. The solution prevents the swelling of endothelial cells in the kidney, which may have otherwise reduced blood flow to this area and resulted in cell damage

 Mannitol is also being developed by an Australian

pharmaceutical company as a treatment for cystic fibrosis and bronchiectasis and as a diagnostic test for airway hyper responsiveness. The mannitol is orally inhaled as a dry powder through what is known as an osmohaler and osmotically draws water into the lungs to thin the thick, sticky mucus characteristic of cystic fibrosis. This is intended to make it easier for the sufferer to cough the mucus up during physiotherapy. The critical characteristic of the mannitol is its particle size distribution.

 Mannitol is also the first drug of choice for the treatment of

acute glaucoma in veterinary medicine. It is administered as a 20% solution IV. It dehydrates the vitreous humor and thus lower the intraocular pressure. However, it requires an intact blood-ocular barrier to work.[3] Mannitol can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an artificial pacemaker) while it is passed through the venous system. Because the mannitol dissolves readily in blood, the sharp point will become exposed at its destination. Mannitol may be administered in cases of severe Ciguatera poisoning. Severe ciguatoxin, or "tropical fish poisoning" can produce stroke-like symptoms. Mannitol is the primary ingredient of Mannitol Salt Agar, a bacterial growth medium, and is used in others. In oral doses larger than 20 g, mannitol acts as an osmotic laxative, and is sometimes sold as a laxative for children citation

GLYCEROL is another useful agent given in oral

dose of 30 ml every 4 6 hrs or daily I/V 50 g in 500 ml 2.5% saline solution although its effectiveness appears to decrease after few days. It is used in a dose of 0.5- 1.0 g/kg body weight. by the use of loop diuretics after the osmotic agent infusion. Loop diuretics (furosemide) can be used as an adjunct. Furosemide ( 0.7 mg/kg) has been shown to prolong the reversal of blood brain osmotic gradient established with the osmotic agents by preferentially excreting water over solute.

2. DIURETICS; The osmotic effects can be prolonged

3. CORTICOSTEROIDS: Corticosteroid lower

intracranial pressure primarily in Vasogenic edema because of their beneficial effect on the blood vessel. They have been less effective in cytotoxic edema and are not recommended in treatment of edema secondary to stroke or hemorrhage. In fact systemic complications of steroids can worsen the patients condition. Corticosteroids have not proven effective in stroke unless stroke is caused by documented cerebral vasculitis. They have also been used in chronic meningitis and acute bacterial meningitis. They are used in the management of malignant brain tumors , edema surrounding brain tumors responds dramatically to high doses of DEXAMETHASONE. The role of corticosteroid in head trauma is uncertain.

4.HYPERVENTILATION:
Controlled hyperventilation is useful in reducing the raised ICP. The cerebral vasculature is most sensitive to arterial Pco2 changes around the normal level of 40 mm Hg. ICP falls within minutes of onset of hyperventilation and although the buffering mechanism in the CSF and extra cellular fluid soon restore PH to normal the effect may last for many hours. It is important to monitor the effects of ventilation carefully by blood gas analysis and chest radiograph. The Pco2 should not be reduced below 25 mm Hg. At this point vasoconstrictor effect of hypocarbia it self will cause hypoxia and ischemic cell damage.

5. OTHER AGENTS:

Barbiturates,Procain derivatives, Indomethacin, Propofol and THAM (Thrometamine) are some other agents which have been tried and used in the past but are not being used routinely in present practice. Barbiturates produce a marked decrease in metabolic rate and it seems likely that the fall in cerebral blood flow and ICP is secondary. Complication of Barbiturates therapy in particular in systemic hypotension and pulmonary failure have caused concern and care full monitoring with swan gauze catheter is recommended. THAM has been used to regulate the acidotic impairment of cerebral auto regulation and the response of the vascular system to hypocapnia can be improved.

6. Role of Benzopyrone:
Vasogenic cerebral edema was induced in rabbits by cold injury. Benzopyrone treatment, started 15 min after freezing, significantly reduced both brain edema and the increased permeability of the blood-brain barrier. On the other hand Benzopyronetreatment was without any effect in cytotoxic brain edema induced in rats by triethyl tin poisoning.

7. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer Most brain tumors over secrete vascular endothelial growth factor

(VEGF), which leads to an abnormally permeable tumor vasculature. This hyper permeability allows fluid to leak from the intravascular space into the brain parenchyma, which causes Vasogenic cerebral edema and increased interstitial fluid pressure. Increased interstitial fluid pressure has an important role in treatment resistance by contributing to tumor hypoxia and preventing adequate tumor penetration of chemotherapy agents. In addition, edema and the corticosteroids needed to control cerebral edema cause significant morbidity and mortality. Agents that block the VEGF pathway are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state. Decreasing cerebral edema minimizes the adverse effects of corticosteroids and could improve clinical outcomes. Anti-VEGF agents might also be useful in other cancerrelated conditions that increase vascular permeability, such as malignant pleural effusions or ascites.

 GENERAL MEASURES:
When signs of elevated ICP are present certain measures for management should be initiated.

Position of the patient: Elevation of the head

end of the bed 15 30 degree to promote cerebral venous drainage is advisable and head is kept in midline to limit neck vein compression. However in acute carotid or basilar artery occlusion bed is not tilted to avoid hypo perfusion distal to occlusion. of factors increasing ICP hypercarbia, hypoxia, hyperthermia, acidosis, hypotension, hypovolemia is helpful.

Correction of contributory factors: Correction

 Fluid restriction: Fluid restriction minimally

affects cerebral edema and if perused to excess may result in episodes of hypotension which may increase the ICP and is associated with worse neurological outcome. Glucose containing solutions should be avoided, euvolumia should be maintained N OR N/2 saline should be used , urinary loses should be replaced with normal saline in patients receiving mannitol. Hypothermia: Multiple mechanisms for reduced brain temperature induced neuroprotection have been identified and include reduced metabolic rate and energy depletion, decreased excitatory neurotransmitter release , reduced vascular permeability ,edema and BBB disruption. Randomized clinical trials are in progress to establish the safety and efficacy of prolonged cerebral hypothermia.

 SURGICAL TRATMENT:
Surgical treatment is occasionally recommended for large hemispherical infarcts with edema and life threatening brain shifts. Temporary venticulostomy and craniectomy may prevent detoriation and may be life saving. Decompressive craniectomy in the setting of acute brain swelling from cerebral infarction is a life saving procedure and should be considered in younger patients who a rapidly deteriorating neurological status. The surgical removal of lesion responsible for cerebral edema results in resolution of cerebral edema. In cases of hydrocephalus VP shunt is very helpful.

 CONCLUSION:
Though there has been good progress in our understanding of pathopysiological mechanisms associated with cerebral edema more effective treatment is required and is still awaited. Certainly the ideal agent for the treatment of cerebral edema- one that would selectively mobilize and or/ prevent the formation of edema fluid with a rapid onset and prolonged duration of action, and with minimal side effects remains to be discovered. Probably in the days to come we can look forward to newer agents specifically acting on the various chemical mediators involved in the pathogenesis of cerebral edema.

Thanks