Topic of the month: Radiological pathology of brain edema

INDEX

INTRODUCTION VASOGENIC EDEMA CYTOTOXIC BRAIN EDEMA ISCHEMIC BRAIN EDEMA CEREBRAL EDEMA ASSOCIATED

WITH NONTRAUMATIC CEREBRALHEMORRHAGE

EDEMA DUE TO MENINGITIS INTERSTITIAL (HYDROCEPHALIC)

EDEMA RADIOLOGICAL PATHOLOGY OF

ASTROGLIOSIS COMPLICATIONS OF BRAIN EDEMA THERAPEUTIC CONSIDERATION

RADIOLOGICAL PATHOLOGY OF BRAIN EDEMA

Brain edema accompanies a wide variety of pathologic processes and contributes to themorbidity and mortality of many neurologic diseases. It plays a major role in head injury,stroke, and brain tumor, as well as in cerebral infections, including brain abscess,encephalitis and meningitis, lead encephalopathy, hypoxia, hypo-osmolality, thedisequilibrium syndromes associated with dialysis and diabetic ketoacidosis, and thevarious forms of obstructive hydrocephalus. Brain edema occurs in several different forms;clearly it is not a single pathologic or clinical entity.

Brain edema is defined best as an increase in brain volume due to an increase in water andsodium content. Brain edema, when well localized or mild in degree, is associated with littleor no clinical evidence of brain dysfunction; however, when it is severe it causes focal orgeneralized signs of brain dysfunction, including various forms of brain herniation andmedullary failure of respiration and circulation. The major forms of herniation are uncal,cerebellar tonsillar, upward cerebellar, cingulate, and transcalvarial herniation.

Brain edema has been classified into three major categories: vasogenic, cellular (cytotoxic),and interstitial (hydrocephalic).

VASOGENIC EDEMA

Vasogenic edema is characterized by increased permeability ofbrain capillary endothelial cells (as consequence of vascularinjury with disruption of the BBB, or due to defectiveendothelial lining of the newly formed blood vessels in brainneoplasms) to macromolecules, such as the plasma proteins andvarious other molecules, whose entry is limited by the capillaryendothelial cells (blood brain barrier). Grossly, the gyri areflattened and the sulci narrowed; the white matter is moist and swollen. Microscopically,there is micro-vacuolization of the white matter, poor staining, and "halo's" around nuclei.

Vasogenic edema is the most common type of edema associated with brain tumors, venouscongestion and other causes and results from local disruption of the blood brain barrier.This leads to extravasation of protein-rich filtrate of plasma into the interstitial space, withsubsequent accumulation of vascular fluid. This disruption results from loosening of thetight junctions between endothelial cells, and the neoformation of pinocytic vesicles. Oncethe barrier is breached, hydrostatic and osmotic forces work together to extravasateintravascular fluid. Once extravasated, fluid is retained outside the vasculature, mostly inthe white matter of the brain, and within the bundles of myelinated axons of long tractsand commissural fibers. This is because axons run in parallel bundles of fibres with looseextracellular space (that offer low resistance and facilitates the extension of vasogenicedema along myelinated axons which are spreaded apart by the edema) as opposed to graymatter, which has high cell density and is enmeshed in an interwoven network ofconnecting fibres that offer high resistance to the formation and spread of edema. Bydefinition, this type of edema is confined to the extracellular space. (70)

More detailed information about the pathophysiology of vasogenic brain edema

Cerebral edema may be defined broadly as a pathologic increase in the amount of totalbrain water content leading to an increase in brain volume 39. It occurs when plasma-likefluid enters the brain extracellular space through impaired capillary endothelial tightjunctions in tumors (vasogenic edema) 40 and is a significant cause of morbidity andmortality. The molecular constituents of brain endothelial tight junctions consist oftransmembrane proteins occludin, claudin 1 and 5, and junctional adhesion molecules thatbind their counterparts on neighboring cells, “gluing” the cells together and creating theblood-brain barrier (BBB) 40. Intracellularly, the occludins and claudins bind to zonulaoccluden (ZO) 1, ZO2, and ZO3, which in turn are attached to the actin cytoskeleton 40.Normal astrocytes help to maintain a normal BBB 41, which is illustrated in Plate. 1. Inhigh-grade tumors, the deficiency of normal astrocytes leads to defective endothelial tightjunctions, resulting in BBB disruption, allowing passage of fluid into the extracellularspace 40. In addition, tumor cells produce factors, such as vascular endothelial growthfactor (VEGF) 42,43 and scatter factor/hepatocyte growth factor 44,45, which increase the

Causes of vasogenic edemainclude trauma, tumor, abscess,hemorrhage, infarction, acute MSplaques, and cerebral contusion. Italso occurs with leadencephalopathy or purulentmeningitis and sinus thrombosis

permeability of tumor vessels by downregulation of occludin and ZO1 40,44,46,47. In addition,the membrane water channel protein, aquaporin-4 (AQP4), is upregulated aroundmalignant brain tumors 40. AQP4-mediated transcellular water movement is important forfluid clearance in vasogenic brain edema, suggesting AQP4 activation or upregulation as anovel therapeutic target in vasogenic brain edema 40,48. High VEGF expression is reportedin human anaplastic astrocytoma and glioblastoma (GBM) 49,50 meningiomas 44, and brainmetastases 51. VEGF is important especially when tumors outgrow their blood supply.Hypoxia is the driving force for VEGF production in glioblastomas and the most importanttrigger for angiogenesis and cerebral edema formation in glioblastoma 52.

Plate 1. The BBB. Normal BBB demonstrating tight junctions betweenendothelial cells forming a barrier between the circulation and the brainparenchyma. Peritumoral edema formation occurs through defectiveendothelial junctions of an abnormal BBB.

Neuroimaging of vasogenic brain edema

The increase in permeability is visualized when contrastenhancement is observed with CT or MRI. Increased CSFprotein levels are also indicative of increased endothelialpermeability. MRI is more sensitive than CT in demonstratingthe increased brain water and increased extracellular volumethat characterize vasogenic edema. Vasogenic edema ischaracteristic of clinical disorders in which there is frequently

a positive contrast-enhanced CT or increased signal intensity with MRI, including braintumor, abscess, hemorrhage, infarction, and contusion. It also occurs with leadencephalopathy or purulent meningitis.

Figure 1. A, Loss of the gray-white interface with obscuration of the lentiform nucleus, lossof the insular ribbon, sulcal effacement and mass effect are seen in the left hemisphere dueto vasogenic edema, B, Grossly , the gyri are flattened and the sulci narrowed; the whitematter is moist and swollen. Notice uncal herniation (arrow).

The functional manifestations of vasogenic edema include focalneurologic deficits, focal EEG slowing, disturbances ofconsciousness, and severe intracranial hypertension. In patientswith brain tumor, whether primary or metastatic, the clinicalsigns are often caused more by the surrounding edema than bythe tumor mass itself. Ultimately, these changes can lead toherniation.

Figure 2. Occipital glioblastoma surrounded by vasogenicedema involving only the white matter

Highly aggressive tumors (glioblastomas, metastatic tumours, etc.) occur at all ages;however, there is a strong trend toward increasing malignancy with age. Highly malignanttumours and rapidly growing tumours are more commonly surrounded by vasogenictumours than more benign tumours and tumours with a lower grade of malignancy. Highly

Increased capillary permeabilityto large molecules is the cornerstone in the aetiopathogenesis ofvasogenic edema. The increase inpermeability is visualized whencontrast enhancement is observedwith CT or MRI.

aggressive tumors are diffusely invasive tumors that typically have a destructive cellularcore. Radiological signs characteristic of vasogenic brain edema is described in thefollowing table.

Table 1. Radiological signs characteristic of vasogenic brain edema

RADIOLOGICAL SIGN COMMENTContrast enhancement. Contrast enhancement is due to break down

of blood brain barrier which is the cornerstone in the aetiopathogenesis of vasogenicedema. The microscopic correlate ofenhancement is hypercellularity, mitoticactivity, neovascularity (in brain tumours)and breakdown of blood brain barrierresulting in increased permeability of braincapillary endothelial cells tomacromolecules, such as the plasma proteinsand various other molecules, whose entry islimited by the capillary endothelial cells(blood brain barrier)

Diffuse low density on CT scan, diffuse MRIT1 hypointensity and diffuse MRI T2hyperintensity with loss of the gray-whiteinterface, obscuration of the lentiformnucleus, loss of the insular ribbon.

Obscuration of the lentiform nucleus, loss ofthe insular ribbon is simply due to loss of thegray-white interface.

Sulcal effacement. Grossly , the gyri are flattened and the sulcinarrowed; the white matter is moist andswollen. Microscopically, there is micro-vacuolization of the white matter, poorstaining, and "halo's" around nuclei.

Mass effect, with ventricular effacement. Is a common cause of brain herniation.The relationship between neuroimagingactual tumor extent is critical to the use ofthese studies in diagnosis and treatmentdesign. In general three zones are identifiedin malignant brain tumours (1) A centralzone (hypointense on the MRI T1 images,hyperintense on the MRI T2 images andhypodense on CT scan) (2) A peripheralenhanced rim with multiple enhanced muralnodules and (3) An ill-defined diffuse largezone surrounding the first two zones.

(hypointense on the T1 images, hyperintense on the T2 images and hypodense on CT scan).The first zone corresponds to the necrotic tumour tissues, the microscopic correlate of

ZONE DESCRIPTIONCENTRALZONE

FORMED OF NECROTICTUMOUR TISSUE

INTERMEDIATECONTRASTENHANCINGRIM

FORMED OF VIABLE TUMOURTISSUE

PERIPHERALDIFFUSE ZONE

FORMED OF OEDEMA,REACTIVE GLIOSIS ANDMALIGNANT CELLINFILTRATIONS

enhancement is hypercellularity, mitotic activity, and neovascularity with breakdown ofblood brain barrier resulting in increased permeability of brain capillary endothelial cellsto macromolecules, such as the plasma proteins and various other molecules, whose entry islimited by the capillary endothelial cells (blood brain barrier), while the third zonecorresponds to edema, malignant glial cell infiltrations and reactive gliosis. Thesurrounding zone of edema demonstrates a decreasing gradient of infiltrating tumor cells.The infiltrating tumor cells primarily follow white matter tracts, accompanied by vasogenicedema that may facilitate migration. 1,2,3,4,5 Although tumor cells may spread a greatdistance, typically, most are within 2 cm of the enhancing margin.6

Glioblastomas characteristically send malignant cells streaming into the surrounding brain. Thismode of spread is apparently facilitated by the widened extracellular spaces created throughvasogenic edema.

Vasogenic edema and peritumoral cyst formation

Two types of cysts—peritumoral and intratumoral— are associated with CNS tumors.Peritumoral cysts develop within the brain or spinal cord and form at the margin of thetumor. Alternatively, intratumoral cysts develop within the tumor itself and are usually theresult of intratumoral necrosis. Overall, cysts are associated with approximately 10% ofbenign, malignant, and metastatic tumors of the CNS. They are most frequently associatedwith hemangioblastomas (83%), cerebellar astrocytomas (77%), and cerebral astrocytomas(29%). The presence of peritumoral cysts can lead to significant neurological impairmentdue to mass effect and increased intracranial pressure. Based on advances in imaging,histological, and molecular techniques, insight into the mechanism behind peritumoral cystformation has been provided, and evidence indicates that peritumoral edema precedes andunderlies the propagation of these cysts.

Peritumoral cysts (those arising immediately adjacent to the tumor mass) are frequentlyassociated with benign and malignant tumors of the brain and spinal cord (syringomyelia).The cystic component of central nervous system (CNS) tumors and associated peritumoralcysts are often the cause of clinical symptoms. Because of the common occurrence ofperitumoral cysts with CNS neoplasms and the morbidity associated with them, advancedimaging, histological, and molecular techniques have been used to determine themechanism underlying cyst formation and propagation. Based on evidence from suchstudies, edema appears to be a common precursor to peritumoral cyst formation in theCNS. Mediators of vascular permeability acting locally in the tumor and/or hydrodynamicforces within abnormal tumor vasculature appear to drive fluid extravasation. When theseforces overcome the ability of surrounding tissue to resorb fluid, edema and subsequentcyst formation occur. These findings support the concept that the tumor itself is the sourceof the edema that precedes cyst formation and that resection of tumors or medicaltherapies directed at decreasing their vascular permeability will result in the resolution ofedema and cysts.

Management of vasogenic edema

Cerebral edema tends to extend along white matter tracts. CT and MRI are helpful in thediagnosis of edema. Therapy includes tumor-directed measures, such as debulking surgery,radiotherapy (RT), chemotherapy, and the use of corticosteroids. Ingraham and coworkerspioneered the use of cortisone to treat postoperative cerebral edema in neurosurgicalpatients in 1952. He first used steroids in an attempt to ameliorate postoperative adrenalinsufficiency in patients undergoing craniotomy for craniopharyngioma resection andnoted the favorable effect on postoperative cerebral edema 53. Galicich and colleagues 54

and French and Galicich 55 introduced dexamethasone therapy as the standard treatmentfor tumor-associated edema. Despite their well-known side effects, better alternatives donot exist and corticosteroids have remained the mainstay of treatment ever since.

The mechanism of action of corticosteroids is not well understood. It has been argued thattheir antiedema effect is the result of reduction of the permeability of tumor capillaries bycausing dephosphorylation of the tight junction component proteins occludin and ZO1 40.Corticosteroids usually are indicated in any patients who have brain tumor who havesymptomatic peritumoral edema. Dexamethasone is used most commonly as it has littlemineralocorticoid activity and, possibly, a lower risk for infection and cognitiveimpairment compared with other corticosteroids 57. The choice of starting dose of acorticosteroid largely is arbitrary and depends on the clinical context. The usual startingdose is a 10-mg load, followed by 16 mg per day in patients who have significantsymptomatic edema. Lower doses may be as effective, especially for less severe edema 58.The dose may be increased up to 100 mg per day if necessary 59. Dexamethasone can begiven twice daily, although many clinicians prescribe it 4 times daily. As a general rule,patients should be treated with the smallest effective dose for the shortest time possible toavoid the harmful effects of steroids. For asymptomatic patients who have peritumoraledema on imaging studies, corticosteroids are unnecessary. Dexamethasone usuallyproduces symptomatic improvement within 24 to 72 hours. Generalized symptoms, such asheadache and lethargy, tend to respond better than focal ones. Improvement on CT andMRI studies often lags behind clinical improvement. Contrast enhancement of tumorstypically decreases, suggesting partial restoration of the BBB 60, whereas tumor perfusioncan increase because of reduced peritumoral water content and local tissue pressure 61.Using diffusion tensor MRI, administration of corticosteroids decreases peritumoralextracellular water content in edematous brain without affecting the water content ofcontralateral normal brain 62.

Occasionally, when there is significant mass effect and impending herniation, othermeasures may be required until corticosteroids have had a chance to take effect or untilpatients undergo debulking surgery. These include elevation of the head of the bed, fluidrestriction, mannitol, hypertonic saline, diuretics, and hyperventilation 63,64.

After more surgical debulking, steroids should be tapered. The taper can start within aweek after surgery but should be delayed in symptomatic patients undergoing RT. Ingeneral, patients who have brain tumors exerting significant mass effect should receive

steroids for 24 hours before starting RT to reduce intracranial pressure and minimizeneurologic symptoms.

CELLULAR (CYTOTOXIC) EDEMA

Cellular edema is characterized by swelling of all the cellular elements of the brain(neurons, glia, and endothelial cells), with a concomitant reduction in the volume of theextracellular fluid space of the brain. Capillary permeability is not usually affected in thevarious cellular edemas. Patients so affected have a normal CSF protein and isotopic brainscan. CT does not reveal enhancement with contrast, and MRI is normal.

Cellular swelling, usually of astrocytes in the grey matter, and classically is seen followingcerebral ischemia caused by cardiac arrest or minor head injury. The blood brain barrier(BBB) is intact. Intracellular edema is usually not clinically significant, and is reversible inits early phases.

There are several causes of cellular edema: hypoxia, acute hypo-osmolality of the plasma,and osmotic" disequilibrium syndromes. Hypoxia after cardiac arrest results in cerebralenergy depletion. The cellular swelling is osmotically determined by the appearance ofincreased intracellular osmoles (especially sodium, lactate, and hydrogen ions) that inducethe rapid entry of water into cells. Acute hypo-osmolality of the plasma and extracellularfluid is caused by acute dilutional hyponatremia, inappropriate secretion of antidiuretichormone, or acute sodium depletion. The brain adapts to hyponatremia by losingintracellular osmoles, chiefly potassium, thereby preserving cellular volume. Osmoticdisequilibrium syndromes occur with hemodialysis or diabetic ketoacidosis, in whichexcessive brain intracellular solutes result in excessive cellular hydration when the plasmaosmolality is rapidly reduced with therapy. The precise composition of the osmoticallyactive intracellular solutes responsible for cellular swelling in the disequilibriumsyndromes that are associated with hemodialysis and diabetic ketoacidosis is not known.

Table 2. Causes of cytotoxic brain edema

CONDITION COMMENTSHypoxia Cerebral energy depletion. The cellular swelling is osmotically

determined by the appearance of increased intracellular osmoles(especially sodium, lactate, and hydrogen ions) that induce the rapidentry of water into cells.

Acute hypo-osmolality ofthe plasma andextracellularfluid

Caused by acute dilutional hyponatremia, inappropriate secretion ofantidiuretic hormone, or acute sodium depletion, The brain adapts tohyponatremia by losing intracellular osmoles, chiefly potassium,thereby preserving cellular volume.

Osmoticdisequilibriumsyndromesoccur withhemodialysis ordiabeticketoacidosis.

Excessive brain intracellular solutes result in excessive cellularhydration when the plasma osmolality is rapidly reduced with therapy.(In uremia, the intracellular solutes presumably include a number oforganic acids, which have been recovered in the dialysis bath. Indiabetic ketoacidosis, the intracellular solutes include glucose andketone bodies; however, there are also unidentified, osmotically active,intracellular solutes, termed idiogenic osmoles that favor cellularswelling.

In uremia, the intracellular solutes presumably include a number of organic acids, whichhave been recovered in the dialysis bath. In diabetic ketoacidosis, the intracellular solutesinclude glucose and ketone bodies; however, there are also unidentified, osmotically active,intracellular solutes, termed idiogenic osmoles that favor cellular swelling. Increasedintracellular osmolality in excess of the plasma level not only causes cellular swelling butalso is responsible for complex changes in brain metabolism affecting the concentrations ofthe neurotransmitter amino acids, ammonia, and other metabolites, which in turn haveprofound effects on brain function.

Major changes in cerebral function occur with the cellular edemas, including stupor, coma,EEG changes and asterixis, myoclonus, and focal or generalized seizures. Theencephalopathy is often severe with acute hypo- osmolality but, in more chronic state's ofhypo-osmolality of the same severity, neurologic function may be spared. Acute hypoxiacauses cellular edema, which is followed by vasogenic edema as infarction develops.Vasogenic edema increases progressively for several days after an acute arterial occlusion.The delay in obtaining contrast enhancement with CT following an ischemic strokeillustrates the passage of time that is needed for defects in endothelial cell function todevelop and mature.

ISCHEMIC BRAIN EDEMA

Most patients with arterial occlusion have a combination of first cellular and thenvasogenic edema, together termed ischemic brain edema. The cellular phase takes place

after acute ischemia over minutes to hours and may be reversible. The vasogenic phasetakes place over hours to days and results in infarction, a largely irreversible process,although the increased endothelial cell permeability usually reverts to normal withinweeks. the factors that determine the reversibility of ischemic edema at the cellular levelare poorly understood.

Figure 3. Vasogenic brain edema following acute embolic brain infarctions, notice loss ofwhite-gray matter interface, loss of sulcation and mass effect

Parenchyma changes of acute infarctiono Pathophysiology

The CT detection of acute infarcts depends on the development of edema within the brainparenchyma, which produces subtle density changes and mass effect. To understand betterthe CT findings of acute ischemia, a brief review of the histologic changes that occur duringa stroke are presented.

Normal cerebral blood flow ranges from 50 to 60 mL/100 g tissue/min. During an ischemicinfarct, blood supply to a portion of the brain is significantly reduced. As cerebral bloodflow decreases, injury occurs in the brain progressing from electrical dysfunction toreversible cellular damage and eventually to cell death. At approximately 20 mL/100 g,electrical activity in the brain ceases, and water homeostasis begins to be disrupted. 13,16 Atcritical flow rates of 10 to 15 mL/100 g, there is disruption of ion homeostasis within the

cells producing rapid increases of extracellular potassium and intracellular sodium. 8,15

This disruption causes water to shift into the intracellular compartment producingastrocytic swelling (cytotoxic edema).

The development of cytotoxic edema aggravatesischemia by causing progressive compression of themicrocirculation, which further decreases blood flow.24As the ischemic changes worsen, capillary wallsbecome permeable allowing leakage of intracellularproteins and subsequent accumulation ofextracellular water (vasogenic edema).21 Worseningedema produces additional mass effect causing a

decrease in cerebral perfusion pressure and collateral flow. Cytotoxic edema may bedetectable within 1 hour of the onset of stroke; however, vasogenic edema usually does notdevelop until 6 hours or more after ictus.

Figure 4. Acute infarctions with mass effect due to edema

Severe ischemia can cause a 7 to 8HU change at I hour that should bevisible on CT. With marginal cerebralblood flows between 15 and 20mL/100 g, ischemic edema takeslonger to develop and may not bedetected on early CT scans.

Figure 5. Acute infarction with masseffect and obscuration of the lentiformnucleus, loss of the insular ribbon, lossof the gray-white interface, and sulcaleffacement.

Table 3. Comparison between the cytotoxic and vasogenic edema of recent infarction

Parameter Cytotoxic (intracellular) Vasogenic (extracellular)Time Within 1 hour of the onset of stroke Does not develop until 6 hours or

more after ictus.Pathophysiology At critical flow rates of 10 to 15

mL/100 g, there is disruption of ionhomeostasis within the cellsproducing rapid increases ofextracellular potassium andintracellular sodium. This disruptioncauses water to shift into theintracellular compartment producingastrocytic swelling (cytotoxic edema).

The development of cytotoxicedema aggravates ischemia bycausing progressive compressionof the microcirculation, whichfurther decreases blood flow. Asthe ischemic changes worsen,capillary walls become permeableallowing leakage of intracellularproteins and subsequentaccumulation of extracellularwater (vasogenic edema).

Composition Increased intracellular water andsodium

Plasma filtrate including plasmaproteins

Location ofedema

Gray and white matter Chiefly white matter

Pathology Cellular swelling, usually ofastrocytes in the grey matter.

Grossly , the gyri are flattened andthe sulci narrowed; the whitematter is moist and swollen.Microscopically, there is micro-vacuolization of the white matter,poor staining, and "halo's"around nuclei.

Capillary Normal Increased

permeability tolarge moleculesNeuroimaging Normal (1) obscuration of the lentiform

nucleus, (2) loss of the insularribbon, (3) diffuse low densitywith loss of the gray-whiteinterface, and (4) sulcaleffacement, (5) mass effect

Figure 6. A, In vasogenicedema the gyri areflattened and the sulcinarrowed; the whitematter is moist andswollen. B, left sided acuteembolic brain infarction,showing evidence of brainedema with mass effect,flattened gyri and sulcaleffacement.

Ischemic changes that occur above 15 mL/ 100 g can be reversible. At flow rates below 10to 15 mL/100 g, tissue damage is usually irrevocable after 1 hour of hypoperfusion.16Otherfactors also play a role in the reversibility of ischemic changes. During low levels ofperfusion, small amounts of glucose may be available to brain tissue for glycolysis, butoxidation cannot occur. The subsequent development of lactic acidosis adversely affects theviability of brain tissue. 23

o Sensitivity of CT in Evaluating Acute Ischemia: How Early Can Stroke BeDetected?

How quickly an acute infarct can be visualized is governed primarily by the severity ofhypoperfusion; however, the duration, size, and location of ischemia also play importantroles.29 When cerebral blood flow drops below the critical value of 10 to 15 mL/100 g,ischemic changes are usually irreversible, and edema develops fast, permitting earlydetections. 15

As edema progresses, water content within the parenchyma increases. This increase causesa subsequent decrease in the brain's specific gravity, which is linearly proportional to CTattenuations. 22 In other words, as edema increases, brain density proportionatelydecreases. A 1 % change in water content changes the CT attenuation by 2.6 HU. Typicallya change of 4 HU or greater is needed to detect the change visually. In cases of severeischemia caused by proximal MCA occlusion, cytotoxic edema can produce a 3% increasein water within 1 hour of the onset of Symptoms. 12,36

This can increase to 6% at 2 to 4 hours. 24 Therefore, severe ischemia can cause a 7 to 8 HUchange at I hour that should be visible on CT. With marginal cerebral blood flows between15 and 20 mL/100 g, ischemic edema takes longer to develop and may not be detected onearly CT scans.

In the future, more advanced imaging techniques, such as MR perfusion and xenon CT,may play an important role in determining the cerebral blood flow of ischemic areas tohelp determine tissue viability. Until then, noncontrast CT can provide importantinformation. If hypoperfusion is less severe and collaterals to an ischemic area areadequate, edema may not develop, and early CT scans are negative. 20 Conversely thepresence of more extensive edema on an early CT scan indicates severe hypoperfusion andmay predict a less favorable outcome after thrombolytic therapy.

The sensitivity of early CT scans in detecting acute strokes also depends on the duration,location, and size of the infarct. As the time of ischemia increases, CT abnormalitiesbecome more obvious; however, the absolute presence or absence of edema primarily relieson the severity of hypoperfusion and adequacy of collateral circulation. Larger infarcts arevisible earlier than smaller infarcts because of the increased volume of tissue involved (i.e.,MCA infarcts are detected sooner than small cortical or lacunar infarcts). 35

Several researchers have studied the sensitivity and accuracy of detecting infarcts on CT.Bryan et al 9 performed MR imaging and CT scans on 31 stroke patients within 24 hours ofthe onset of their symptoms. The locations of the infarcts included the posterior fossa aswell as supratentorial cortical, subcortical, and combined lesions. Eighty-two percent ofearly MR imaging scans showed an abnormality compared with 58% of CT scans. Onfollow- up examinations performed 7 to 10 days later, approximately 90% of both MRimaging and CT scans were abnormal. Mohr et al 18 demonstrated that although CTshowed deep and brain stem infarcts less often than MR imaging, it was equally sensitive indetecting convexity lesions.

When analysis is restricted to the assessment of MCA infarcts, the overall sensitivity of CTsignificantly increases. Moulin et al 19 reviewed 100 patients with MCA stroke. Ninety-fourpercent of all CT scans performed within 14 hours after the onset of symptoms wereabnormal; 88% of CT scans obtained within 6 hours of ictus were abnormal. These resultscompare favorably with data of von Kummer et al. A review of 44 patients demonstratedthat CT performed within 6 hours of the onset of symptoms has an accuracy of 95% and amean sensitivity of 82% of detecting MCA infarcts. CT scans performed within the first 2hours of symptoms, however, were much less sensitive in detecting early ischemia. Truwit

et al 26 and Tomura et al 25described subtle findings of MCA stroke that can increase thesensitivity of CT to greater than 90% in detecting major MCA occlusions.

The presence of parenchymal changes on early CT scans also correlates with the degree ofintracranial occlusive disease. Horowitz et al 14 studied 50 patients with ischemic strokesthat produced at least hemiparesis. CT scans were performed within 4 hours of ictus andwere correlated with angiography or carotid ultrasound. Acute CT abnormalities,including hypodensities and mass effect, were seen in 56% of patients. When there wasmajor vascular occlusion, however, either occlusion of the MCA trunk or two or moreMCA branches, the CT scan was positive in 86% of cases

o CT Findings

Several articles describing early CT findings of acute infarcts have been published inrecent years. These findings have primarily focused on MCA ischemia and havesignificantly improved the overall sensitivity of CT in detecting early MCA infarcts. Themajor CT findings of acute MCA stroke include (1) obscuration of the lentiform nucleus,(2) loss of the insular ribbon, (3) diffuse low density with loss of the gray-white interface,and (4) sulcal effacement.

Obscuration of the Lentiform Nucleus.

In 1988, Tomura et al 25 described obscuration of the lenticular nucleus as an early sign ofMCA infarct. This finding is caused by cellular edema arising within the basal ganglia andclosely correlates with a proximal MCA occlusion. Twenty-five patients who had clinicalevidence of MCA infarcts underwent CT scanning within 6 hours of the onset of symptoms.The scans were then retrospectively reviewed for obscuration of the lenticular nuclei aswell as decreased density within the brain parenchyma and sulcal effacement. Twentythree of the patients (92%) demonstrated an obscured outline or partial disappearance ofthe lentiform nucleus. This sign was visualized earlier than other CT findings and in a fewcases was present within 1 hour after the onset of the stroke. Parenchymal hypodensitiesand sulcal effacement occurred later and were present on significantly fewer initial scans.

The lenticular nuclei receive their blood supply from the lenticulostriate arteries whicharise from the MI trunk of the MCA. Collateral circulation to this area is poor comparedwith the cortex. Occlusion of the proximal MCA disrupts the primary blood supply to thesestructures. 10 As a result of the insufficient collaterals as well as the relatively highmetabolic rate of the lenticular nuclei, 8 proximal MCA occlusion can quickly causecritically low cerebral blood flow, which produces early ischemic changes on CT.

Firlick et al 11 performed CT, xenon CT, and angiography on 20 patients with acute MCAinfarcts. Early CT changes in the basal ganglia were associated with significantly lowercerebral blood flows in the MCA territory compared with patients with normal CT scans.An early basal ganglia hypodensity correlated with a mean cerebral blood flow in theaffected MCA territory of less than 10 mL/100 g. Patients with more distally located

occlusions, beyond the origins of the lenticulostriate arteries, preserve blood supply to thebasal ganglia and do not develop this early sign.

Bozzao et al 7 evaluated 36 patients with acute MCA infarcts with CT and angiography andcorrelated changes on early CT scans with the angiographic findings. CT scans wereperformed within 4 hours, and angiograms were obtained within 6 hours from the onset ofsymptoms. Bozzao et al 7 noted that all patients with early CT findings of MCA infarctsdemonstrated an arterial occlusion on angiography. Involvement of the lenticular nucleicorresponded closely with a proximal MCA occlusion.

Loss of the Insular Ribbon. (LIR)

Another early sign of acute MCA infarction is loss of the insular ribbon (LIR) which isdescribed as loss of definition of the gray-white interface in the lateral margins of theinsula. This area is supplied by the insular segment of the MCA and its claustral branchesand is the region most distal from anterior and posterior cerebral collateral circulation. Asa result, collateral flow to the insular region is decreased compared with other portions ofthe cerebral cortex.

Truwit et al 26 performed both retrospective and prospective evaluations of CT scans inpatients with clinical evidence of acute MCA distribution infarcts to evaluate the sensitivityand accuracy of the LIR sign. In a retrospective analysis of 11 cases, LIR was seen in allpatients (100%). In a prospective study, the LIR sign was identified in 12 of 16 patients(75%). Obscuration of the lenticular nucleus occurred less frequently and was identified in73% and 63% of patients. They concluded that LIR is more frequently observed in acuteMCA infarcts than other early CT findings.

In two patients, the LIR was localized to the posterior segment of the insula and wasassociated with a more limited infarct. This situation may be due to more distal occlusion ofposterior MCA branches within the operculum.

The presence of obscuration of the lenticular nucleus or LIR without other signs ofextensive infarct does not preclude the use of thrombolytic agents. These patients mayreceive significant benefit from intravenous or intraarterial thrombolysis; because of thepresence of early CT changes, however, they may be more likely to have areas ofirreversible damage compared with patients with negative CT scans.

Diffuse Parenchymal Hypodensity and Sulcal effacement.

As ischemic changes progress, both cytotoxic and vasogenic edema increase producingareas of hypoattenuation throughout the affected circulation. In larger infarcts, mass effectalso increases producing effacement of sulci and compression of ventricles.

Figure 7. A 52-year-old womanwho presented with sudden onsetof left arm weakness. A and B, CTscan performed three hours afterthe onset of symptomsdemonstrates focal loss of theinsular ribbon posteriorly(arrows). A more superior imageperformed through the lateralventricles demonstrates an area oflow attenuation in the rightposterior frontal cortex with lossof the gray-white interface(arrows) consistent with ischemicchange in the right MCAdistribution.

Detection of anterior and posterior cerebral artery infarcts as well as posterior fossa lesionsrelies predominantly on the presence of parenchymal hypodensity and sulcal effacement .As a result of the lack of other subtle CT findings, such as obscuration of the lenticularnucleus and LIR, these infarcts may not be detected as early as large MCA strokes.

In cases of MCA infarcts, extensive parenchymal hypodensity on early CT scans isassociated with a high mortality rate as well as a poor clinical outcome in survivors. Whengreater than 50% of the vascular territory was involved, the mortality rate increased up to85% because of malignant brain edema. 28 Early craniectomy decreases the mortality ratefor patients with severe edema ; however,clinical outcome remains poor.

Figure 8. A 67-year-old man who presented with a 5-hour history of left leg weakness. Aand B, CT scan shows subtle low attenuation and loss of sulcation in the right parasagittalfrontal lobe extending to the convexity (arrowheads) consistent with an anterior cerebral

artery distribution infarct. C, MR diffusion scan demonstrates abnormal high signal in theright frontal parasagittal region confirming the diagnosis of an ACA infarct.

The presence of extensive ischemic change typically excludes the use of thrombolytictherapy. 27 The likelihood of clinical improvement is low, whereas the rate of complication,including hemorrhage, is significantly increased. 17,28,29 In the future, faster mechanicalmethods of removing clot within the MCA may offer benefit to these patients; however, inmost cases, irreversible damage has been done.

Table 4. Early CT scan features of acute ischemic stroke

Radiological feature DescriptionDiffuse ParenchymalHypodensity andSulcal effacement.

A 1 % change in water content changes the CT attenuation by 2.6HU. Typically a change of 4 HU or greater is needed to detect thechange visually. In cases of severe ischemia caused by proximalMCA occlusion, cytotoxic edema can produce a 3% increase inwater within 1 hour of the onset Of Symptoms. This can increase to6% at 2 to 4 hours. Therefore, severe ischemia can cause a 7 to 8HU change at I hour that should be visible on CT. If hypoperfusionis less severe and collaterals to an ischemic area are adequate,edema may not develop, and early CT scans are negative.Conversely the presence of more extensive edema on an early CTscan indicates severe hypoperfusion and may predict a lessfavorable outcome after thrombolytic therapy.

Loss of the InsularRibbon. (LIR)

Loss of definition of the gray-white interface in the lateral marginsof the insula .

Obscuration of theLentiform Nucleus.

Obscuration of the lenticular nucleus is an early sign of MCAinfarct . This finding is caused by cellular edema arising within thebasal ganglia and closely correlates with a proximal MCAocclusion.

CEREBRAL EDEMA ASSOCIATED WITH NONTRAUMATIC CEREBRALHEMORRHAGE

Traditionally, ICH was believed to cause permanent brain injury directly by mass effect.However, the importance of hematoma-induced inflammatory response and edema ascontributors to secondary neuronal damage has since been recognized. 65,66,67

At least three stages of edema development occur after ICH (Table 5). In the first stage, thehemorrhage dissects along the white matter tissue planes, infiltrating areas of intact brain.Within several hours, edema forms after clot retraction by consequent extrusion ofosmotically active plasma proteins into the underlying white matter 65,66. The second stage

occurs during the first 2 days and is characterized by a robust inflammatory response. Inthis stage, ongoing thrombin production activates by the coagulation cascade, complementsystem, and microglia. This attracts polymorphonuclear leukocytes andmonocyte/macrophage cells, leading to up-regulation of numerous immunomediators thatdisrupt the blood-brain barrier and worsen the edema. 65,66,67 A delayed third stage occurssubsequently, when red blood cell lysis leads to hemoglobin-induced neuronal toxicity.65,66,67 Perihematomal edema volume increases by approximately 75% during the first 24hours after spontaneous ICH and has been implicated in the delayed mass effect thatoccurs in the second and third weeks after ICH. 68.69

Thrombin is an essential component of the coagulation cascade, which is activated in ICH.In low concentrations thrombin is necessary to achieve hemostasis. However, in highconcentrations, thrombin induces apoptosis and early cytotoxic edema by a direct effect.Furthermore, it can activate the complement cascade and matrix metalloproteinases(MMP) which increase the permeability of the blood brain barrier. 65,66

Delayed brain edema has been attributed, at least in part, to iron and hemoglobindegradation. Hemoglobin is metabolized into iron, carbon monoxide, and biliverdin byheme oxygenase. Studies in animal models show that heme oxygenase inhibition attenuatesperihematomal edema and reduces neuronal loss. 65,66,67 Furthermore, intracerebralinfusion of iron causes brain edema and aggravates thrombin-induced brain edema. Inaddition, iron induces lipid peroxidation generating reactive oxygen species (ROS), anddeferoxamine, an iron chelator, has been shown to reduce edema after experimental ICH.65,66,67

Table 5. Stages of edema after ICH

First stage (hours) Second stage (within first 2 days) Third stage (after first 2days)

Clot retraction andextrusion ofosmotically activeproteins

Activation of thecoagulation cascade andthrombin synthesis

Complement activation Perihematomal

inflammation and leukocyteinfiltration

Hemoglobin inducedneuronal toxicity

EDEMA DUE TO MENINGITIS

Early in the course of meningitis, changestake place in the meningeal and cerebralcapillaries, including an increase inpermeability of the blood-brain barrier. Themajor physiologic consequence of thisaltered vascular permeability is vasogenicedema. The observed brain edema may alsohave a cytotoxic component emanating frominflammatory mediators in the meningealexudate and from parenchymal hypoxia anda complex interstitial (edematous)component resulting from impaired

cerebrospinal fluid absorption resulting from arachnoid villi dysfunction from blockage byfibrin and leukocytes. Increased intracranial pressure resulting from cerebral edema andreduced cerebrospinal fluid resorption produce vomiting and obtundation. In extremeinstances, cerebral edema may produce transtentorial herniation with brain stemcompression and eventual respiratory arrest and death.

Figure 9. Vasogenic edema due tomeningitis. Inflammatory vascularinjury results in increased permeabilityof brain capillary endothelial cells (asconsequence of vascular injury withdisruption of the BBB) tomacromolecules, such as the plasmaproteins and various other molecules,whose entry is limited by the capillaryendothelial cells (blood brain barrier)

INTERSTITIAL (HYDROCEPHALIC) EDEMA

Interstitial edema is the third type of edema, best characterized in obstructivehydrocephalus, in which the water and sodium content of the periventricular white matteris increased because of the movement of CSF across the ventricular walls. Obstruction ofthe circulation of the CSF results in the transependymal movement of CSF and thereby anabsolute increase in the volume of the extracellular fluid of the brain. This is observed inobstructive hydrocephalus with CT and MRI . Low-density changes are observed at theangles of the lateral ventricles. The chemical changes are those of edema, with oneexception: the volume of periventricular white matter is rapidly reduced rather thanincreased. After successful shunting of CSF, interstitial edema is reduced and the thicknessof the mantle is restored.

The major physiologic consequence of alteredvascular permeability in meningitis is vasogenicedema. The observed brain edema may alsohave a cytotoxic component emanating frominflammatory mediators in the meningealexudate and from parenchymal hypoxia and acomplex interstitial (edematous) componentresulting from impaired cerebrospinal fluidabsorption resulting from arachnoid villidysfunction from blockage by fibrin andleukocytes.

Figure 10. Periventricularhyperintensities is seen inthis patient withobstructivehydrocephalus.Obstruction of thecirculation of the CSFresults in thetransependymalmovement of CSF andthereby an absoluteincrease in the volume ofthe extracellular fluid ofthe brain.

Functional manifestations of interstitial edema are usually relatively minor in chronichydrocephalus unless the changes are advanced, when dementia and gait disorder becomeprominent. This finding indicates that the accumulation of CSF in the periventricularextracellular fluid space is much better tolerated than is the presence of plasma in theextracellular fluid space, as seen with vasogenic edema, which is characterized by focalneurologic signs.

SUMMARY

Condition Vasogenic Cytotoxic Interstitial(Hydrocephalic)

Pathogenesis Increased capillarypermeability

Cellular swelling(neuronal,endothelial, glial)

Increased brain fluiddue to block of CSFabsorption

Location of edema Chiefly white matter Gray and whitematter

Chieflyperiventricular whitematter inhydrocephalus

Edema fluidcomposition

Plasma filtrateincluding plasmaproteins

Increasedintracellular waterand sodium

CSF

Capillarypermeability to largemolecules (RISA,inuhn)

Increased Normal Normal

Disease conditions Brain tumor, abscess,infarction, trauma,

Hypoxia, hypo-osmolality

Obstructivehydrocephalus

hemorrhageSteroids Effective No effect No effect

RADIOLOGICAL PATHOLOGY OF ASTROGLIOSIS

Astrogliosis( reactive astrogliosis as seen in old infarction, old MS plaques , head trauma,etc. and neoplastic astrogliosis as seen in low grade gliomas) is seen hypodense of CT scan,hypointense on T1 MRI images and hyperintense on the T2 MRI images. This radiologicalpicture would suggest edema. The question then arises: Is this vasogenic edema or cytotoxicedema? Because the blood-brain barrier is intact, vasogenic edema is unlikely. The cells arenot dead or dying, so that cytotoxic edema is also unlikely.

Figure 11. A, subacute infarction, B, old infarction with extensive gliosis and cavitations

Figure 12. (A) Old infarction with extensive gliosis, microcavitations, the infarction ishypodense with negative mass effect (B)

Perhaps the edema results from the increased number of astrocytic cells that spread apartthe normal myelinated axons of the white matter. The presence of significant amount ofnormal appearing astrocytes (hyperplasia), with marked cytoplasmic hypertrophy and lownuclear to cytoplasm ratio result in total increase in the water content of the brain. Thesecells may merely have different physical and chemical properties than the normal tightlypacked bundles of axons that traverse through the brain. Astrogliosis is commonlyassociated with widened fluid filled extracellular spaces (microcavitations andmacrocavitations) which definitely increase tissues water content resulting in thecharacteristic CT scan/MRI picture. 37,38,39

Figure 13. With progression of time (from A to C) the infarction gets more hypodense andthe mass effect gradually decreases with time due to gradual reduction of brain edemabecause the blood brain barrier is once again sealed. The initial hypodensity in acuteinfarction is due to edema (A) while the the ultimate hypodensity in old infarction (C) isdue to astrogliosis with widened fluid filled extracellular spaces (microcavitations andmacrocavitations). During the evolution of the infarction the edema and the swellingdecreases and the infarction boundary becomes better defined , and the infarcted areabecomes more hypodense.

Figure 14. Astrocytes have extensive vascular foots, Astrogliosis (astrocytic hyperplasia)commonly results in the formation of a mesh with enlargement of extracellular spaces andextensive fluid-filled microcavitations. This, coupled with marked cytoplasmic hypertrophyof astrocytes-that results in low nuclear to cytoplasm ratio- are responsible for the CT scanpicture of old infarction.

Table 6. Comparison between CT hypodensity of recent and old infarctions

Recent infarction Old infarctionAetiology of CT hypodensity Vasogenic edema (cytotoxic edema

does not contribute to CThypodensity)

Astrogliosis withwidened fluid filledextracellularspaces(microcavitationsandmacrocavitations)

Figure 15. MRI T2, FLAIR, and T1 postcontrast images showing a well circumscribedlesion in the left frontal lobe, the lesion is hyperintense in T2 and FLAIR images,hypointense on T1 image with no postcontrast enhancement. This radiological picturewould suggest edema probably due to neoplastic astrogliosis.

COMPLICATIONS OF BRAIN EDEMA

Brain herniation

The cranial cavity is partitioned by the tentorium cerebelli and falx cerebri. When a part ofthe brain is compressed by an extrinsic lesion such as a subdural hematoma or is expandedbecause of a contusion or other intrinsic pathology, it is displaced (herniates) from onecranial compartment to another. Three major herniations can occur, either alone or incombination.

Is a major consequence of cerebral edema. Because of the rigid skull and partitioning of thecranial vault by the falx cerebri and tentorium cerebelli, when the brain swells it isdisplaced relative to these partitions or is pushed toward the foramen magnum. There areseveral types of brain herniations - classified by the part that is herniated or the structureunder which it has been pushed.

Subfalcial herniation is displacement of the cingulate gyrus from one hemisphere to theother, under the falx cerebri. Subfalcial herniation can compress the pericallosal arteries,causing an infarct in their distribution.

Figure 16. Subfalcine herniation (arrows). Subfalcial herniation is displacement of thecingulate gyrus from one hemisphere to the other, under the falx cerebri. Subfalcialherniation can compress the pericallosal arteries, causing an infarct in their distribution.

Uncal (transtentorial) herniation is herniation of the medial temporal lobe from the middleinto the posterior fossa, across the tentorial notch. The uncus of the temporal lobe is forcedinto the gap between the midbrain and the tentorium.

Figure 17. A, This figure represents a view of the ventral part of both cerebralhemispheres. The brain stem has been removed at the mid brain level. The occipital lobesshows the dura representing the tentorium of the cerebellum. There is bilateral herniationof the hippocampal gyri (arrows). B, The right hippocampus (seen on the left side of thephotograph) shows the larger herniation. Uncal (transtentorial) herniation is herniation of

the medial temporal lobe from the middle into the posterior fossa, across the tentorialnotch. The uncus of the temporal lobe is forced into the gap between the midbrain and thetentorium.

Figure 18. As the herniating uncus displaces the midbrain laterally, the contralateralcerebral peduncle is compressed against the edge of the tentorium, causing paralysis on thesame side as the primary lesion, another false localizing sign. Caudal displacement of thebrainstem and stretching of its vessels causes a variety of hemorrhagic lesions in themidbrain and pons (secondary brainstem hemorrhages) - so-called Duret hemorrhages-that can devastate the reticular activating substance and other brainstem centers, resultingin focal neurological deficits and coma.

Figure 20. Postmortem specimens showing hemorrhage within the dorsal brainstemconsistent with a Duret's hemorrhage. The so-called Duret hemorrhages seen here in thepons are secondary to downward compression that leads to stretching, ischemia andrupture of perforating arterioles and brain stem hemorrhage

This compresses the ipsilateral oculomotor nerve, causing a fixed and dilated pupil, andcollapses the ipsilateral posterior cerebral artery, causing an infarct in its distribution.Cortical blindness resulting from this infarct is a false localizing sign because it gives theerroneous impression that the primary lesion is in the occipital lobe. As the herniatinguncus displaces the midbrain laterally, the contralateral cerebral peduncle is compressedagainst the edge of the tentorium, causing paralysis on the same side as the primary lesion,another false localizing sign. Caudal displacement of the brainstem and stretching of itsvessels causes a variety of hemorrhagic lesions in the midbrain and pons (secondarybrainstem hemorrhages) that can devastate the reticular activating substance and otherbrainstem centers, resulting in focal neurological deficits and coma. Bilateral temporal lobeherniation occurs in global cerebral edema.

Pressure on the posterior fossa contents from above or from within flattens the ponsagainst the clivus and displaces the cerebellar tonsils into the foramen magnum (cerebellartonsillar herniation). Compression of the pons and medulla damages vital centers forrespiration and cardiac function, and causes cardiorespiratory arrest.

Cerebral edema in TBI, HIE, brain tumors, meningitis, brain abscess, and otherpathologies is caused by accumulation of water in interstitial spaces due to increasedvascular permeability (vasogenic edema) and in some cases also by accumulation in injuredcells (cytotoxic edema). Vasogenic edema involves more severely the white matter andextends along the optic nerves. The edematous optic papillae protrude forward into thevitreous chamber and displace the retina causing blurring of vision. Fundoscopicexamination reveals blurred disk margins.

Understanding the anatomy and warning signs of herniations and promptly takingmeasures to reduce intracranial pressure will save lives. Herniations are important notonly in trauma but in any condition associated with cerebral edema and increasedintracranial pressure, including HIE, stroke, meningitis, brain abscess, brain tumors, andhydrocephalus.

Figure 21. Cerebellar tonsillarherniation

o Complication of brain herniation Coma

As the midbrain is compressed and shifted the reticular activating system may be damaged,causing coma.

Cardio-respiratory arrest

If the medulla is compressed by severe transtentorial herniation or by tonsillar herniation,the cardio-respiratory centers may be damaged, causing death.

Kernohan's notch

Unilateral cerebral expansion with uncal herniation may push the contralateral cerebralpeduncle against the tentorium, secondarily damaging it. A pressure groove (Kernohan'snotch) may be seen on the peduncle. Thus, while the primary lesion may directly causecontralateral hemiparesis, the secondary damage to the contralateral peduncle may causehemiparesis ipsilateral to the primary lesion.

Figure 22. Kernohan's notch

THERAPEUTIC CONSIDERATION

The therapy of brain edema depends on the cause. Appropriate and early treatment ofintracranial infection is essential. Surgical therapy is directed toward alleviating the causeby excision or decompression of intracranial mass lesions, as well as by a variety ofshunting procedures. A patent airway, maintenance of an adequate blood pressure, and theavoidance of hypoxia are fundamental requirements in the care of these patients.

The administration of appropriate parenteral fluids to meet the needs of the patient is alsoessential. Caution is necessary in the choice of isotonic parenteral fluids. Administration ofsalt-free fluids should be avoided. Intravenous infusion of a 5% glucose solution results in a

significant increase in intracranial pressure, which may be avoided with use of normalsaline or 5% glucose in saline. If the excessive administration of salt is to be avoided, theuse of 2.5% or 5% glucose in half-normal saline is satisfactory. In patients with cerebraledema, serum hypo-osmolality has deleterious effects and should be avoided.

The pharmacologic treatment of brain edema is based on the use of glucocorticoids,osmotherapy, and drugs that reduce CSF formation. Hyperventilation, hypothermia, andbarbiturate therapy have also been tested experimentally and in clinical practice.

Glucocorticoids

The rationale for the use of steroids is largely empirical. There is widespread convictionthat glucocorticoids dramatically and rapidly (in hours) begin to reduce the focal andgeneral signs of brain edema around tumors. The major mechanism suggested to explaintheir usefulness in vasogenic brain edema is a direct effect on endothelial cell function thatrestores normal permeability.

The biochemical basis, of the changes in membrane integrity that underlie vasogenic andcellular edema is now under study. Attention has focused on the role of free radicals (i.e.,superoxide ions and singlet oxygen) and on the effect of polyunsaturated fatty acids, mostnotably arachidonic acid, in the peroxidation of membrane phospholipids. The ability ofadrenal glucocorticoids to inhibit the release of arachidonic acid from cell membranes mayexplain their beneficial effects in vasogenic edema; however, steroids have not been shownto be therapeutically useful in the brain edema of hypoxia or ischemia. Cellular damage ismore important than brain edema in these conditions.

There are no convincing data, clinical or Experimental, that glucocorticoids have beneficialeffects in the cellular edema associated with hypo-osmolality, asphyxia, or hypoxia in theAbsence of infarction with mass effects. There is little basis for recommending steroids inthe treatment of the cerebral edema associated with cardiac arrest or asphyxia.

When intracranial hypertension and obstructive hydrocephalus occur because ofinflammatory changes in the subarachnoid space or at the arachnoid villi, whetherattributable to leukocytes or to blood, there is a reasonable rationale for the use of steroids.However, despite the frequent use of steroids in purulent or tuberculous meningitis, fewdata are available to document the effectiveness of steroids against the brain edema of theacute disease. There are conflicting reports about the efficacy of steroids in acute bacterialmeningitis or tuberculous meningitis. The use of steroids has not been shown to affect thesubsequent incidence of chronic sequelae such as obstructive hydrocephalus or seizures.Steroids appear useful in the management of other conditions characterized by aninflammatory CSF, such as chemical meningitis following meningeal sarcoidosis, orcysticercosis.

Osmotherapy

Hypertonic solutions (including urea, mannitol, and glycerol) have been used to treat theintracranial hypertension associated with brain edema. The several solutes have beendifficult to compare because a large variety of laboratory models, dosages, time intervals,and pathologic processes have been used.

A few principles seem certain. First, brain volume falls as long as there is an osmoticgradient between blood and brain. Second, osmotic gradients obtained with hypertonicparenteral fluids are short-lived because each of the solutes reaches an equilibriumconcentration in the brain after a delay of only a few hours. Third, the parts of the brainmost likely to "shrink" are normal areas; thus, with focal vasogenic edema, the normalregions of the hemisphere shrink but edematous regions with increased capillarypermeability do not. Fourth, a rebound in the severity of the edema may follow use of anyhypertonic solution because the solute is not excluded from the edematous tissue; if tissueosmolality rises,the tissue water is increased. Finally, there is scant rationale for chronicuse of hypertonic fluids, either orally or parenterally, because the brain adapts to sustainedhyperosmolality with an increase in intracellular osmolality due to the solute and toidiogenic osmoles.

There is some uncertainty about the size of an increase in plasma osmolality that causes atherapeutically significant decrease in brain volume and intracranial pressure in humans.Acute increases as small as 10 mOsm/L may be therapeutically effective. It should beemphasized that accurate dose-response relationships in different clinical situations havenot been well defined with any of the hypertonic agents.

Other therapeutic Measures. Hyperventilation, hypothermia, and barbiturates have beenused in the management of intracranial hypertension, but none is established and theextensive literature is not reviewed here. Acetazolamide and furosemide reduce CSFformation in animals but have limited usefulness in the management of interstitial edema.

Prevention and treatment of increased intracranial pressure (ICH)

In addition to the effects of the edema itself, there are a number of possible contributors toincreased ICP. They need to be treated aggressively since any increases in ICP result in thelowering of cerebral perfusion pressure (CPP), which results in further compromise ofneurological function. They include: hypertension, hypoxia, hyperthermia, seizures, andelevations of intrathoracic pressure. 32 Hypertension in patients with a mass lesion resultsin increased CPP in areas of brain with impaired autoregulation, contributing to theformation of brain oedema. There are no specific guidelines for the management ofhypertension in this setting, except for the maintenance of normal CPP, in the 60-70 mmHgrange. The medications of choice are those without cerebral vasodilator properties, and auseful combination is labetalol and furosemide. 32

However, in instances of severe hypertension the use of rapid-acting vasodilators such asnitroprusside is justified, as they produce rapid and easily titrable management of blood

pressure in emergency situations. Hypoxia produces an increase in cerebral blood flow(CBF) and cerebral blood volume, with an increase in ICP in patients with poor cerebralcompliance. 34 Adequate oxygenation is thus essential in patients with ICH and increasedICP, with the aim of maintaining pO, in the 100-1 50 mmHg range. Hyperthermiaincreases CBF and ICP, and also elevates arterial pCO, the latter partially counteractingthe effects of therapeutic hyperventilation. 32 This calls for vigorous treatment of fever andinfections. The occurrence of seizures in the setting of acute ICH, especially likely in thelobar variety, can result in increased CBF, cerebral blood volume, and ICP. Their controlis generally achieved by using intravenous diazepam, followed by loading doses ofphenytoin or phenobarbitone. Elevations in intrathoracic pressure produced byendotracheal suction, coughing, chest therapy, and the use of positive end-expiratorypressure can result in transient elevations in ICP. These measures, otherwise criticallyimportant in maintaining airway potency and adequate oxygenation, need to be usedjudiciously and monitored closely in the setting of ICH with increased ICP.

The specific measures that are useful in the treatment of increased ICP are listed in Table7. Hyperventilation reduces ICP by producing vasoconstriction, which is maximal innormal areas of the brain, where autoregulation is preserved. 30 The ideal partial pressureof carbon dioxide (pCO,) for this purpose is between 28 and 35 mmHg. 32 The effects ofhyperventilation are transient, as compensatory mechanisms within the central nervoussystem overcome the vasoconstriction that results from hypocarbia. A potential side-effectof the use of therapeutic hyperventilation is hypotension, that results from lowered cardiacfilling pressure. It can be avoided by maintaining a normal intravascular volume, withisotonic or slightly hypertonic solutions. The use of osmotic diuretics is highly effective inrapidly lowering elevated ICP. Their effect is exerted by shifting water from the brainsubstance into the intravascular space, along with a small additional effect of reducingcerebrospinal fluid production and volume. 32 High-dose intravenous barbiturateseffectively reduce CBF and brain metabolism, resulting in a decrease in ICP. 33 The mostcommonly used agent is thiopentone, 1-5 mg/kg. Its main side-effects are hypotension andmarkedly reduced neurological function, at times making the neurological examinationuseless as a way of monitoring therapy. The use of corticosteroids in the treatment ofincreased ICP in ICH is controversial, since their value in reducing brain oedema in otherconditions, such as brain metastases, has not been established in patients with ICH. In acontrolled, randomized, double-blind clinical trial conducted by Poungvarin et al (1987), 31

dexamethasone was not superior to placebo in terms of mortality at 21 days from onset ofICH, and the rate of complications was significantly higher in the dexamethasone-treatedgroup.

Table 7. Major therapies for acutely raised ICP Treatment

Major therapies foracutely raised ICPTreatment

Dose Advantages Limitations

Hypocarbia[hyperventilation]

pCO, 25-33 mmHg ,RR 10-16/minute

Immediate onset, welltolerated

Hypotension, shortduration

Osmotic Mannitol, 0.5-1 g/kg Rapid onset, titrable,predictable

Hypotension,hypokalaemia, shortduration

Barbiturates Pentobarbital, 1.5mg/kg

Mutes BP andrespiratoryfluctuation

Hypotension, smallfixed fluctuationspupils, long duration

MEDICATION

The goal of pharmacotherapy is to reduce morbidity and prevent complications.

Drug Category: Corticosteroids - Reduces edema around tumor, frequently leading tosymptomatic and objective improvement.

Drug Name

Dexamethasone (Decadron, Dexasone)-Postulated mechanisms of action ofcorticosteroids in brain tumors include reductionin vascular permeability, cytotoxic effects ontumors, inhibition of tumor formation, anddecreased cerebrospinal fluid (CSF) production.

Adult Dose

16 mg/d PO/IV in significant peritumoral dividedq6h; May continue dose until patient showsimprovement; tapered to discontinue or tominimum effective dose

Pediatric Dose 0.15 mg/kg/d PO/IV divided q6h in pediatrictumors

Contraindications

Documented hypersensitivity; active bacterial orfungal infection, peptic ulcer disease, psychosis,or hypertension; in peritumoral edema, carefullywatched for adverse sequelae

Interactions

Effects decrease with coadministration ofbarbiturates, phenytoin and rifampin; decreaseseffects of salicylates and vaccines used forimmunization

Pregnancy C - Safety for use during pregnancy has not beenestablished.

Precautions

Increases risk of multiple complications,including severe infections; monitor adrenalinsufficiency when tapering drug; abruptdiscontinuation of glucocorticoids may causeadrenal crisis; hyperglycemia, edema,osteonecrosis, Cushing's syndrome, myopathy,peptic ulcer disease, hypokalemia, osteoporosis,euphoria, psychosis, myasthenia gravis, growthsuppression, and infections are possiblecomplications of glucocorticoid use

References

1. Burger PG, Heinz ER, Shibata T, et al: Topographic anatomy and CT correlations in theuntreated glioblastoma multiforme. J Neurosurg 68:698-704,1988

2. Johnson PC, Hunt Sj, Drayer BP: Human cerebral gliomas: Correlation of postmortemMR imaging and neuropathologic findings. Radiology 170:211-217, 1989

3. Kelly Pj, Daumas-Duport C, Kispert DB, et al: Imaging-based stereotactic serial biopsiesin untreated intracranial glial neoplasms. J Neurosurg 66:865-874, 1987

4. Kelly Pj, Daumas-Duport C, Scheithauer BW, et al: Stereotactic histologic correlationsof computed tomography and magnetic resonance imaging-defined abnormalities inpatients with glial neoplasms. Mayo Clin Proc 62:450-459, 1987

5. Scherer Hj: The forms of growth in gliomas and their practical significance. Brain 63:1 -35, 1940

6. Wallner K, Galicich JH, Krol G, et al: Patterns of failure following treatment forglioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys16:1405-1409, 1989

7. Bozzao, L, Bastianello S, Fantozzi LM, et al: Correlation of angiographic and sequentialCT findings in patients with evolving cerebral infarctions. AJNR Am j Neuroradiol10:1215-1222,1989

8. Brant-Zawadski M, Pereira B, Weinstein P, et al: MR imaging of acute experimentalischemia in cats. AJNR Am j Neuroradiol 7:7-11, 1986

9. Bryan RN, Levy LM, Whitlow WD, et al: Diagnosis of acute cerebral infarction:Comparison of CT and MR imaging. AJNR Am j Neuroradiol 12:611-620,19

10. Caplan V, Babikian V, Helgason C, et al: Occlusive disease of the middle cerebralartery. Neurology 35:975- 982,1985

11. Firlick AD, Kaufmann AM, Weschler LR, et al: Quantitative cerebral blood flowdeterminations in acute ischemic stroke: Relationship to computed tomography andangiography. Stroke 28:2208-2213, 1997

12. Garcia JH: Experimental ischemic stroke: A review. Stroke 15:5-14, 1984

13. Heiss WD, Hayakawa T, Walta AG: Cortical neuronal function during ischemia:Effects of occlusion of one middle cerebral artery on single unit activity in cats. ArchNeurol 33:813-820, 1976

14. Horowitz Sli, Zito JL, Donnaromma R, et al: Computed tomographic-angiographicfindings within the first five hours of cerebral infarction. Stroke 22:1245- 1253,1991

15. Hossman KA, Schuier Fj: Experimental brain infarcts in cats: I. Pathophysiologicalobservations. Stroke 11:583-592, 1980

16. Iannotti F, Hoff J: Ischemic brain edema with and without reperfusion: Anexperimental study in gerbils. Stroke 14:562-567, 1983

17. Levy DE, Brott TG, Haley EC, et al: Factors related to intracranial hematomaformation in patients receiving tissue-type plasminogen activator for acute ischemic stroke.Stroke 25:291-297, 1994

18. Mohr JP, Biller J, Hilal SK, et al: MR vs CT imaging in acute stroke. Stroke 23:142-149, 1992

19. Moulin T, Cattin F, Crepin-Leblond T, et al: Early CT signs in acute middle cerebralartery infarction: Prdictive value for subsequent infarct locations and outcome. Neurology47:366-375, 1996

20. NINDS Stroke Study Group: Intracerebral hemorrhage after intravenous tPA therapyfor ischemic stroke. Stroke 28:2109-2188, 1997

21. O'Brien MD: Ischemic cerebral edema: A review. Stroke 10:623-628, 1979

22. Phelps ME, Gado MH, Hoffman EJ: Correlation of effective atomic number andelectron density with attenuation coefficients measured with polychromatic X-rays.Radiology 11 7:585-588, 1975

23. Plum F: What causes infarction in ischemic brain? The Robert Wartenburg Lecture.Neurology 33:222-233,. 1983

24. Raichle ME: The pathophysiology of brain ischemia. Ann Neurol 13:2-10,1983

25. Tomura N, Uemura K, Inugan-d A, et al: Early CT finding in cerebral infarction:Obscuration of the lentiform nucleus. Radiology 168:463-467,1988

26. Truwit CL, Barkovich Aj, Gean-Marton A, et al: Loss of the insular ribbon: Anotherearly CT sign of acute middle cerebral artery infarction. Radiology 176:801- 806,1990

27. von Kummer R, Allen KL, Holle R, et al: Acute stroke: Usefulness of early CT findingsbefore thrombolytic therapy. Radiology 205:327-333, 1997

28. von Kununer R, Meyding-Lamade U, Forsting M, et al: Sensitivity and prognosticvalue of early CT in occlusion of the middle cerebral artery trunk. AJNR Am JNeuroradiol 15:9-15, 1994

29. Yokogami K, Nakdno S, Ohta H, et al: Prediction of hemorrhagic complications afterthrombolytic therapy for middle rerebral artery occlusion: Value of pre- and post-therapeutic computed tomographic findings and angiographic occlusive site. Neurosurgery49:1102- 1107,1996

30. Lassen NA (1974) Control of cerebral circulation in health and disease. CirculationResearch 34: 749-760.

31. Poungvarin N, Bhoopat W, Viriyavejakul A et at (1987) Effects of dexamethasone inprimary supra- tentorial intracerebral hemorrhage. New England Journal of Medicine316: 1229-1233.

32. Ropper AH (1993) Treatment of intracranial hypertension. In Ropper AH (ed.)Neurological and Neurosurgical Intensive Care, pp 29-52. New York: Raven Press.

33. Shapiro HM (1975) Intracranial hypertension: therapeutic and anestheticconsiderations. Anesthesiology 43: 445-47 1.

34. Siesjp BK, Carlsson C, Hagerdal M et al (1976) Brain metabolism in the critically ill.Critical Care Medicine 4: 283-294.

35. Bell BA, Symon L, Branston NM: CBF and time thresholds for the formation ofischemic edema, and effect of reperfusion in baboons. J Neurosurg 62:31-41,1985

36. von Kummer R, Weber J: Brain and vascular imaging in acute ischemic stroke: Thepotential of computed tomography. Neurology 4(suppl):S52-55,1997

37. Bames D, McDonald WI, Landon DN, et al: The characterization of experimentalgliosis by quantitative nuclear magnetic resonance imaging. Brain 111:83-94, 1988

38. Newcombe J, Hawkins CP, Henderson CL, et al: Histopathology of multiple sclerosislesions detected by magnetic resonance imaging in unfixed postmortem central nervoussystem tissue. Brain 114:1013- 1023, 1991

39. Stewart WA, Hall LD, Berry K, et al: Correlation between NMR scan and brain slices:Data in multiple sclerosis. Lancet 2:412, 1984

40. Papadopoulos MC, Saadoun S, Binder DK, et al.. Molecular mechanisms of braintumor edema. Neuroscience. 2004;129(4):1011–1020.

41. Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelialcells. Nature. 1987;325(6101):253–257.

42. Bates DO, Lodwick D, Williams B. Vascular endothelial growth factor andmicrovascular permeability. Microcirculation. 1999;6(2):83–96.

43. Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol. 2000;50(1–2):109–120.

44. Lamszus K, Lengler U, Schmidt NO, et al.. Vascular endothelial growth factor,hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and placentagrowth factor in human meningiomas and their relation to angiogenesis and malignancy.Neurosurgery. 2000;46(4):938–947[discussion: 938–47].

45. Arrieta O, Garcia E, Guevara P, et al.. Hepatocyte growth factor is associated withpoor prognosis of malignant gliomas and is a predictor for recurrence of meningioma.Cancer. 2002;94(12):3210–3218.

46. Behzadian MA, Windsor LJ, Ghaly N, et al.. VEGF-induced paracellular permeabilityin cultured endothelial cells involves urokinase and its receptor. Faseb J. 2003;17(6):752–754.

47. Wang W, Dentler WL, Borchardt RT. VEGF increases BMEC monolayer permeabilityby affecting occludin expression and tight junction assembly. Am J Physiol Heart CircPhysiol. 2001;280(1):H434–H440.

48. Wang F, Feng XC, Li YM, et al.. Aquaporins as potential drug targets. Acta PharmacolSin. 2006;27(4):395–401.

49. Ludwig HC, Feiz-Erfan I, Bockermann V, et al.. Expression of nitric oxide synthaseisozymes (NOS I-III) by immunohistochemistry and DNA in situ hybridization. Correlationwith macrophage presence, vascular endothelial growth factor (VEGF) and oedemavolumetric data in 220 glioblastomas. Anticancer Res. 2000;20(1A):299–304.

50. Lafuente JV, Adan B, Alkiza K, et al.. Expression of vascular endothelial growth factor(VEGF) and platelet-derived growth factor receptor-beta (PDGFR-beta) in humangliomas. J Mol Neurosci. 1999;13(1–2):177–185.

51. Ludwig HC, Ahkavan-Shigari R, Rausch S, et al.. Oedema extension in cerebralmetastasis and correlation with the expression of nitric oxide synthase isozymes (NOS I-III). Anticancer Res. 2000;20(1A):305–310.

52. Plate KH, Breier G, Risau W. Molecular mechanisms of developmental and tumorangiogenesis. Brain Pathol. 1994;4(3):207–218.

53. Ingraham FD, Matson DD, Mc LR. Cortisone and ACTH as an adjunct to the surgeryof craniopharyngiomas. N Engl J Med. 1952;246(15):568–571.

54. Galicich JH, French LA, Melby JC. Use of dexamethasone in treatment of cerebraledema associated with brain tumors. J Lancet. 1961;81:46–53.

55. French LA, Galicich JH. The use of steroids for control of cerebral edema. ClinNeurosurg. 1964;10:212–223.

56. Romero IA, Radewicz K, Jubin E, et al.. Changes in cytoskeletal and tight junctionalproteins correlate with decreased permeability induced by dexamethasone in cultured ratbrain endothelial cells. Neurosci Lett. 2003;344(2):112–116.

57. Batchelor T, DeAngelis LM. Medical management of cerebral metastases. NeurosurgClin N Am. 1996;7(3):435–446.

58. Vecht CJ, Hovestadt A, Verbiest HB, et al.. Dose-effect relationship of dexamethasoneon Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8,and 16 mg per day. Neurology. 1994;44(4):675–680.

59. Vick NA, Wilson CB. Total care of the patient with a brain tumor with consideration ofsome ethical issues. Neurol Clin. 1985;3(4):705–710.

60. Zaki HS, Jenkinson MD, Du Plessis DG, et al.. Vanishing contrast enhancement inmalignant glioma after corticosteroid treatment. Acta Neurochir (Wien). 2004;146(8):841–845.

61. Bastin ME, Carpenter TK, Armitage PA, et al.. Effects of dexamethasone on cerebralperfusion and water diffusion in patients with high-grade glioma. AJNR Am JNeuroradiol. 2006;27(2):402–408.

62. Lu S, Ahn D, Johnson G, et al.. Peritumoral diffusion tensor imaging of high-gradegliomas and metastatic brain tumors. AJNR Am J Neuroradiol. 2003;24(5):937–941.

63. Rabinstein AA. Treatment of cerebral edema. Neurologist. 2006;12(2):59–73.

64. Gomes JA, Stevens RD, Lewin JJ, et al.. Glucocorticoid therapy in neurologic criticalcare. Crit Care Med. 2005;33(6):1214–1224.

65. Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment:experience from preclinical studies. Neurol Res. 2005;27:268–279.

66. Hua Y, Keep RF, Hoff JT, et al. Brain injury after intracerebral hemorrhage: the roleof thrombin and iron. Stroke. 2007;38:759–762.

67. Xi G, Keep R, Hoff J. Mechanisms of brain injury after intracerebral haemorrhage.Lancet Neurol. 2006;5:53–63.

68. Gebel JM, Jauch EC, Brott TG, et al. Natural history of perihematomal edema inpatients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33:2631–2635.

69. Zazulia AR, Diringer MN, Derdeyn CP, et al. Progression of mass effect afterintracerebral hemorrhage. Stroke. 1999;30:1167–1173.