Central Nervous SystemEdema

Essay

In Neuropsychiatry

Submitted for partial fulfillment of Master Degree

By

Mina Ibrahim Adly IbrahimM.B.B.CH

Supervisors of

Prof. Mohammed Yasser MetwallyProfessor of Neuropsychiatry

Faculty of Medicine-Ain Shams Universitywww.yassermetwally.com

Prof. Naglaa Mohamed ElkhayatProfessor of Neuropsychiatry

Faculty of Medicine-Ain Shams University

Dr. Ali Soliman Ali ShalashLecturer of Neuropsychiatry

Faculty of Medicine-Ain Shams University

Faculty of MedicineAin Shams University

2011

1

CCoonntteennttssSubject page

1. Acknowledgment………………………………………………2

2. List of abbreviations……………………………………………3

3. List of figures…………………………………………………..6

4. List of tables…………………………………………………....8

5. Introduction and aim of the work……………………………....9

6. Chapter (1): Pathogenesis of cerebral edema…………………15

7. Chapter (2): Chemical Mediators Involved in The Pathogenesis

Of Brain Edema…………………………………37

8. Chapter (3): Diagnosing cerebral edema……………………...53

9. Chapter (4): Cerebral Edema in Neurological Diseases………69

10.Chapter (5): Treatment of Cerebral Edema…………………...79

11. Chapter (6): Spinal Cord Edema In Injury and Repair……...101

12. Summary…………………………………………....………115

13. Discussion……..……………………………………………120

14. References………..…………………………………………123

15. Arabic summary……...…………………………………………

2

AAcckknnoowwlleeddggmmeenntt

Thanks to merciful lord for all the countless gifts you have

offered me, and thanks to my family for their love and support.

It is a great pleasure to acknowledge my deepest thanks and

gratitude to Prof. Mohammed Yasser Metwally, Professor of

Neuropsychiatry, Faculty of Medicine-Ain Shams University, for

suggesting the topic of this essay, and his kind supervision. It is a great

honour to work under his supervision.

I would like to express my deepest thanks and sincere appreciation

to Prof. Naglaa Mohamed Elkhayat, Professor of Neuropsychiatry,

Faculty of Medicine-Ain Shams University, for her encouragement,

creative and comprehensive advice until this work came to existence.

I would like to express my extreme sincere gratitude and

appreciation to Dr. Ali Soliman Ali Shalash, Lecturer of

Neuropsychiatry, Faculty of Medicine-Ain Shams University, for his

kind endless help, generous advice and support during the study.

Mina Ibrahim Adly

2011

3

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ADC: Apparent diffusion coefficient.

AMP& ADP: Adenosine monophosphate& Adenosine diphosphate.

Ang: Angiopoietin.

AQP: Aquaporins.

ATP: Adenosine triphosphate.

BBB: Blood–brain barrier.

BDNF: Brain derived neurotrophic factor.

BK: Bradykinin.

BSCB: Blood-spinal cord barrier.

Cav-1: Caveolin-1.

CBF: Cerebral blood flow.

CPP: Cerebral perfusion pressure.

CSF: Cerebrospinal fluid.

CT: Computed tomography.

Da: Dalton unit.

DPTA: Diethylenetriaminepentaacetic Acid.

DWI: Diffusion-weighted imaging.

EBA: Evans blue albumin.

ECS: Extracellular space.

FLAIR: Fluid-attenuated inversion recovery.

G: gram.

GCS: Glasgow coma scale.

HRP: Horseradish peroxidase.

4

HS: Hypertonic saline.

I 125: Iodine 125.

ICH: Intracranial hemorrhage.

ICP: Intracranial pressure.

ICUs: Intensive care units.

IGF-1: Insulin like growth factor 1.

IL: Interleukins.

JAM: Junctional adhesion molecule.

MAP: Mean arterial pressure.

MCA: Middle cerebral artery.

Meq/L: Milliequevalent per litre.

MIP: Macrophage inflammatory proteins.

MmHg: Millimetrs of mercury.

Mmol/L: Millimoles per litre.

MMPs: Matrix metalloproteinases.

MOsm/L: Milliosmoles per litre.

MRI: Magnetic resonance imaging.

mRNA: messenger Ribonucleic acid.

MS: Multiple sclerosis.

MT1-MMP: Membrane-type Matrix metalloproteinases.

Nm: Nanometre.

Nor-BNI: Nor-binaltrophimine.

NOS: Nitric oxide synthase.

PGs: Prostaglandins.

PWI: perfusion-weighted imaging.

5

SAH: Subarachnoid hemorrhage.

SCI: Spinal cord injury.

TBI: Traumatic brain injury.

TIMPs: Tissue inhibitors of metalloproteinases.

TNF-: Tumor necrosis factor alpha.

VEGF: Vascular endothelial growth factors.

ZO: zonula occludens.

6

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Figure Page

Figure 1: Gross image demonstrating edema in human brain compared

with a normal one...………………………………..…….18

Figure 2: White matter from an area of edema…………………....…19

Figure 3: Illustrated picture of blood brain barrier…………………..20

Figure 4: An axial CT scan with glioblastoma multiforme…….……21

Figure 5: The cold injury site…………………..……………………23

Figure 6: Endothelial phosphorylated Cav-1………………………...25

Figure 7: expression of caveolins and tight junction proteins during

BBB breakdown…..……………………………….………29

Figure 8: Axial CT scans with whole right hemisphere infarction…..32

Figure 9: An axial MR image of a 4 year old with hydrocephalus….34

Figure 10: Pathways for water entry into and exit from brain……….42

Figure 11: Temporal expression of growth factor proteins is shown

during the period of BBB breakdown in the cold injury

mode……………………………………………………..51

Figure 12: Cerebral herniation syndromes..…………………………55

Figure 13: CT scan of global brain edema...…………………………60

Figure 14: CT scan showing brain edema caused by a tumor……….61

Figure 15: An area which represents an infarct………………….…..61

Figure 16: Intracranial hemorrhage depicted by MRI……………….63

Figure 17: Periventricular FLAIR hyperintensity due to hydrocephalic

edema………………………………………………….…….63

7

Figure 18: MRI showing central pontine myelinolysis…...................63

Figure 19: The cytotoxic component of acute cerebral ischemia is

demonstrated by ADC hypointensity, whereas T2 weighted

sequences may be unrevealing …….………………………..65

Figure 20: MRI of status epilepticus reveals evidence of cytotoxic

edema..............................................................................…...65

Figure 21: Disruption of the BBB associated with a glioma….…….66

Figure 22: Mass effect from infarction and midline shift.

Hemicraniectomy performed with herniation through the

skull defect…………………………………………….…100

8

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Table Page

Table 1: Vasoactive agents that increase the blood–brain barrier

permeability……………………..……………………….39

Table 2: Summary of the clinical subtypes of herniation

syndromes…………………………………………….…56

Table 3: Summary of experimental studies comparing different

formulations of hypertonic saline with mannitol 20%….…90

Table 4: Theoretical potential complications of using hypertonic saline

solutions………………..………………………………….93

Table 5: Treatment Strategies in Spinal Cord Injury…………..…...109

9

IInnttrroodduuccttiioonnSurprising as it may sound cerebral edema is a fairly common

pathophysiological entity which is encountered in many clinical

conditions. Many of these conditions present as medical emergencies.

By definition cerebral edema is the excess accumulation of water in

the intra-and/or extracellular spaces of the brain (Kempski, 2001).

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, cerebral spinal fluid and blood is at all times constant. Since

skull is like a rigid box which cannot be stretched, if there is excessive

water, the volume of brain as well as blood inside the skull is

compressed. Further increase in the intracranial pressure (ICP)

eventually causes a reduction in cerebral blood flow throughout the

brain which can correspondingly cause extensive cerebral infarction. If

these changes continue further, it leads to the disastrous condition of

brain herniation, which is the fore runner of irreversible brain damage

and death (Rosenberg, 2000).

Despite the classification of edema into distinct forms as:

vasogenic, cytotoxic, hydrocephalic and osmotic, it is recognized that

in most clinical situations there is a combination of different types of

edema depending on the time course of the disease. For example, early

cerebral ischemia is associated with cellular swelling and cytotoxic

edema; however, once the capillary endothelium is damaged there is

10

BBB breakdown and vasogenic edema results. While in traumatic

brain injury both vasogenic and cytotoxic edema coexist (Marmarou

et al, 2006).

Vasogenic cerebral edema refers to the influx of fluid and solutes

into the brain through an incompetent blood brain barrier. This is the

most common type of brain edema and results from increased

permeability of the capillary endothelial cells; the white matter is

primarily affected. Breakdown in the BBB allows movement of

proteins from the intravascular space through the capillary wall into

the extracellular space. This type of edema is seen in: trauma, tumor,

abscess, hemorrhage, infarction, acute MS plaques, and cerebral

contusion (Metwally, 2009).

Cellular (cytotoxic) cerebral edema refers to a cellular swelling. It is

seen in conditions like head injury, severe hypothermia,

encephalopathy, pseudotumor cerebri and hypoxia. It results from the

swelling of brain cells, most likely due to the release of toxic factors

from neutrophils and bacteria within minutes after an insult. Cytotoxic

edema affects predominantly the gray matter (Liang et al, 2007).

Interstitial edema is seen in hydrocephalus when outflow of CSF is

obstructed and intraventricular pressure increases. The result is

movement of sodium and water across the ventricular wall into the

paraventricular space. Interstitial cerebral edema occurring during

11

meningitis is due to obstruction of normal CSF pathways (Abbott,

2004).

Osmotic cerebral edema occurs when plasma is diluted by

hyponatremia, syndrome of inappropriate antidiuretic hormone

secretion, hemodialysis, or rapid reduction of blood glucose in

hyperosmolar hyperglycemic state, the brain osmolality will then

exceed the serum osmolality creating an abnormal pressure gradient

down which water will flow into the brain causing edema (Nag, 2003)

a.

Pathophysiology of cerebral edema at cellular 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 which

begins with glutamate release into the extracellular space. Calcium

and sodium entry channels 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 (Marmarou,

2007).

It appears that injury in the spinal cord induce blood-spinal cord

barrier (BSCB) disruption. The BSCB breakdown involves cascade of

events involving several neurochemicals like: serotonin,

prostaglandins, neuropeptides and amino acids (Sharma, 2004).

Serial neuroimaging by CT scans and magnetic resonance imaging

can be particularly useful in confirming intracranial compartmental

12

and midline shifts, herniation syndromes, ischemic brain injury, and

exacerbation of cerebral edema (sulcal effacement and obliteration of

basal cisterns), and can provide valuable insights into the type of

edema present (focal or global, involvement of gray or white matter).

CT scan provides an excellent tool for determination of abnormalities

in brain water content. CT is an excellent method for following the

resolution of brain edema following therapeutic intervention. MRI

appears to be more sensitive than CT at detecting development of

cerebral edema (Kuroiwa et al, 2007).

Management of cerebral edema involves using a systematic and

algorithmic approach, from general measures to specific therapeutic

interventions, and decopressive surgery. The general measures

include: elevation of head end of bed 15-30 degrees to promote

cerebral venous drainage, fluid restriction, hypothermia, and

correction of factors increasing ICP e.g. hypercarbia, hypoxia,

hyperthermia, acidosis, hypotension and hypovolaemia (Ng et al,

2004).

Specific therapeutic interventions include: 1. osmotherapy:

mannitol, the most popular osmotic agent (Toung et al, 2007).

2. Diuretics: the osmotic effect can be prolonged by the use of loop

diuretics after the osmotic agent infusion (Thenuwara et al, 2002).

3. Corticosteroids: they lower intracranial pressure primarily in

vasogenic edema because of their effect on the blood vessel (Sinha et

al, 2004).

13

4. Controlled hyperventilation: is helpful in reducing the raised ICP

which falls within minutes of onset of hyperventilation (Mayer &

Rincon, 2005).

Cerebral edema, irrespective of the underlying origin of brain

injury, is a significant cause of morbidity and death, and though there

has been good progress in understanding pathophysiological

mechanisms associated with cerebral edema more effective treatment

is required and is still awaited (Rabinstein, 2006).

14

Aim of the work The aim of this review is to discuss different types and

etiologies of brain edema and to overview recent management of the

various chemical mediators involved in the pathogenesis of cerebral

edema.

15

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IInnttrroodduuccttiioonn::Brain edema is defined as an increase in brain volume resulting

from a localized or diffuse abnormal accumulation of fluid within the

brain parenchyma (Johnston & Teo, 2000). This definition excludes

volumetric enlargement due to cerebral engorgement which results

from an increase in blood volume on the basis of either vasodilatation

due to hypercapnia or impairment of venous flow secondary to

obstruction of the cerebral veins and venous sinuses (Nag, 2003) b.

Initially, the changes in brain volume are compensated by a

decrease in cerebrospinal fluid (CSF) and blood volume. In large

hemispheric lesions, progressive swelling exceeds these compensatory

mechanisms and an increase in the intracranial pressure (ICP) results

in herniations of cerebral tissue leading to death (Wolburg et al,

2008).

Hence the significance of brain edema, which continues to be a

major cause of mortality after diverse types of brain pathologies such

as major cerebral infarcts, hemorrhages, trauma, infections and

tumors. The lack of effective treatment for brain edema remains a

stimulus for continued interest and research into the pathogenesis of

this condition (Marmarou, 2007).

17

GGeenneerraall ccoonnssiiddeerraattiioonnss::The realization that brain edema is associated with either extra- or

intra-cellular accumulation of abnormal fluid led to its classification

into vasogenic and cytotoxic edema. Vasogenic edema is associated

with dysfunction of the blood–brain barrier (BBB) which allows

increased passage of plasma proteins and water into the extracellular

compartment, while cytotoxic edema results from abnormal water

uptake by injured brain cells. Other types of edema described include

hydrocephalic or interstitial edema and osmotic or hypostatic edema

(Czosnyka et al, 2004).

18

AAeettiiooppaatthhooggeenneessiiss ooff vvaarriioouuss ttyyppeess ooffcceerreebbrraall eeddeemmaa::

11.. VVaassooggeenniicc eeddeemmaa::Brain diseases such as hemorrhage, infections, seizures, trauma,

tumors, radiation injury and hypertensive encephalopathy are

associated with BBB breakdown to plasma proteins leading to

vasogenic edema. Vasogenic edema also occurs in the later stages of

brain infarction. Vasogenic edema may be localized or diffuse

depending on the underlying pathology. The overlying gyri become

more flattened, and the sulci are narrowed (Figure 1). When diffuse

edema is present the ventricles are slit-like (Hemphill et al, 2001).

Figure 1: 1b. Gross image demonstrating edema in human braincompared with a normal one (figure 1 a) (Hemphill et al, 2001).

Breakdown of the BBB to plasma proteins can be demonstrated by

immunohistochemistry using antibodies to whole serum proteins,

19

albumin, fibrinogen or fibronectin in human autopsy brain tissue or

brains of experimental animals (Kimelburg, 2004).

The white matter is more edema-prone since it has unattached

parallel bands of fibers with an intervening loose extracellular space

(ECS). The grey matter has a higher cell density with many inter-

cellular connections which reduce the number of direct linear

pathways making the grey matter ECS much less subject to swelling.

Light microscopy in acute edema shows vacuolation and pallor of the

white matter (Figure 2a & b) (Ballabh et al, 2004).

Figure 2: (figure 2a) Light microscopic appearance of normal white matterstained with hematoxylin–eosin and Luxol fast blue. (Figure 2b) White matter

from an area of edema adjacent to a meningioma (not shown) shows myelin pallorand an increased number of astrocytes (arrowheads) (Ballabh et al, 2004).

In long standing cases of edema there is fragmentation of the

myelin sheaths which are phagocytosed by macrophages resulting in

myelin pallor. An astrocytic response is present in the areas of edema.

mRNA levels are maximal on days 4–5 and they remain elevated up to

day 14 post-injury. Spatial mRNA expression follows the pattern of

post-injury edema being present in the cortex adjacent to the lesion,

20

and the ipsilateral and contralateral callosal radiations (Hawkins,

2008).

TThhee bblloooodd––bbrraaiinn bbaarrrriieerr ((BBBBBB))::It is well known that cerebral vessels differ from non-neural vessels

and have a structural, biochemical and physiological barrier, which

limits the passage of various substances including plasma proteins

from blood into brain (Nag, 2003) b.

Cellular components of the BBB include endothelium, pericytes

and the perivascular astrocytic processes, which together with their

associated neurons form the ‘‘neurovascular unit’’. The best studied

cell type is cerebral endothelium which has two distinctive structural

features that limit their permeability to plasma proteins (figure 3).

These cells have fewer caveolae or plasmalemmal vesicles than non-

neural vessels and circumferential tight junctions are present along the

interendothelial spaces. Breakdown of the BBB is assessed by tracers.

Gadolinium DPTA is the most commonly used tracer in human

studies (Figure 4).

Figure 3: illustrated picture of blood brain barrier (Nag, 2003) b.

21

Tracers like 125 Iodine-labeled serum albumin, Evans blue,

horseradish peroxidase (HRP) and dextrans, having molecular weights

of 60,000–70,000 Da, are used in experimental animals. The diameter

of the HRP molecule is 600 nm which is very close to the diameter of

albumin which is 750 nm, making HRP a good tracer for protein

permeability studies. Tracers having molecular weights less than

3,000 Da such as lanthanum, small molecular weight dextrans, and

sodium fluorescein or 14C sucrose are indicators of BBB dysfunction

to ions (Zlokovic, 2008).

Although small amounts of water may also enter brain, the

magnitude is not sufficient to produce edema. Therefore, studies using

these tracers have no relevance to the BBB breakdown to plasma

proteins which is a key feature of vasogenic brain edema (Volonte et

al, 2001).

Figure 4: an axial CT scan post-gadolinium from a case diagnosed withglioblastoma multiforme showing a mass in the right hemisphere with midlineshift. A serpiginous area of enhancement is present in the center of the mass

indicating breakdown of the BBB (Zlokovic, 2008).

22

Permeability properties of cerebral endothelium are not uniform in

all brain vessels. In rodents, aside from regions outside the BBB, a

significant number of normal cerebral vessels are permeable to HRP.

Thus, the demonstration of increased permeability in these areas

cannot be ascribed to pathology. Also, freeze fracture studies show

that there is variation in the number of interconnected strands that

make up tight junctions in the different types of brain vessels, with

cortical vessels having junctions of the highest complexity, while

junctions of the postcapillary venules are least complex. The latter

would explain why increased permeability of the postcapillary venules

occurs in inflammation (Nag, 2007).

TThhee ccoolldd iinnjjuurryy mmooddeell::This model was developed by Klatzo to study the pathophysiology

of vasogenic edema and has been used extensively in studies. A

unilateral focal cortical freeze lesion is produced by placing the tip of

a cold probe cooled with liquid nitrogen on the dura for 45 seconds.

There are variations in the method of producing the cold lesion which

makes it difficult to compare the results obtained from different

laboratories (Klatzo, 1958 coated from Sukriti Nag, et al, 2009).

The ensuing edema was initially studied using exogenous tracers

such as Evans blue and HRP. BBB breakdown to HRP was present at

12 h, which was the earliest time point studied and the BBB was

restored on day 6 post-injury. Similar results were obtained using

immunohistochemistry to demonstrate endogenous serum protein

23

extravasation using an antibody to serum proteins, fibrinogen or

fibronectin (Lossinsky & Shivers, 2004).

Two peaks of active BBB breakdown occur in the cold injury

model. An initial phase which extends from 6 hours to day 2 affects

mainly arterioles and large venules at the margin of the lesion and

leads to extravasation of plasma proteins at the lesion site (Figure 5a).

There is spread of edema fluid through the ECS into the underlying

white matter of the ipsilateral and contralateral side (Figure 5b). The

second phase of BBB breakdown accompanies angiogenesis and is

maximal on day 4 (Figure 5c). Arterioles, veins and neovessels at the

lesion site show extravasation of plasma proteins which remain

confined to the lesion site (Furuse & Tsukita, 2006).

Figure 5: (figure 5a): the cold injury site on day 0.5 shows severalvessels with BBB breakdown to fibronectin (arrowheads).

(Figure 5b): On day 1, immunostaining with an antibody to serumproteins demonstrates extravasation of serum proteins into the white

matter.(Figure 5c): On day 4, there is spread of fibronectin from permeable

vessels into the extracellular spaces (Furuse & Tsukita, 2006).

24

BBBBBB bbrreeaakkddoowwnn iinn vvaassooggeenniicc eeddeemmaa::Ultrastructural studies demonstrate an increase in the number of

endothelial caveolae only in the vessels with BBB breakdown to HRP

within minutes after the onset of pathological states such as

hypertension, spinal cord injury, seizures, experimental autoimmune

encephalomyelitis, excitotoxic brain damage, brain trauma, and BBB

breakdown- induced by bradykinin, histamine, and leukotriene C4

(Nag, 2002).

These findings suggest that enhanced caveolae (figure 6) are the

major route by which early passage of plasma proteins occurs in brain

diseases associated with vasogenic edema. Caveolae allow protein

passage across endothelium via fluid-phase transcytosis and

transendothelial channels. These enhanced caveolae represent the

response of viable endothelial cells to injury since both caveolar

changes and BBB breakdown are reversed 10 minutes after the onset

of acute hypertension induced by a single bolus of a pressor agent. No

alterations in tight junctions were noted in the studies mentioned

above (Parton & Simons, 2007).

Convincing demonstration of tight junction breakdown has only

been reported following the intracarotid administration of

hyperosmotic agents using the tracer lanthanum, which is a marker of

ionic permeability. Thus, junctional breakdown to proteins occurs late

in the course of brain injury probably during end-stage disease and

precedes endothelial cell breakdown. Research in the last decade has

led to the isolation of novel proteins in both caveolae and tight

25

junctions and studies are underway to define their role in brain injury

(Minshall & Malik, 2006).

Figure 6: a vein with BBB breakdown to fibronectin showsendothelial phosphorylated Cav-1 (PY14Cav-1) (Parton &

Simons, 2007).

CCaavveeoolliinn--11 ((CCaavv--11))::The specific marker and major component of caveolae is Cav-1, an

integral membrane protein, which belongs to a multigene family of

caveolin-related proteins that show similarities in structure but differ

in properties and distribution (Virgintino et al, 2002).

Of the two major isoforms of Cav-1 only the -isoform is

predominant in the brain. Cav-2 has a similar distribution as Cav-1

and non-neural endothelial cells express both Cav-1 and -2. Cav-1 has

been localized in human and murine cerebral endothelial cells. The

properties of Cav-1 are the subject of many reviews (Boyd et al,

2003).

Brain injury is associated with increased expression of Cav-1. Time

course studies in the rat cortical cold injury model demonstrate a

26

threefold increase in Cav-1 expression at the lesion site on day 0.5

post-injury. At the cellular level, a marked increase in endothelial

Cav-1 protein is present in vessels showing BBB breakdown to

fibronectin (Rizzo et al, 2003).

Further studies demonstrate that the endothelial Cav-1 in vessels

with BBB breakdown is phosphorylated. It is well established that

dilated vascular segments show enhanced permeability and leak

protein. Phosphorylation of Cav-1 is known to be an essential step for

formation of caveolae (figure 6). Thus, phosphorylation of Cav-1 is

essential for transcytosis of proteins across cerebral endothelium

leading to BBB breakdown and brain edema following brain injury

(Minshall et al, 2003).

In summary, caveolae and Cav-1 have a significant role in early

BBB breakdown; hence, they could be potential therapeutic targets in

the control of early brain edema (Williams & Lisanti, 2004).

TTiigghhtt jjuunnccttiioonn pprrootteeiinnss::Tight junctions are localized at cholesterol-enriched regions along

the plasma membrane associated with Cav-1. Tight junctions are

formed of three integral transmembrane proteins: occludin, the

claudin, and junctional adhesion molecule (JAM) families of proteins

(Forster, 2008).

The extracellular loops of these proteins originate from neighboring

cells to form the paracellular barrier of the tight junction, which

27

selectively excludes most blood borne substances from entering brain.

Several accessory cytoplasmic proteins have also been isolated which

are necessary for structural support at the tight junctions. They include

zonula occludens (ZO)-1 to -3, and cingulin (Nusrat et al, 2000).

Occludin, the first tight junction protein to be identified is an

approximately 60-kDa tetraspan membrane protein with two

extracellular loops. High expression of occludin in brain endothelial

cells as compared to nonneural endothelia provides an explanation for

the different properties of both these endothelia (Song et al, 2007).

Claudins are 18- to 27-kDa tetraspan proteins with two extracellular

loops, and they do not show any sequence similarity to occludin. The

claudin family consists of 24 members in humans and exhibits distinct

expression patterns in tissue. Claudins may be the major

transmembrane proteins of tight junctions as occludin knockout mice

are still capable of forming interendothelial tight junctions while

claudin knockout mice are nonviable (Nitta et al, 2003).

The JAMs belong to the immunoglobulin superfamily. JAM-A, the

first member of the family to be isolated has been implicated in a

variety of physiologic and pathologic processes involving cellular

adhesion including tight junction assembly and leukocyte

transmigration (Turksen & Troy, 2004).

Occludin, claudins-3, -5 and -12, JAM-A and ZO-1 proteins have

been localized in normal cerebral endothelium. Decreased expression

of the tight junction proteins in vessels with BBB breakdown in the

cold injury model follows a specific sequence with transient decreases

28

in expression of JAM-A on day 0.5 only, of claudin-5 on day 2 only

while occludin expression is attenuated from day 2 onwards and

persists up to day 6 (figure 7) (Plumb et al, 2002).

RReessoolluuttiioonn ooff eeddeemmaa::Much of our information about the resolution of vasogenic edema is

derived from the earlier studies of the cortical cold injury model.

During the period of BBB breakdown to plasma proteins there is

progressive increase in I 125-labeled albumin, paralleled by an increase

in water content (Van Itallie & Anderson, 2006).

Disappearance of serum proteins from the ECS coincides with the

return of water content to normal values. Resolution of edema occurs

immediately after closure of the BBB to proteins (figure 7). These

studies support previous observations that caveolae and Cav-1

changes precede significant tight junction changes during early BBB

breakdown (Xi et al, 2002).

Reduction of CSF pressure accelerates the clearance of edema fluid

into the ventricle. Recent evidence suggests that aquaporin 4 channels

located in the ependyma and astrocytic foot processes (digesting

serum proteins), have an important role in the clearance of the

interstitial water (Turksen & Troy, 2004).

29

(Figure 7) Expression of caveolins and junction proteins duringBBB breakdown:

Days post-lesion

0.5 2 4 6BBB break down

Caveolin-1 and PY14 Caveolin-1

Junctional adhesion molecule-A

Claudin-5

Occludin

Basal Increased Decreased

Figure 7: expression of caveolins and tight junction proteins during BBBbreakdown in the cold injury model. Increased expression of both caveolin-1 and

phosphorylated caveolin-1 (PY14 Caveolin-1) was observed. Decreasedexpression of junctional adhesion molecule-A was observed on day 0.5 only and

of claudin-5 on day 2 only, while decreased expression of occludin was present onday 2 and persisted throughout the period of observation (Vorbrodt, 2003).

Other mechanisms for clearance of edema fluid include passage of

extravasated proteins via the abluminal plasma membrane of

endothelial cells back into blood. Edema fluid can also pass across the

glia limitans externa into the CSF in the subarachnoid space and enter

the arachnoid granulations for clearance into the superior sagittal

venous sinus (Papadopoulos et al, 2004).

30

Quantitative studies of the relative involvement of the various

routes indicate that the clearance of edema by bulk flow into the CSF

is restricted to the early phase of edema. Clearance by brain

vasculature is small compared to that of CSF (Stummer, 2007).

22.. CCyyttoottooxxiicc EEddeemmaa::The most commonly encountered cytotoxic edema occurs in

cerebral ischemia, which may be focal due to vascular occlusion, or

global due to transient or permanent reduction in brain blood flow.

Other causes include traumatic brain injury, infections, and metabolic

disorders including kidney and liver failure (Vaquero & Butterworth,

2007).

Intoxications such as exposure to methionine sulfoxime, cuprizone,

and isoniazid are associated with cytotoxic edema and swelling of

astrocytes. Triethyl tin and hexachlorophene intoxications cause

accumulation of water in intramyelinic clefts and produce striking

white matter edema, while axonal swelling is a hallmark of exposure

to hydrogen cyanide. Since toxins are not involved in many cases of

cytotoxic edema some prefer the term ‘‘cellular edema’’ rather than

cytotoxic edema (Ranjan et al, 2005).

Experimental models used to study cytotoxic edema include the

focal and global ischemia models and the water intoxication model. In

cytotoxic edema astrocytes, neurons and dendrites undergo swelling

with a concomitant reduction of the brain ECS. This cellular swelling

31

does not constitute edema which implies a volumetric increase of

brain tissue (Lo et al, 2003).

Astrocytes are more prone to pathological swelling than neurons

because they are involved in clearance of potassium and glutamate,

which cause osmotic overload that in turn promotes water inflow.

Astrocytes outnumber neurons 20:1 in humans and astrocytes can

swell up to five times their normal size, therefore glial swelling is the

main finding in this type of edema (Rosenblum, 2007).

Cytotoxic edema is best studied in focal ischemia models where an

interruption of energy supply due to decrease in blood flow below a

threshold of 10 ml/100 g leads to failure of the ATP-dependent Na

pumps. This results in intracellular Na accumulation, with shift of

water from the extracellular to the intracellular compartment to

maintain osmotic equilibrium. This can occur within seconds. The Na

is accompanied by influx of Cl¯, H¯ and HCO3¯ ions (Unterberg et al,

2004).

These changes are reversible. However, ischemia of less than 6

minutes results in irreversible brain damage forming the ‘‘ischemic

core’’. This infracted tissue is surrounded by a region referred to as

the ‘‘penumbra’’ where the blood flow is greater than 20 ml/100 g per

min. Neurons and astrocytes in the penumbra undergo cytotoxic

edema. If hypoxic conditions persist, death of these neurons and glia

results in release of water into the ECS (Liang et al, 2007).

Damage to endothelium leads to vasogenic edema which can be

demonstrated by computed tomography in human brain by 24–48

32

hours after the onset of ischemic stroke (Figure 8a & b) (Ayata &

Ropper, 2002).

Figure 8a Figure 8b

Figure 8: (figure 8a): Axial CT scans of a 52-year-old patient showing an area ofdecreased density and loss of grey/white differentiation representing an infarct

present in the right insular region (day 1).(Figure 8b): Axial CT scans of the same man (on day 3); a large area of

decreased density involving almost the whole right hemisphere is present due toinfarction associated with vasogenic edema (Ayata & Ropper, 2002).

The vasogenic component of ischemic brain edema is biphasic. The

first opening of the BBB is hemodynamic in nature and occurs 3–4 h

after the onset of ischemia. There is marked reactive hyperemia which

develops in the previously ischemic area due to a rush of blood into

vessels that are dilated by acidosis and devoid of autoregulation. This

opening may be brief but it allows the entry of blood substances into

the tissue. The second opening of the BBB follows the release of

ischemic occlusion and may be associated with a progressive increase

in the infarct size (Rosenberg & Yang, 2007).

33

Exudation of protein into the infarct area combined with an increase

in osmolarity due to breakdown of cell membranes results in an

increase in local tissue pressure. This leads to depression of regional

blood flow below the critical thresholds for viability in penumbral

regions and to further extension of the territory which undergoes

irreversible tissue damage. Elimination routes for excess water may be

the same as those in vasogenic edema (Kuroiwa et al, 2007).

33.. HHyyddrroocceepphhaalliicc oorr iinntteerrssttiittiiaall eeddeemmaa::This is best characterized in noncommunicating hydrocephalus

where there is obstruction to flow of CSF within the ventricular

system or communicating hydrocephalus where the obstruction is

distal to the ventricles and results in decreased absorption of CSF into

the subarachnoid space. In hydrocephalus, a rise in the intraventricular

pressure causes CSF to migrate through the ependyma into the

periventricular white matter, thus, increasing the extracellular fluid

volume (figure 9). The edema fluid consists of Na and water and has

the same composition as CSF (Johnston & Teo, 2000).

The white matter in the periventricular regions is spongy and on

microscopy there is widespread separation of glial cells and axons.

Astrocytic swelling is present followed by gradual atrophy and loss of

astrocytes (Abbott, 2004).

In chronic hydrocephalus, increase in the hydrostatic pressure

within the white matter results in destruction of myelin and axons and

34

this is associated with a microglial response. The end result is thinning

of the corpus callosum and compression of the periventricular white

matter. Other changes reported are destruction of the ependyma which

may be focal or widespread, distortion of cerebral vessels in the

periventricular region with collapse of capillaries and occasionally

there is injury of neurons in the adjacent cortex (Czosnyka et al,

2004).

Figure 9: An axial MR image of a 4 year old with hydrocephalus involving thelateral and third ventricles due to a posterior fossa tumor (not shown). The flair

sequence highlights the transependymal edema (Johnston & Teo, 2000).

In normal pressure hydrocephalus where normal intraventricular

pressure is recorded, ependymal damage with backflow of CSF is

postulated to produce edema. Functional manifestations in these cases

are minor unless changes are advanced when dementia and gait

disorder become prominent (Ball & Clarke, 2006).

35

44.. OOssmmoottiicc eeddeemmaa::

In this type of edema an osmotic gradient is present between plasma

and the extracellular fluid and the BBB is intact, otherwise an osmotic

gradient could not be maintained. Edema may occur with a number of

hypo-osmolar conditions including: improper administration of

intravenous fluids leading to acute dilutional hyponatremia,

inappropriate antidiuretic hormone secretion, excessive hemodialysis

of uremic patients and diabetic ketoacidosis (Kimelburg, 2004).

There is a decrease of serum osmolality due to reduction of serum

Na and when serum Na is less than 120 mmol/L, water enters the

brain and distributes evenly within the ECSs of the grey and white

matter. Astrocytic swelling may be present. The spread of edema

occurs by bulk flow along the normal interstitial fluid pathways.

Following a 10% or greater reduction of plasma osmolarity, there is a

pronounced increase in interstitial fluid volume flow, and extracellular

markers are cleared into the CSF at an increased rate (Katayama &

Katayama, 2003).

The formation of osmotic edema can lead to a significant increase

in the rate of CSF formation without any contribution of the choroid

plexuses. Since osmotic edema is vented rapidly, the increase in brain

volume tends to be modest. Experimentally, this type of edema is

induced following intraperitoneal infusion of distilled water. The BBB

is not affected and cytotoxic mechanisms are not involved. Osmotic

brain edema can also occur when the plasma osmolarity is normal but

36

tissue osmolarity is high in the core of the lesion as in brain

hemorrhage, infarcts or contusions (Nag, 2003) a.

37

CChhaapptteerr ((22)):: CChheemmiiccaallMMeeddiiaattoorrss IInnvvoollvveedd iinn

tthhee PPaatthhooggeenneessiiss ooffBBrraaiinn EEddeemmaa

38

CChheemmiiccaall MMeeddiiaattoorrss IInnvvoollvveeddiinn TThhee PPaatthhooggeenneessiiss OOff BBrraaiinn

EEddeemmaa

IInnttrroodduuccttiioonn::Brain edema continues to be a major cause of mortality after

diverse types of brain pathologies such as major cerebral infarcts,

hemorrhages, trauma, infections and tumors. The classification of

edema into vasogenic, cytotoxic, hydrocephalic and osmotic has

stood the test of time although it is recognized that in most clinical

situations there is a combination of different types of edema during

the course of the disease (Schilling & Wahl, 1999).

It is well established that vaso-active agents can increase BBB

permeability and promote vasogenic brain edema (Table 1)

(Yamamoto et al, 2001).

Basic information about the types of edema is provided for better

understanding of the expression pattern of some of the newer

molecules implicated in the pathogenesis of brain edema. These

molecules include the aquaporins (AQP), matrix metalloproteinases

(MMPs) and growth factors such as vascular endothelial growth

factors (VEGF) A and B and the angiopoietins. The potential of

these agents in the treatment of edema is the subject of many

reviews (Dolman et al, 2005).

39

Table 1: Vasoactive agents that increase blood–brain barrierpermeability:

Arachidonic acid

Bradykinin

Complement-derived polypeptide C3a-desArg Glutamate

Histamine

Interleukins: IL-1a, IL-1b, IL-2 Leukotrienes

Macrophage inflammatory proteins MIP-1, MIP-2

Nitric oxide

Oxygen-derived free radicals

Phospholipase A2, platelet activating factor,

prostaglandins

Purine nucleotides: ATP, ADP, AMP

Thrombin

Serotonin

(Yamamoto et al, 2001).

40

AAqquuaappoorriinnss aanndd bbrraaiinn eeddeemmaa::Aquaporins (AQP) are a growing family of molecular water-

channel proteins that assemble in membranes as tetramers. Each

monomer is 30 kDa and has six membrane-spanning domains

surrounding a water pore that allows bidirectional passage of water

(Badaut et al, 2001).

At least 13 AQPs have been found in mammals and more than

300 in lower organisms. Expression of AQP 1, AQP3, AQP4,

AQP5, AQP8 and AQP9 has been reported in rodent brain. Only

AQP1 and AQP4 are reported to have a role in human brain edema

and will be discussed (Oshio et al, 2005)..

AAqquuaappoorriinn11 ((AAQQPP11))::Localization of AQP1 in the apical membrane of the choroid

plexus epithelium suggests that it may have a role in CSF secretion.

This could be supported by the finding that AQP1 is upregulated in

choroid plexus tumors, which are associated with increased CSF

production. AQP1 is also expressed in tumor cells and peritumoral

astrocytes in high grade gliomas (Longatti et al, 2006).

Although AQP1 is present in endothelia of non-neural vessels, it

is not observed in normal brain capillary endothelial cells. Brain

capillary endothelial cells cultured in the absence of astrocytes and

those in brain tumors that are not surrounded by astrocytic end-feet

do express AQP1, suggesting that astrocytic end-feet may signal

41

adjacent endothelial cells to switch off AQP1 expression (Verkman,

2005).

AQP1-null mice show a 25% reduction in the rate of CSF

secretion, reduced osmotic permeability of the choroid plexus

epithelium and decreased ICP. These findings support the role of

AQP1 in facilitating CSF secretion into the cerebral ventricles by the

choroid plexuses and suggest that AQP1 inhibitors may be useful in

the treatment of hydrocephalus and benign intracranial hypertension,

both of which are associated with increased CSF formation or

accumulation (Tait et al, 2008).

AAqquuaappoorriinn44 ((AAQQPP44))::AQP4, the principal AQP in mammalian brain, is expressed in

glia at the borders between major water compartments and the brain

parenchyma (figure 10). AQP4 is expressed in the basolateral

membrane of the ependymal cells lining the cerebral ventricles and

subependymal astrocytes which are located at the ventricular CSF

fluid– brain interface (Furman et al, 2003).

Expression of AQP4 in astrocytic foot processes brings it in close

proximity to intracerebral vessels, and thus, the blood–brain

interface. Water molecules moving from the blood pass through the

luminal endothelial membranes by diffusion and across the

astrocytic foot processes through the AQP4 channels. AQP4 is also

expressed in the dense astrocytic processes that form the glia

limitans which is at the subarachnoid– CSF fluid interface (Rash et

al, 2004).

42

Figure 10: Pathways for water entry into and exit from brain are shown. TheAQP4- dependent water movement across the blood–brain barrier, through

ependymal and arachnoid barriers is shown (Furman et al, 2003).

Two AQP4 splice variants are expressed in brain, termed M1 and

M23, which can form homo- and hetero-tetramers, respectively. The

location of AQP 4 at the brain–fluid interfaces suggests that it is

important for brain water balance and may play a key role in brain

edema. AQP4 overexpression in human astrocytomas correlates with

the presence of brain edema on magnetic resonance imaging

(Silberstein et al, 2004).

However, decrease in AQP4 protein expression is associated with

early stages of edema in rodents subjected to permanent focal brain

ischemia and hypoxia-ischemia. In traumatic brain injury AQP4

mRNA is decreased in the area of edema adjacent to a cortical

43

contusion. AQP4-null mice provide strong evidence for AQP4

involvement in cerebral water balance in the various types of edema

(Warth et al, 2007).

Vasogenic edema:

Data derived from AQP4-null mice suggest that AQP4 is involved

in the clearance of extracellular fluid from the brain parenchyma in

vasogenic edema (Meng et al, 2004).

A number of models in which vasogenic edema is the

predominant form of edema, including the cortical cold injury,

tumor implantation and brain abscess models, demonstrate that the

AQP4-null mice have a significantly greater increase in brain water

content and ICP than the wild-type mice suggesting that brain water

elimination is defective after AQP4 deletion (Papadopoulos &

Verkman, 2007).

Melanoma cells implanted into the striatum of wild-type and

AQP4-null mice produce peritumoral edema and comparable sized

tumors in both groups after a week. However, the AQP4- null mice

have a higher ICP and water content. This suggests that in vasogenic

edema, excess water enters the brain ECS independently of AQP4,

but exits the brain primarily through AQP4 channels into the CSF

and via astrocytic foot processes into blood (Papadopoulos &

Verkman, 2007).

44

Cytotoxic edema:

Swelling of astrocytic foot processes is a major finding in

cytotoxic edema and since AQP4 channels are located in the

astrocytic foot processes, it was hypothesized that they may have a

role in formation of cell swelling. This was found to be the case

since water intoxicated AQP4-null mice show a significant reduction

in astrocytic foot process swelling, a decrease in brain water content

and a profound improvement in their survival (Saadoun et al, 2002).

Since water intoxication is of limited clinical significance, AQP4-

null mice were subjected to ischemic stroke and bacterial meningitis.

In both models AQP4-null mice showed decreased cerebral edema

and improved outcome and survival. These studies imply that AQP4

has a significant role in water transport and development of cellular

edema following cerebral ischemia (Zador et al, 2007).

Hydrocephalic edema:

Obstructive hydrocephalus produced by injecting kaolin in the

cistern magna of AQP4-null mice show accelerated ventricular

enlargement compared with wild-type mice.

Reduced water permeability of the ependymal layer,

subependymal astrocytes, astrocytic foot processes and glia limitans

produced by AQP4 deletion reduces the elimination rate of CSF

across these routes. Thus, AQP4 induction could be evaluated as a

nonsurgical treatment for hydrocephalus (Bloch et al, 2006).

In summary, AQP4 has opposing roles in the pathogenesis of

vasogenic and hydrocephalic edema when compared to cytotoxic

45

edema. Therefore, AQP4 activators or upregulators have the

potential to facilitate the clearance of vasogenic and hydrocephalic

edema, while AQP4 inhibitors have the potential to protect the brain

in cytotoxic edema. This is an area of ongoing research since none

of the AQP4 activators or inhibitors investigated thus far are suitable

for development for clinical use (Sun et al, 2003).

MMaattrriixx mmeettaalllloopprrootteeiinnaasseess ((MMMMPPss))::The MMPs are zinc- and calcium-dependent endopeptidases

which are known to cleave most components of the extracellular

matrix including fibronectin, proteoglycans and type IV collagen.

Activation of MMPs involves cleavage of the secreted proenzyme,

while inhibition involves a group of four endogenous tissue

inhibitors of metalloproteinases (TIMPs). The balance between

production, activation, and inhibition prevents excessive proteolysis

or inhibition (Asahi et al, 2001).

Type IV collagenases are members of the larger MMP gene

family of proteolytic enzymes that have the ability of destroying the

basal lamina of vessels and thereby play a role in the development of

many pathological processes including vasogenic edema in multiple

sclerosis and bacterial meningitis and ischemic stroke (Chang et al,

2003).

MMPs are found in all of the elements of the neurovascular unit,

but different MMPs have a predilection for certain cell types.

46

Endothelial cells express mainly MMP-9; pericytes express MMP-3

and -9, while astrocytic end-feet express MMP-2 and its activator,

membrane-type MMP (MT1-MMP) (Rosenberg, 2002).

Normally MMP-2 is expressed at low levels but is markedly

upregulated in many brain diseases. In human ischemic stroke,

active MMP-2 is increased on days 2–5 compared with active MMP-

9 which is elevated up to months after the ischemic episode.

Molecular studies in experimental permanent and temporary

ischemia have shown that MMPs contribute to disruption of the

BBB leading to vasogenic cerebral edema (Yang et al, 2007).

Middle cerebral artery occlusion in rats for 90 min with

reperfusion causes biphasic opening of the BBB in the piriform

cortex with a transient, reversible opening at 3 h which correlates

with a transient increase in expression of MMP-2. This is associated

with a decrease in claudin-5 and occludin expression in cerebral

vessels. By 24 h the tight junction proteins are no longer observed in

lesion vessels, an alteration that is reversed by treatment with the

MMP inhibitor, BB-1101. The later BBB opening between 24 and

48 h is associated with a marked increase of MMP-9 which is

released in the extracellular matrix where it degrades multiple

proteins, and produces more extensive blood vessel damage

(Rosenberg & Yang, 2007).

The role of MMPs in BBB breakdown is further supported by the

observation that treatment with MMP inhibitors or MMP

neutralizing antibodies decreases infarct size and prevents BBB

47

breakdown after focal ischemic stroke. The MMP inhibitors used so

far restore early integrity of the BBB in rodent ischemia models.

Since these inhibitors block MMPs involved in angiogenesis and

neurogenesis as well, they slow recovery. Therefore, the challenge is

to identify agents that will protect the BBB and block vasogenic

edema without interfering with recovery (Candelario-Jalil et al,

2008).

GGrroowwtthh ffaaccttoorrss aanndd bbrraaiinn eeddeemmaa:: VVaassccuullaarr eennddootthheelliiaall ggrroowwtthh ffaaccttoorr--AA ((VVEEGGFF--AA))::

VEGF, the first member of the six member VEGF family to be

discovered is now designated as VEGF-A. Initial reports described

the potent hyperpermeability effect of VEGF-A on the

microvasculature of tumors hence its designation ‘vascular

permeability factor’. VEGF-A has a significant role in vascular

permeability and angiogenesis during embryonic vasculogenesis and

in physiological and pathological angiogenesis (Adams & Alitalo,

2007).

There is agreement that vascular endothelial growth factor

receptor- 2 (VEGFR-2), which is present on endothelial cells, is the

major mediator of the mitogenic, angiogenic and permeability-

enhancing effects of VEGF-A.

The permeability inducing properties of VEGF-A have also been

demonstrated in the brain; Intracortical injections of VEGF-A

48

produces BBB breakdown at the injection site. Normal adult cortex

shows basal expression of VEGF-A mRNA and protein, while high

expression of VEGF-A mRNA and protein is present in normal

choroid plexus epithelial cells and ependymal cells (Ferrara et al,

2003).

Although several studies reported VEGF-A gene up regulation in

cerebral ischemia models, increased expression was related to

angiogenesis and not to BBB breakdown. In non-neural vessels,

VEGF-A is reported to cause vascular hyperpermeability by opening

of interendothelial junctions and induction of fenestrae in

endothelium (Marti et al, 2000).

A single ultrastructural study reported interendothelial gaps and

segmental fenestrae-like narrowings in brain vessels permeable to

endogenous albumin following a single intracortical injection of

VEGF-A. VEGF-A can also increase permeability by inducing

changes in expression of tight junction proteins. Reduced occludin

expression occurs in retinal and brain endothelial cells exposed to

VEGF-A (Machein & Plate, 2000).

VVaassccuullaarr eennddootthheelliiaall ggrroowwtthh ffaaccttoorr--BB ((VVEEGGFF--BB))::This member of the VEGF family displays strong homology to

VEGF-A. Mice embryos (day 14) and adults show high expression

of VEGF-B mRNA in most organs with very high levels in the heart

and the nervous system. Moderate down regulation of VEGF-B

occurs prior to birth and VEGF-B is the only member of the VEGF

49

family that is expressed at detectable levels in the adult CNS (Nag et

al, 2005).

Constitutive expression of VEGF-B protein is present in the

endothelium of all cerebral vessels including those of the choroid

plexuses. Thus, VEGF-B has a role in maintenance of the BBB in

steady states and VEGF-B may be protective against BBB

breakdown and edema formation (Nag et al, 2002).

AAnnggiiooppooiieettiinn ((AAnngg)) ffaammiillyy::Four members of this family have been isolated thus far and

designated Ang1–4, Ang1 and 2 are best characterized. Endothelial

Ang1 is expressed widely in normal adult tissues, consistent with it

playing a constitutive stabilization role by maintaining normal

endothelial cell to cell and cell to matrix interactions. Studies of the

rodent brain show constitutive expression of Ang1 protein in

endothelium of all cerebral cortical vessels and only weak

expression of Ang2 (Raab & Plate, 2007).

Functional studies indicate that Ang1 and Ang2 have reciprocal

effects in many systems. Ang1 has an antiapoptotic effect on

endothelial cells, while Ang2 is reported to promote apoptosis.

Presence of Ang1 is associated with smaller gaps in the endothelium

of postcapillary venules during inflammation. Ang1 is reported to

stabilize interendothelial junctions. This demonstrates that Ang1 is a

potent antileakage factor (Otrock et al, 2007).

50

Time course of growth factor expression post-

injury:The cold injury model was used to study the temporal alterations

in expression of growth factors and their relation to BBB breakdown

(figure 11). In the early phase post-injury up to day 2, there is

increased expression of VEGF-A protein, VEGFR-2 protein and a

sevenfold increase in Ang2 mRNA. During this period, vessels with

BBB breakdown show endothelial immunoreactivity for VEGF-A

and Ang2 but not for VEGF-B or Ang1 (Reiss, 2005).

On days 4 and 6 post-injury, there is progressive increase in Ang1

and VEGF-B mRNA and protein and decrease in Ang2 and VEGF-

A mRNA coinciding with maturation of neovessels and restoration

of the BBB (Roviezzo et al, 2005).

Increased expression of growth factors has been reported in

gliomas. VEGF-A is overexpressed up to 50-fold in the peri-necrotic

tumor cells in glioblastomas, Increased expression of the

angiopoietins has also been reported in glioblastomas. High

expression of Ang1 has been reported in areas of high vascular

density in all stages of glioblastoma progression while high

expression of Ang2 has been reported in endothelial cells in

glioblastomas. In these studies a strong association is made between

these growth factors and tumor angiogenesis (Roy et al, 2006).

51

Figure 11: Expression of growth factors during BBBbreakdown:

Days post-lesion0.5 2 4 6

BBB breakdown

VEGF-A

VEGF-B

VEGFR-2

Ang1

Ang2

Protein ExpressionBasal Increased Decreased

Figure 11: Temporal expression of growth factor proteins and their receptors isshown during the period of BBB breakdown in the cold injury model. Protein

expression was determined by immunohistochemistry and/orimmunofluorescence (Reiss, 2005).

There is the potential of using growth factors to treat early and

massive edema associated with large hemispheric lesions which are

lethal due to the effects of early edema. Potential candidates include

inhibitors of VEGF-A or administration of Ang1 or VEGF-B (Zadeh

& Guha, 2003).

52

Inhibitors of VEGF-A or recombinant Ang1 have been tried in

rodent models of ischemia. Pretreatment of rodents with VEGF-A

receptor protein, which inactivates endogenous VEGF-A or

recombinant Ang1 attenuates BBB breakdown and edema associated

with cerebral infarcts (Zhang, 2002).

The long-term effects of administering these agents on

angiogenesis and repair were not studied in these models. This must

be assessed before these agents can be used for the treatment of

brain edema (Yla-Herttuala et al, 2007).

53

CChhaapptteerr ((33)):: DDiiaaggnnoossiinnggcceerreebbrraall eeddeemmaa

54

DDiiaaggnnoossiinngg cceerreebbrraall eeddeemmaa

Introduction:Brain edema is a life-threatening complication following several

kinds of neurological and non-neurological conditions. Neurological

conditions include: ischemic stroke and intracerebral hemorrhage,

brain tumors meningitis, encephalitis of all etiologies and other brain

traumatic and metabolic insults (Rosenberg, 1999).

Non-neurological conditions include: diabetic ketoacidosis, lactic

acidotic coma, hypertensive encephalopathy, fulminant viral hepatitis,

hepatic encephalopathy, Reye’s syndrome systemic poisoning (carbon

monoxide and lead), hyponatraemia, opioid drug abuse and

dependence, bites of certain reptiles and marine animals, and high

altitude cerebral edema (Glasr et al, 2001).

Most cases of brain injury that result in elevated intracranial

pressure (ICP) begin as focal cerebral edema. Consistent with the

Monroe–Kellie doctrine as it applies to intracranial vault physiology,

the consequences of cerebral edema can be lethal and include cerebral

ischemia from compromised cerebral blood flow and intracranial

compartmental shifts due to ICP gradients, resulting in compression of

vital brain structures (herniation syndromes; Table 2) (Harukuni et al,

2002).

Prompt recognition of these clinical syndromes and institution of

targeted therapies constitutes the basis of cerebral resuscitation. It is

55

imperative to emphasize the importance of a patient displaying

cerebral herniation syndrome (figure 12) without increments in global

ICP; in these cases, elevations in ICP may or may not accompany

cerebral edema, particularly when the edema is focal in distribution

(Victor & Ropper, 2001) a.

Figure 12a, b&c: (figure12a): Subfalcine midline shift due to a frontal lobeglioma. (Figure12b): Coronal brain slices illustrating uncal herniation due to

hematoma expansion. (figure12c): Compression of the cerebellar tonsils followingelevated ICP. (Courtesy of Harry V. Vinters, M.D.) (Victor & Ropper, 2001) a.

56

Table 2: Summary of the clinical subtypes of herniationsyndromes:

HerniationSyndrome

Clinical Manifestations

subfalcianor cingulate

usually diagnosed using neuroimaging; cingulategyrus herniates under the falx cerebrii (usuallyanteriorly); may cause compression of ipsilateralanterior cerebral artery, resulting in contralaterallower extremity paresis

centraltentorial

downward displacement of one or both cerebralhemispheres, resulting in compression ofdiencephalon and midbrain through tentorial notch;typically due to centrally located masses; impairedconsciousness and eye movements; elevated ICP;bilateral flexor or extensor posturing

lateraltranstentorial(uncal)

most commonly observed clinically; usually due tolaterally located (hemispheric) masses (tumors andhematomas); herniation of the mesial temporal lobe,uncus, and hippocampal gyrus through the tentorialincisura; compression of oculomotor nerve,midbrain, and posterior cerebral artery; depressedlevel of consciousness; ipsilateral papillary dilationand contralateral hemiparesis; decerebrate posturing;central neurogenic hyperventilation; elevated ICP

tonsillarherniation of cerebellar tonsils through foramenmagnum, leading to medullary compression; mostfrequently due to masses in the posterior fossa;precipitous changes in blood pressure and heart rate,small pupils, ataxic breathing, disturbance ofconjugate gaze and quadriparesis

external due to penetrating injuries to the skull, loss of CSFand brain tissue; ICP may not be elevated due todural opening

(Harukuni et al, 2002)

57

CClliinniiccaall FFeeaattuurreess::A high index of suspicion is very important. The features of cerebral

edema add on to and often complicate the clinical features of the

primary underlying condition. Cerebral edema alone will not produce

obvious clinical neurological abnormalities until elevation of ICP

occurs. Symptoms of elevation of intracranial pressure are headache,

vomiting, papilledema, abnormal eye movements, neck pain or

stiffness, cognitive decline, seizures, hemiparesis, dysphasia, other

focal neurologic deficits, and depression of consciousness (Rosenberg,

2000).

The headache associated with an increased intracranial pressure,

especially when resulting from mass lesions, is mainly due to

compression or distortion of the dura mater and of the pain-sensitive

intracranial blood vessels. It is often paroxysmal, at first worse on

waking or after recumbency, throbbing in character, corresponding

with the arterial pressure wave. Exertion, coughing, sneezing,

vomiting, straining, or sudden changes in posture accentuate it. Such

headache is often frontal or occipital or both (Pollay, 1996).

The vomiting that accompanies increased intracranial pressure often

occurs in the mornings when the headache is at its height, it is more

common in children than in adults. It is generally attributed to

compression or ischemia of the vomiting center in the medulla

oblongata (Hemphil et al, 2001).

58

Similarly, the bradycardia, which is also common, results from

dysfunction in the cardiac centre but, in some patients with

infratentorial lesions, tachycardia eventually develops. Papilledema

develops more rapidly with mass lesions in the posterior fossa because

of their especial tendency to cause sudden obstructive hydrocephalus.

Obstruction of CSF flow in the subarachnoid space and impaired

absorption both appear to be important factors in patients with tumors

(Schilling, 1999).

Breathing control is often impaired. Slow and deep respiratory

movements often accompany a sudden rise in intracranial pressure

sufficient to impair consciousness. Later, breathing may become

irregular, Cheyne–Stokes respiration, and periods of apnea then

alternate with phases during which breathing waxes and wanes in

amplitude. Central neurogenic hyperventilation, or so-called ataxic

breathing, is less common effects of brainstem compression or

distortion but, in terminal coma, breathing is often rapid or shallow.

These abnormalities of respiratory rate and rhythm may be due to

compression or distortion of the brainstem (Victor & Ropper, 2001) b.

59

IInnvveessttiiggaattiioonnss::A. Computed Tomography (CT):

CT technology may noninvasively illustrate the volumetric changes

and alterations in parenchymal density resulting from cerebral edema.

Expansion of brain tissue due to most forms of edema may be detected

on CT, although diffuse processes like fulminant hepatic failure may

be more difficult to discern. Diffuse swelling may be recognized by a

decrease in ventricular size with compression or obliteration of the

cisterns and cerebral sulci (figure 13) (Vo Kd et al, 2003).

Cellular swelling associated with cytotoxic and ischemic edema can

manifest as subtle enlargement of tissue with obscuration of normal

anatomic features, such as the differentiation between gray matter and

white matter tracts (figure 14). Vasogenic edema may also cause tissue

expansion, although the associated density changes may be more

prominent (Coutts et al, 2004).

In contrast, hydrocephalic edema may be suspected in cases in

which ventricular expansion has occurred. Extensive volumetric

changes and the associated pressure differentials resulting in herniation

may be noted on CT as shifts in the location of various anatomic

landmarks (Rother, 2001).

The increased water content associated with edema causes the

density of brain parenchyma to decrease on CT (figure 15). The

attenuation effects of other tissue contents complicate precise

correlation of water content with density on CT. Although slight

60

decrements in tissue density result from cytotoxic and osmotic

processes, more conspicuous areas of hypodensity result from the

influx of fluid associated with disruption of the BBB in vasogenic

edema (Jaillard et al, 2002).

Contrast CT improves the demonstration of infectious lesions and

tumors that present with significant degrees of vasogenic edema. The

differentiation of specific forms of edema is limited with CT, but this

modality may provide sufficient information to guide therapeutic

decisions in many situations. CT may be inferior to MRI in the

characterization of cerebral edema, but logistic constraints may

preclude MRI in unstable trauma patients, uncooperative patients, and

patients with contraindications due to the presence of metallic implants

or pacemakers (Mullins et al, 2004).

Figure 13: CT scan of global brain edema showing the effacement of the gray-white matter junction, and decreased visualization of the sulci, and lateral

ventricles (Vo Kd et al, 2003).

61

Figure 14: CT scan showing imaging characteristics of brain edema caused by atumor (Coutts et al, 2004).

Figure 15 a&b: (figure 15a) an area of decreased density and loss of grey/whitedifferentiation is present in the right insular region which represents an infarct.(Figure 15b): On day 3, a large area of decreased density involving almost thewhole right hemisphere is present due to infarction associated with vasogenic

edema (Jaillard et al, 2002).

62

B. Magnetic Resonance Imaging (MRI):Volumetric enlargement of brain tissue due to edema is readily

apparent on MRI and the use of gadolinium, an MRI contrast agent,

enhances regions of altered BBB. Differences in water content may be

detected on MRI by variations in the magnetic field generated

primarily by hydrogen ions. T2-weighted sequences and fluid-

attenuated inversion recovery (FLAIR) images reveal hyperintensity in

regions of increased water content (figure 16). FLAIR images

eliminate the bright signal from CSF spaces and are therefore helpful

in characterizing periventricular findings such as hydrocephalic edema

(figure 17) (Cosnard et al, 2000).

These conventional MRI sequences are more sensitive in the

detection of lesions corresponding to hypodensities on CT. MRI is also

superior in the characterization of structures in the posterior fossa

(figure 18). Recent advances in MRI technology make it possible to

specifically discern the type of edema based on signal characteristics

of a sampled tissue volume (Weber et al, 2000).

This discriminatory capability resulted from the development of

diffusion imaging techniques. The use of strong magnetic field

gradients increases the sensitivity of the MR signal to the random,

translational motion of water protons within a given volume element

(Scarabino et al, 2004).

63

Figure 16: Intracranial hemorrhage depicted by MRI. T2-weighted sequenceshowing hyperintensity associated with vasogenic edema in the right frontal lobe

(Cosnard et al, 2000).

Figure 17: Periventricular FLAIR hyperintensity due to hydrocephalic edema(Cosnard et al, 2000).

Figure 18 a&b: Central pontine myelinolysis illustrated as (a) T2- weightedhyperintensity and (b) T1-weighted hypointensity in the pons (Weber et al, 2000).

64

Cytotoxic edema and cellular swelling produce a net decrease in the

diffusion of water molecules due to the restriction of movement,

imposed by intracellular structures such as membranes and

macromolecules, and diminished diffusion within the extracellular

space due to shrinkage and tortuosity (figure 19). In contrast, the

accumulation of water within the extracellular space as the result of

vasogenic edema allows for increased diffusion (Scott et al, 2006).

Diffusion-weighted imaging (DWI) sequences yield maps of the

brain, with regions of restricted diffusion appearing bright or

hyperintense. The cytotoxic component of ischemic edema has been

demonstrated on DWI within minutes of ischemia onset (Simon et al,

2004).

Apparent diffusion coefficient (ADC) maps may be generated from a

series of DWI images acquired with varying magnetic field gradients.

ADC elevations, resulting from vasogenic edema, appear hyperintense

on ADC maps, whereas decreases in ADC due to cytotoxic edema

appear hypointense (figure 20). These maps may be sampled to

measure the ADC of a given voxel for multiple purposes, such as

differentiating tumor from tumor associated edema (Yamasaki et al,

2005).

The development of perfusion-weighted imaging (PWI) with MR

technology provided parametric maps of several hemodynamic

variables, including cerebral blood volume. Elevations in cerebral

blood volume associated with cerebral edema are detectable by this

technique. Simultaneous acquisition of multiple MRI sequences

65

enables the clinician to distinguish various forms of cerebral edema.

T2-weighted sequences and FLAIR images permit sensitive detection

of local increases in water content (Bastin et al, 2002).

Figure 19 a, b&c: the cytotoxic component of acute cerebral ischemia isdemonstrated by ADC hypointensity (a). The ischemic region appears

hyperintense on DWI (b), whereas T2 weighted sequences may be unrevealing atthis early stage (c) (Scott et al, 2006).

Figure 20 a, b&c: MRI of status epilepticus reveals evidence of cytotoxic edemawithin cortical structures, illustrated by (a) T2-weighted and (b) DWI

hyperintensity, with (c) mild hypointensity on ADC maps(Yamasaki et al, 2005)

66

Gadolinium-enhanced T1- weighted sequences reveal sites of BBB

leakage that may be present surrounding tumors (figure 21) or

abscesses. DWI localizes abnormal areas of water diffusion, with ADC

maps differentiating various forms of edema. PWI can detect regional

elevation of cerebral blood volume (Kim & Garwood, 2003).

The composite interpretation of these studies has revolutionized the

diagnosis of cerebral edema. These images often reflect the combined

effects of multiple types of edema. For instance, the cytotoxic

component of ischemic edema will cause a reduction in the ADC,

whereas the vasogenic component will counter this trend. A pseudo-

normalization of the ADC may result from these opposing influences

(Roberto & Alan, 2006).

Figure 21a, b&c: Disruption of the BBB in vasogenic edema associated with aglioma appears hyperintense on gadolinium-enhanced MRI (a). Peritumoral

vasogenic edema is demonstrated by hyperintensity on T2-weighted sequences (b)and ADC maps (c) (Kim & Garwood, 2003).

67

Serial imaging with this noninvasive modality also allows for the

temporal characterization of edema evolution. The relative

contributions of cytotoxic and vasogenic edema with respect to the

ADC during acute ischemic stroke and TBI have been investigated in

this manner. The main limitations of this technology logistically relate

to cost, availability, contraindications, and its restricted use in

critically ill individuals (Doerfler et al, 2002).

C. Intracranial pressure monitoring: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 measurements of

ICP and aggressive measures to counteract high pressures have not

yielded uniformly beneficial results, and after two decades of

popularity the routine use of ICP monitoring remains controversial

(Bullock et al, 1996).

The problem may be partly a matter of the timing of monitoring and

the proper selection of patients for aggressive treatment of raised ICP.

Only if the ICP measurements are to be used as a guide to medical

therapy and the timing of surgical decompression is the insertion of a

monitor justified (Ayata & Ropper, 2002).

Monitoring of ICP is helpful in patients in whom neurological status

is difficult to ascertain serially, particularly in the setting of

pharmacological sedation and neuromuscular paralysis. The Brain

Trauma Foundation guidelines recommend ICP monitoring in patients

68

with TBI, a GCS score of less than 9, and abnormal CT scans, or in

patients with a GCS score less than 9 and normal CT scans in the

presence of two or more of the following: age greater than 40 years,

unilateral or bilateral motor posturing, or systolic blood pressure

greater than 90 mmHg (Suarez, 2001).

No such guidelines exist for ICP monitoring in other brain injury

paradigms (ischemic stroke, ICH, cerebral neoplasm), and decisions

made for ICP monitoring in this setting are frequently based on the

clinical neurological status of the patient and data from neuroimaging

studies. Whether ICP monitoring adds much to the management of

patients of stroke is still open to question, clinical signs and imaging

data on shift of brain tissue are probably more useful (Xi, et al 2006).

69

CChhaapptteerr ((44)):: CCeerreebbrraallEEddeemmaa iinn NNeeuurroollooggiiccaall

DDiisseeaasseess

70

CCeerreebbrraall EEddeemmaa iinn NNeeuurroollooggiiccaallDDiisseeaasseess

IInnttrroodduuccttiioonn::Cerebral edema is associated with a wide spectrum of clinical

disorders. Edema can either result from regional abnormalities

related to primary disease of the central nervous system or be a

component of the remote effects of systemic toxic–metabolic

derangements. In either scenario, cerebral edema may be a life

threatening complication that deserves immediate medical attention

(Banasiak et al, 2004).

Several challenges surround the management of cerebral edema,

because the clinical presentation is extremely variable. This

variability reflects the temporal evolution of a diverse combination

of edema types because most forms of cerebral edema have the

capacity to generate other types. The specific clinical

manifestations are difficult to categorize by type and are better

described by precipitating etiology. In other words, it is essential to

outline the prominent forms of edema that are present in a given

clinical scenario. The location of edema fluid determines

symptomatology. Focal neurologic deficits result from isolated

regions of involvement, whereas diffuse edema produces

generalized symptoms such as lethargy (Amiry-Moghaddam &

Ottersen, 2003).

71

11.. CCeerreebbrroovvaassccuullaarr DDiisseeaassee::Cerebral ischemia frequently causes cerebral edema. Tissue

hypoxia that results from ischemic conditions triggers a cascade of

events that leads to cellular injury. The onset of ischemic edema

initially manifests as glial swelling occurring as early as 5 min

following interruption of the energy supply. This cytotoxic phase of

edema occurs when the BBB remains intact, although continued

ischemia leads to infarction and the development of vasogenic

edema after 48–96 hours (Latour et al, 2004).

Clinical symptoms are initially representative of neuronal

dysfunction within the ischemic territory, although the spread of

edema may elicit further neurological deficits in patients with large

hemispheric infarction. This clinical syndrome involves increasing

lethargy, asymmetrical pupillary examination, and abnormal

breathing. The mechanism of neurologic deterioration appears to

involve pressure on brain stem structures due to the mass effect of

infarcted and edematous tissue. Elevation of ICP may be

generalized or display focal gradients that precipitate herniation

syndromes. Herniation may lead to compression and infarction of

other vascular territories, in turn initiating a new cycle of infarction

and edema (Hawkins & Davis, 2005).

Intracerebral hemorrhage presents with focal neurologic deficits,

headache, nausea, vomiting, and evidence of mass effect. The

edema associated with intracerebral hemorrhage is predominantly

vasogenic, climaxing 48–72 hours following the initial event.

72

Secondary ischemia with a component of cytotoxic edema may

result from impaired diffusion in the extracellular space of the

perihemorrhage region. Other forms of hemorrhage, including

hemorrhagic transformation of ischemic territories and

subarachnoid hemorrhage may be associated with edema that

results from the noxious effects of blood degradation products

(Wang X & Lo, 2003).

22.. TTrraauummaattiicc BBrraaiinn IInnjjuurryy (TTBBII))::Raised ICP attributed to cerebral edema is the most frequent

cause of death in TBI. Focal or diffuse cerebral edema of mixed

types may develop following TBI. Following contusion of the

brain, the damaged BBB permits the extravasation of fluid into the

interstitial space. Areas of contusion or infarction may release or

induce chemical mediators that can spread to other regions. These

factors activated during tissue damage are powerful mediators of

extravasation and vasodilation (Marcella et al 2007).

TBI is associated with a biphasic pathophysiologic response

heralded by a brief period of vasogenic edema immediately

following injury, followed after 45–60 minutes by the development

of cytotoxic edema. Vasogenic edema may be detected by

neuroimaging modalities within 24–48 hours and reach maximal

severity between Days 4 and 8. Autoregulatory dysfunction is a

common sequela of TBI that may promote the formation of

hydrostatic edema in regions where the BBB remains intact. Recent

73

efforts have also demonstrated a prominent role of cytotoxic edema

in head-injured patients. Tissue hypoxia with ischemic edema

formation and neurotoxic injury due to ionic disruption contribute

to this cytotoxic component. In addition, osmotic edema may result

from hyponatremia, and hydrocephalic edema may complicate the

acute phase of TBI when subarachnoid hemorrhage or infections

predominate. Diffuse axonal injury may produce focal edema in

white matter tracts experiencing shear-strain forces during

acceleration/deceleration of the head (Stanley & Swierzewski,

2011).

33.. IInnffeeccttiioonnss::A combination of vasogenic and cytotoxic edema arises from

many infectious processes within the central nervous system. Other

forms of edema may also occur in infections, including

hydrocephalic edema secondary to CSF obstruction and osmotic

edema due to SIADH. Numerous infectious agents have direct toxic

effects generating vasogenic edema through alteration of the BBB

and cytotoxic edema from endotoxin-mediated cellular injury.

Bacterial wall products stimulate the release of various endothelial

factors, resulting in excessive vascular permeability (Simon &

Beckman, 2002).

Cerebral edema is a critical determinant of morbidity and

mortality in pediatric meningitis. Abscess formation or focal

invasion of the brain results in an isolated site of infection

74

surrounded by a perimeter of edema encroaching on the

neighboring parenchyma. This ring of vasogenic and cytotoxic

edema may produce more symptoms than the actual focus of

infection. Similar regions of focal or diffuse edema may

accompany encephalitis, particularly viral infections such as herpes

simplex encephalitis (Nathan & Scheld, 2000).

44.. CCeerreebbrraall VVeennoouuss SSiinnuuss TThhrroommbboossiiss::A major life-threatening consequence of cerebral venous sinus

thrombosis is cerebral edema. Two different kinds of cerebral

edema can develop. The first, cytotoxic edema is caused by

ischemia, which damages the energy-dependent cellular membrane

pumps, leading to intracellular swelling. The second type,

vasogenic edema, is caused by a disruption in the blood–brain

barrier and leakage of blood plasma into the interstitial space

(Masuhr et al, 2004).

The clinical manifestations of cerebral venous thrombosis are

highly variable. Individuals may be asymptomatic, and others may

suffer a progressive neurologic deterioration with headaches,

seizures, focal neurologic deficits, and severe obtundation leading

to death (Lemke & Hacein-Bey, 2005).

75

55.. NNeeooppllaassttiicc DDiisseeaassee::The detrimental effects of cerebral edema considerably influence

the morbidity and mortality associated with brain tumors. Tumor-

associated edema continues to be a formidable challenge,

producing symptoms such as headache and focal neurologic deficits

and, considerably altering the clinical outcome (partial resection,

chemotherapeutic agents and radiation have also been shown to

encourage the formation of edema). The predominant form of

tumor-associated edema is vasogenic, although cytotoxic edema

may occur through secondary mechanisms, such as tumor

compression of the local microcirculation or tissue shifts with

herniation. Individuals with hydrocephalus can also develop

hydrocephalic edema because of ventricular outflow obstruction

(Pouyssegur et al, 2006).

66.. SSeeiizzuurreess::Prolonged seizure activity may lead to neuronal energy depletion

with eventual failure of the Na+/K+ ATPase pump and concomitant

development of cytotoxic or ischemic edema. Unlike ischemia

produced by occlusion of a cerebral artery, a more heterogeneous

cellular population is affected. The reactive hyperemic response

driven by excessive metabolic demands increases the hydrostatic

forces across a BBB already damaged by the vasogenic component

of ischemic edema. The disruption of normal ionic gradients,

extracellular accumulation of excitotoxic factors, and lactic acidosis

76

further exacerbate vasogenic edema. Consequently, cessation of

seizure activity usually results in the complete resolution of

cerebral edema (Vespa et al, 2003).

77.. MMuullttiippllee SScclleerroossiiss::One of the crucial stages in the evolution of a multiple sclerosis

lesion is considered to be the disruption of the blood brain barrier,

leading to edema in the CNS by accumulation of plasma fluids.

This process is believed to be initiated by autoreactive CD4+

lymphocytes which migrate into the CNS and start an inflammatory

response. Although BBB breakdown imaged as focal enhancement

in T1- weighted MRI after gadolinium DTPA injection is the gold

standard of lesion detection during the course of the disease, the

deposition of contrast agent in the CNS has been shown to correlate

with clinical disability (Vos et al, 2005).

88.. HHyyddrroocceepphhaalluuss::Isolated hydrocephalic edema may result from acute obstructive

hydrocephalus with impairment of CSF drainage. Transependymal

pressure gradients result in edema within periventricular white

matter tracts. The rapid disappearance of myelin lipids under

pressure causes the periventricular white matter to decrease in

volume. The clinical manifestations may be minor, unless

progression to chronic hydrocephalus becomes apparent with

77

symptoms including dementia and gait abnormalities (Abbott,

2004).

99.. HHyyppeerrtteennssiivvee EEnncceepphhaallooppaatthhyy::This potentially reversible condition presents with rapidly

progressive neurological signs, headache, seizures, altered mental

status, and visual disturbances. The pathogenesis of edema

formation is controversial but is thought to involve elevated

hydrostatic forces due to excessive blood pressure, with lesser

degrees of involvement attributed to vasogenic edema and

secondary ischemic components. The rate of blood pressure

elevation is a critical factor, because hypertensive encephalopathy

usually develops during acute exacerbations of hypertension. Early

recognition and treatment of hypertensive encephalopathy may

reverse cerebral edema, preventing permanent damage to the BBB,

and ischemia, although severe cases may be fatal (Johnston et al,

2005).

1100.. HHyyppeerrtthheerrmmiiaa::The pathophysiology of this rare cause of cerebral edema is poorly

understood. Although the fatal consequences of heat stroke have been

recognized since ancient times, the underlying mechanisms await

clarification. Scant pathologic material suggests a combination of

cytotoxic and vasogenic components, secondary to an increase in

BBB permeability due to the release of multiple chemical factors and

78

direct cytotoxic damage. Age and physiologic state of the individual

appear to be important determinants of clinical outcome in

hyperthermic injury (Bruno et al, 2004).

79

CChhaapptteerr ((55)):: TTrreeaattmmeennttooff CCeerreebbrraall EEddeemmaa

80

TTrreeaattmmeenntt ooff CCeerreebbrraall EEddeemmaa

IInnttrroodduuccttiioonn::Cerebral edema is frequently encountered in clinical practice in

critically ill patients with acute brain injury from diverse origins and

is a major cause of increased morbidity and death in this subset of

patients. The consequences of cerebral edema can be lethal and

include cerebral ischemia from compromised regional or global

cerebral blood flow (CBF) and intracranial compartmental shifts due

to intracranial pressure gradients that result in compression of vital

brain structures (Rabinstein, 2004).

The overall goal of treatment of cerebral edema is to maintain

regional and global CBF to meet the metabolic requirements of the

brain and prevent secondary neuronal injury from cerebral ischemia

(Broderick et al, 1999).

Treatment of cerebral edema involves using a systematic and

algorithmic approach, from general measures (optimal head and neck

positioning for facilitating intracranial venous outflow, avoidance of

dehydration and systemic hypotension, and maintenance of

normothermia) to specific therapeutic interventions (controlled

hyperventilation, administration of corticosteroids and diuretics,

osmotherapy, and pharmacological cerebral metabolic suppression)

,and decompressive surgery (Wakai et al, 2007).

81

II.. GGeenneerraall mmeeaassuurreess ffoorr ttrreeaattiinnggCCeerreebbrraall eeddeemmaa::

Several general measures that are supported by principles of altered

cerebral physiology and clinical data from patients with brain injury

should be applied to patients with cerebral edema. The primary goal

of these measures is to optimize cerebral perfusion, oxygenation, and

venous drainage; minimize cerebral metabolic demands; and avoid

interventions that may disturb the ionic or osmolar gradient between

the brain and the vascular compartment (Ahmed & Anish, 2007).

1. Optimizing head and neck positions:Finding the optimal neutral head position in patients with cerebral

edema is essential for avoiding jugular compression and impedance of

venous outflow from the cranium, and for decreasing CSF hydrostatic

pressure. In normal uninjured patients, as well as in patients with

brain injury, head elevation decreases ICP (Ng et al, 2004).

These observations have led most clinicians to incorporate a 30°

elevation of the head in patients with poor intracranial compliance.

Head position elevation may be a significant concern in patients with

ischemic stroke, however, because it may compromise perfusion to

ischemic tissue at risk. It is also imperative to avoid the use of

restricting devices and garments around the neck (such as devices

used to secure endotracheal tubes), as these may lead to impaired

cerebral venous outflow via compression of the internal jugular veins

(Ropper et al, 2004).

82

2. Ventilation and oxygenation:Hypoxia and hypercapnia are potent cerebral vasodilator and

should be avoided in patients with cerebra edema. It is recommended

that any patients with Glasgow coma scale (GCS) scores less than or

equal to 8 and those with poor upper airway reflexes be intubated

preemptively for airway protection. This strategy is also applicable to

patients with concomitant pulmonary disease, such as aspiration

pneumonitis, pulmonary contusion, and acute respiratory distress

syndrome (Eccher & Suarez, 2004).

Avoidance of hypoxemia and maintenance of PaO2 at

approximately 100 mmHg are recommended. Careful monitoring of

clinical neurological status, ICP is recommended in mechanically

ventilated patients with cerebral edema with or without elevations in

ICP. Blunting of upper airway reflexes (coughing) with endobronchial

lidocaine before suctioning, sedation, or, rarely, pharmacological

paralysis may be necessary for avoiding increases in ICP (Schwarz et

al, 2002).

3. Seizure prophylaxis:Anticonvulsants (predominantly phenytoin) are widely used

empirically in clinical practice in patients with acute brain injury of

diverse origins, including traumatic brain injury (TBI), subarachnoid

hemorrhage (SAH), and intracranial hemorrhage (ICH), although data

supporting their use are lacking (Vespa et al, 2003).

83

Early seizures in TBI can be effectively reduced by prophylactic

administration of phenytoin for 1 or 2 weeks without a significant

increase in drug-related side effects. The use of prophylactic

anticonvulsants in ICH can be justified, as subclinical seizure activity

may cause progression of shift and worsen outcome in critically ill

patients with ICH. Yet the benefits of prophylactic use of

anticonvulsants in most causes leading to brain edema remain

unproven, and caution is advised in their use (Glantz et al, 2000).

4. Management of fever and hyperglycemia:Numerous experimental and clinical studies have demonstrated the

deleterious effects of fever on outcome following brain injury, which

theoretically result from increases in oxygen demand. Therefore,

normothermia is strongly recommended in patients with cerebral

edema, irrespective of underlying origin. Acetaminophen (325–650

mg orally, or rectally every 4–6 hours) is the most common, and the

safest agent used, and is recommended to avoid elevations in body

temperature (Bruno et al, 2004).

Evidence from clinical studies in patients with ischemic stroke,

subarachnoid hemorrhage, and TBI suggests a strong correlation

between hyperglycemia and worse clinical outcomes. Hyperglycemia

can exacerbate brain injury and cerebral edema. Significantly

improved outcome has been reported in general ICU patients with

good glycemic control; although larger studies focused on specific

brain injury paradigms are forthcoming. Nevertheless, current

evidence suggests that rigorous glycemic control may be beneficial in

84

all patients with brain injury and cerebral edema (Parsons et al,

2002).

5. Blood pressure management:The ideal blood pressure will depend on the underlying cause of the

brain edema. In trauma and stroke patients, blood pressure should be

supported to maintain adequate perfusion, avoiding sudden rises and

very high levels of hypertension. Keeping cerebral perfusion pressure

above 60–70 mm Hg is generally recommended after traumatic brain

injury (Johnston et al, 2005).

6. Nutritional support and fluid management:Prompt maintenance of nutritional support is imperative in all

patients with acute brain injury. Unless contraindicated, the enteral

route of nutrition is preferred. Special attention should be given to the

osmotic content of formulations Low serum osmolality must be

avoided in all patients with brain swelling since it will exacerbate

cytotoxic edema. This objective can be achieved by strictly limiting

the intake of hypotonic fluids. In fact, there is clear evidence that free

water should be avoided in patients with head injuries and brain

edema (Leira et al, 2004).

In patients with pronounced, prolonged serum hyperosmolality, the

disorder must be corrected slowly to prevent rebound cellular

swelling. Fluid balance should be maintained neutral. Negative fluid

balance has been reported to be independently associated with adverse

outcomes in patients with severe brain trauma. Avoiding negative

85

cumulative fluid balance is essential to limit the risk of renal failure in

patients receiving mannitol (Powers et al, 2001).

IIII.. SSppeecciiffiicc mmeeaassuurreess ffoorr mmaannaaggiinnggCCeerreebbrraall eeddeemmaa::

1. CCoonnttrroolllleedd hhyyppeerrvveennttiillaattiioonn::Based on principles of altered cerebral pathophysiology associated

with brain injury, controlled hyperventilation remains the most

efficacious therapeutic intervention for cerebral edema, particularly

when the edema is associated with elevations in ICP (Carmona et al,

2000).

A decrease in PaCO2 by 10 mmHg produces proportional

decreases in regional CBF, resulting in rapid ICP reduction. The

vasoconstrictive effect of respiratory alkalosis on cerebral arterioles

has been shown to last for 10 to 20 hours, beyond which vascular

dilation may result in exacerbation of cerebral edema and rebound

elevations in ICP (Mayer & Rincon, 2005).

Overaggressive hyperventilation may actually result in cerebral

ischemia. Therefore, the common clinical practice is to lower and

maintain PaCO2 by 10 mmHg to a target level of approximately 30–

35 mmHg for 4 to 6 hours, although identifying the correct strategy

for achieving this goal is unclear in terms of adjusting tidal volumes

and respiratory rate (Marion et al, 2002).

86

It should be noted that controlled hyperventilation is to be used as a

rescue or resuscitative measure for a short duration until more

definitive therapies are instituted and maintained. Caution is advised

when reversing hyperventilation gradually over 6 to 24 hours, to

avoid cerebral hyperemia and rebound elevations in ICP secondary to

effects of reequilibration (Diringer, 2002).

22.. OOssmmootthheerraappyy uussee::Historical perspective:

The earliest description of the use of osmotic agents dates back to

1919, Weed and McKibben observed that intravenous administration

of a concentrated salt solution resulted in an inability to withdraw

CSF from the lumbar cistern due to a collapse of the thecal sac. This

observation was followed by a set of experiments in an animal model

in which they demonstrated (under direct visualization via a

craniotomy) egress of the brain away from the cranial vault with

intravenous infusion of hypertonic saline solutions and herniation of

brain tissue with administration of hypotonic fluids (Weed et al, 1919,

coated from Ahmed & Anish, 2007).

This set of observations has formed the basis for osmotherapy.

Concentrated urea was the first agent to be used clinically as an

osmotic agent. Its use was short-lived and is of historic interest only

because of several untoward side effects (nausea, vomiting, diarrhea,

and coagulopathy). The interest in elevating plasma oncotic pressure

as a strategy to ameliorate cerebral edema with the use of

concentrated human plasma proteins, which appeared briefly in 1940,

87

was short-lived due to several concerns, including cost, short half-life,

cardiopulmonary effects, and allergic reactions. Glycerol was possibly

the second osmotic agent to be used clinically and is still used

(Alejandro & Rabinstein, 2006).

Mannitol, an alcohol derivative of simple sugar mannose, was

introduced in 1960 and has since remained the major osmotic agent of

choice in clinical practice. Its long duration of action and relative

stability in solution has enhanced its use over the years (Dennis,

2003).

Renewed interest in hypertonic saline solutions reappeared in the

1980s, in these studies; cerebral effects of these solutions were

investigated in well-controlled experimental studies in animal models

of acute brain injury. These studies continue to provide evidence for

the potential use of these solutions in the clinical domains (Harukuni

et al, 2002).

Therapeutic basis and goal of osmotherapy:

Put simply, the fundamental goal of osmotherapy is to create an

osmotic gradient to cause egress of water from the brain extracellular

(and possibly intracellular) compartment into the vasculature, thereby

decreasing intracranial volume. A serum osmolality in the range of

300 to 320 mOsm/L has traditionally been recommended for patients

with acute brain injury who demonstrate poor intracranial

compliance; however, values greater than 320 mOsm/L can be

attained with caution, without apparent untoward side effects

(Korenkov et al, 2000).

88

An ideal osmotic agent is one that produces a favorable osmotic

gradient, is inert and nontoxic, is excluded from an intact BBB, and

has minimal systemic side effects. Mannitol has remained the major

osmotic agent of choice in clinical practice. Its long duration of action

(4–6 hours) and relative stability in solution have enhanced its use

over the years (Battison et al, 2005).

The extraosmotic properties of mannitol have been studied

extensively and may provide additional beneficial effects in brain

injury, including decreases in blood viscosity, resulting in increases in

CBF and CPP, free radical Scavenging and inhibition of apoptosis

(Qureshi et al, 2000).

Like mannitol, hypertonic saline also possesses unique

extraosmotic properties, including modulation of CSF production and

resorption, accentuation of tissue oxygen delivery, and modulation of

inflammatory and neurohumoral responses (arginine-vasopressin and

atrial natriuretic peptide) following brain injury that may act together

to ameliorate cerebral edema (Bhardwaj et al, 2004).

Comparison between mannitol and hypertonic saline:

Few studies have made direct comparisons between mannitol and

hypertonic saline (table 3). In a prospective, randomized comparison

of 2.5 ml/kg of either 20% mannitol (1400 mOsm/kg) or 7.5%

hypertonic saline (2560 mOsm/ kg) in patients undergoing elective

supratentorial procedures, ICP and intraoperative clinical assessment

of brain swelling were similar in both treatment groups (Toung et al,

2005).

89

In a prospective, randomized trial of hypertonic saline with

hydroxyethyl starch, hypertonic saline was shown to be more

effective than equiosmolar doses of mannitol in lowering elevated

ICP and augmenting CPP in patients with ischemic stroke (Mirski et

al, 2000).

Likewise, intravenous bolus injection of 10% hypertonic saline was

shown to be effective in lowering ICP in patients with ischemic stroke

who failed to show such a response to conventional doses of

mannitol. More recently, in a small prospective study, isovolemic

intravenous infusion of 7.5% hypertonic saline was more effective in

the control of ICP following TBI, compared with mannitol treatment

(Vialet et al, 2003).

In summary, the literature supports the use of hypertonic saline as a

therapy to decrease ICP in patients following TBI and stroke and to

optimize intravascular fluid status in patients with SAH-induced

vasospasm. However, no definite conclusions can be drawn at present

because the studies involved a wide range of saline concentrations,

and equiosmolar solutions were not consistently used. Further

carefully designed studies comparing the 2 agents are needed before

superiority of one of them can be firmly postulated (Ware et al,

2005).

90

Table 3: Summary of experimental studies comparing differentformulations of hypertonic saline (HS) with mannitol 20% (M) (Toung et

al, 2005).Study: Experimental

Model:HS Formulation &Mode of Infusion:

Results:

Gemmaet al, 1997

(50/Electiveneurosurgery)

7.5% NaClBolus

No differences in CSF pressure

Schwarzet al, 1998

(9/Ischemicinfarction withraised ICP)

75 g/L NaCl plus 60 g/Lhydroxyethylstarch (2570 mOsm/L)Serial boluses

HS lowered ICP moreeffectively M increasedCPP more effectively.

Vialet etal, 2003

(20/TBI withcoma and raisedICP)

7.5% NaClSerial boluses

HS had lower rate offailure to drop ICP.

Battisonet al,

2005

(9/TBI) 7.5% NaCl plus 6%dextran-70*Two boluses of HS and M

HS produced greater andlonger ICP reductions.

Mirski etal, 2000

Focal cryogeniclesion in rats

11 mOsm/kg NaCl*Bolus

Greater and longer ICPreduction with HS.Similar brain watercontent.

Tuong etal, 2005

Temporary MCAocclusion (2 h) inrats

7.5%NaCl/acetateContinuous

HS attenuated maximaledema in bothhemispheres less robustlythan M

Tuong etal, 2002

Permanent MCAocclusion in rats

5% And 7.5% NaCl/acetateContinuous

HS (both concentrations)reduced lung and brainwater content moreeffectively than M.

Zornowet al,

1990

Focal cryogeniclesion in rabbits

3.2% NaClBolus

Similar ICP reduction.Similar MAP response.

Freshmanet al, 1993

ICP elevation byepidural ballooninflation in sheep

7.5% NaClBolus

Similar ICP reduction.Similar brain watercontent.

CPP, cerebral perfusion pressure; MAP, mean arterial pressure; MCA, middle cerebralartery.*Equiosmolar doses of mannitol 20% (osmolarity 1160 mOsm/L) and HS were used

91

Treatment protocol for osmotherapy:

The conventional osmotic agent mannitol, when administered at a

dose of 0.25 to 1.5 g/kg by intravenous bolus injection, usually lowers

ICP, with maximal effects observed 20 to 40 minutes following its

administration. Repeated dosing of mannitol may be instituted every 6

hours and should be guided by serum osmolality to a recommended

target value of approximately 320 mOsm/L; higher values result in

renal tubular damage (Alejandro & Rabinstein, 2006).

A variety of formulations of hypertonic saline solutions (2, 3, 7.5,

10, and 23%) are used in clinical practice for the treatment of cerebral

edema with or without elevations in ICP. Hypertonic saline solutions

of 2, 3, or 7.5% contain equal amounts of sodium chloride and

sodium acetate (50:50) to avoid hyperchloremic acidosis. Potassium

supplementation (20–40 meq/L) is added to the solution as needed

(Ahmed & Anish, 2007).

Continuous intravenous infusions are begun through a central

venous catheter at a variable rate to achieve euvolemia or slight

hypervolemia (1–2 ml/ kg/hr). A 250-ml bolus of hypertonic saline

can be administered cautiously in select patients if more aggressive

and rapid resuscitation is warranted. Normovolemic fluid status is

maintained, guided by central venous pressure (Battison et al, 2005).

The goal in using hypertonic saline is to increase serum sodium

concentration to a range of 145 to 155 mEq/L (serum osmolality

approximately 300–320 mOsm/L), but higher levels can be targeted

cautiously. This level of serum sodium is maintained for 48 to 72

92

hours until patients demonstrate clinical improvement or there is a

lack of response despite achieving the serum sodium target (Toung et

al, 2002).

During withdrawal of therapy, special caution is emphasized due to

the possibility of rebound hyponatremia leading to exacerbation of

cerebral edema. Serum sodium and potassium are monitored every 4

to 6 hours, during both institution and withdrawal of therapy. Chest

radiographs are obtained to find evidence of pulmonary edema from

congestive heart failure, especially in elderly patients (Mirski et al,

2000).

Intravenous bolus injections (30 ml) of 23.4% hypertonic saline

have been used in cases of intracranial hypertension refractory to

conventional ICP-lowering therapies; repeated injections of 30 ml

boluses of 23.4% saline may be given if needed to lower ICP.

Administration of this osmotic load, to lower ICP and maintain CPP,

may allow extra time for other diagnostic or therapeutic interventions

(such as decompressive surgery) in critically ill patients (Diringer et

al, 2004).

Potential complications of osmotherapy:

Safety concerns with mannitol include hypotension, hemolysis,

hyperkalemia, renal insufficiency, and pulmonary edema. Clinical

experiences suggest that the side-effect profile of hypertonic saline is

superior to mannitol, but some theoretical complications that are

93

possible with hypertonic saline therapy are notable (Table 4) (Dennis,

2003).

Table 4: Theoretical potential complications of using hypertonicsaline solutions:

1. CNS changes (encephalopathy, lethargy, seizures, coma)central pontine myelinolysis.

2. Congestive heart failure, pulmonary edema.3. Electrolyte derangements (hypokalemia, hypomagnesemia,

hypocalcemia).4. Cardiac arrhythmias.5. Metabolic academia (hyperchloremic with use of chloride

solutions).6. Potentiation of non tamponaded bleeding.7. Subdural hematomas that result from shearing of bridging veins

due to hyperosmolar contracture of brain.8. Hemolysis with rapid infusions.9. Phlebitis with infusion via peripheral route.10.Coagulopathy (elevated prothrombin and partial thromboplastin

time, platelet dysfunction).11.Rebound hyponatremia leading to cerebral edema with rapid

withdrawal.Modified from Bhardwaj and Ulatowski, 1999 and Shell et al. (Dennis, 2003).

Myelinolysis, the most serious complication of hypertonic saline

therapy, typically occurs when rapid corrections in serum sodium

arise from a chronic hyponatremic state to a normonatremic or

hypernatremic state. Experimental studies suggest that for myelin

injury to occur, the degree of rapid change in serum sodium is much

greater from a normonatremic to a hypernatremic state (change of

94

approximately 40 mEq/L), but further study with neuroimaging

techniques is required (Takefuji et al, 2007).

3.. LLoooopp ddiiuurreettiiccss::

The use of loop diuretics (commonly furosemide) for the treatment

of cerebral edema, particularly when used alone, remains

controversial. Combining furosemide with mannitol produces a

profound diuresis; however, the efficacy and optimum duration of this

treatment remain unknown (Steiner et al, 2001).

If loop diuretics are used, rigorous attention to systemic hydration

status is advised, as the risk of serious volume depletion is substantial

and cerebral perfusion may be compromised. A common strategy

used to raise serum sodium rapidly is to administer an intravenous

bolus of furosemide (10 to 20 mg) to enhance free water excretion

and to replace it with a 250-ml intravenous bolus of 2 or 3%

hypertonic saline (Thenuwara et al, 2002).

Acetazolamide, a carbonic anhydrase inhibitor that acts as a weak

diuretic and modulates CSF production, does not have a role in

cerebral edema that results from acute brain injuries; however, it is

frequently used in outpatient practice, particularly for the treatment of

cerebral edema associated with pseudo tumor cerebrii (Eccher &

Suarez, 2004).

4. CCoorrttiiccoosstteerrooiidd aaddmmiinniissttrraattiioonn::

The main indication for the use of steroids is for the treatment of

vasogenic edema associated with brain tumors or accompanying brain

95

irradiation and surgical manipulation. Although the precise

mechanisms of the beneficial effects of steroids in this paradigm are

unknown, steroids decrease tight-junction permeability and, in turn,

stabilize the disrupted BBB (Rabinstein, 2006).

Glucocorticoids, especially dexamethasone, are the preferred

steroidal agents, due to their low mineralocorticoid activity; the usual

initial dose is 10 mg intravenously or by mouth, followed by 4 mg

every 6 hours. This is equivalent to 20 times the normal physiologic

production of cortisol (Papadopoulos et al, 2004).

Responses are often prompt and remarkable, sometimes dramatic,

but some tumors are less responsive. Higher doses, up to 96 mg per

day, may be used with chances of success in more refractory cases.

After several days of use, steroids should be tapered gradually to

avoid potentially serious complications from recurrent edema and

adrenal suppression (Kaal & Vecht, 2004).

The therapeutic role of steroids in TBI and stroke has been studied

extensively. In TBI, steroids failed to control elevations in ICP or to

show any benefit in outcome, and they may even be harmful. In

stroke, steroids have failed to show any substantial benefit despite

some success in animal models. Given the deleterious side effects of

steroid use (peptic ulcers, hyperglycemia, impairment of wound

healing, psychosis, and immunosuppression), until further studies are

published, caution is advised in the use of steroids for cerebral edema

unless absolutely indicated (Roberts et al, 2004).

96

Glucocorticoids are also useful to treat brain edema in cases of

bacterial meningitis. Edema in these patients develops as part of the

inflammatory reaction triggered by the lysis of bacterial cell walls

induced by antibiotics. Inflammation is mediated through the

increased production of cytokines and chemokines by microglia,

astrocytes, and macrophages. Interleukin-1 (IL-1) and tumor necrosis

factor (TNF) increase vascular permeability both directly and

indirectly by increasing leukocyte adherence to the endothelium

(Sinha et al, 2004).

Apart from previously mentioned mechanisms, glucocorticoids

exert a depressant effect on both the synthesis and translation of IL-1

and TNF mRNA. The timing of glucocorticoid use may be critical as

the maximal reduction in the production of these inflammatory

cytokines occurs only if therapy is started prior to the release of the

bacterial cell wall components (Slivka & Murphy, 2001).

5. PPhhaarrmmaaccoollooggiiccaall ccoommaa::

Barbiturates were introduced since the 1960s, and have gained

acceptance for the treatment of cerebral edema associated with

intractable elevations in ICP. Barbiturates lower ICP, principally via a

reduction in cerebral metabolic activity, resulting in a coupled

reduction in CBF and CBV (Mayer & Rincon, 2005).

Yet their use in clinical practice is not without controversy. In

patients with TBI, barbiturates are effective in reducing ICP, but have

failed to show evidence of improvement in clinical outcome.

97

Evidence is limited for the utility of barbiturate treatment in cerebral

diseases that include space-occupying lesions such as tumor and ICH

(Schwab et al, 1997).

When used in the acute setting, pentobarbital, a barbiturate with an

intermediate physiological half-life (approximately 20 hours) is the

preferred agent rather than phenobarbital. The recommended regimen

entails a loading intravenous bolus dose of pentobarbital (3–10

mg/kg), followed by a continuous intravenous infusion (0.5–3.0

mg/Kg/hr, serum levels of 3 mg/dL) (Alejandro & Rabinstein, 2006).

Several adverse effects of barbiturates that limit their clinical use

are to be noted, including sustained lowering of systemic blood

pressure and CPP, cardiodepression, immunosuppression, and

systemic hypothermia. Perhaps the most important limitation with

barbiturate coma treatment is the inability to track subtle changes in a

patient’s clinical neurological status, which necessitates frequent

serial neuroimaging (Ropper et al, 2004).

6. HHyyppootthheerrmmiiaa::

Induced hypothermia has generated enormous interest as a potential

neuroprotective intervention in patients with acute brain insults.

Sound experimental data provide a solid foundation to the clinical

evaluation of hypothermia to treat acute brain ischemia and traumatic

injury (Krieger et al, 2001).

Different cooling methods are currently available, including

external (ice packs, iced gastric lavage, water or air circulating

98

blankets, cooling vest) and endovascular means. The superiority of

endovascular cooling is probable but still under evaluation. Target

core temperature is usually 32–34°C, measured with thermistors

placed inside the urinary bladder (Clifton et al, 2001).

Shivering must be prevented using deep sedation and

neuromuscular paralysis when necessary; the combination of oral

buspirone and intravenous meperidine. Hypothermia is usually

maintained for 12–72 hours, followed by a period of controlled

rewarming over 12–24 hours (Gadkary et al, 2002).

Induction of hypothermia is associated with several potential

complications. The most frequent and dangerous are sepsis

(particularly from pneumonia), cardiac arrhythmias and hemodynamic

instability (often seen during rewarming), coagulopathy (especially

thrombocytopenia), and electrolyte disturbances (potassium,

magnesium, calcium, phosphate) (Holzer et al, 2005).

99

IIIIII.. SSuurrggiiccaall iinntteerrvveennttiioonnss::In patients with ICP elevation, cerebrospinal fluid drainage is a fast

and highly effective treatment measure. This assertion holds true even

in the absence of hydrocephalus. Unfortunately, external ventricular

drainage carries a substantial risk of ventriculitis, even under the best

care. Controlled lumbar drainage may be a safe alternative, though its

use should be accompanied by extreme caution (Buschmann et al,

2007).

A comprehensive and updated discussion on the value of

hemicraniectomy to treat ischemic brain edema associated with

massive hemispheric strokes has been recently published. While it is

clear that hemicraniectomy can be lifesaving, its beneficial impact on

the long-term functional outcome of survivors remains unproven. An

example of this surgical intervention is presented in (Figure 22)

(Coplin et al, 2001).

In patients with critical intracranial hypertension after head trauma

who fail to respond to all other therapeutic measures, craniectomy

with duraplasty may be a valuable alternative. Hemicraniectomy may

be preferable in patients with focal lesions, such as hemorrhagic

contusions. Good long-term functional outcomes have been reported

in 25–56% of young patients after this surgery (Bullock, 2006).

Although the optimal timing and indications for this intervention

are not well established, the expeditious decision by an experienced

neurosurgeon to proceed with holocraniectomy in a young patient

100

with massive intractable traumatic brain edema should probably not

be delayed by attempts to keep trying additional medical options

(Subramaniam & Hill, 2005).

Figure 22. A 58-year-old man: in A shows mass effect from theswollen infarction with early hemorrhagic transformation and shiftof midline structures. Hemicraniectomy was promptly performed

without complications. Postoperative CT scan shown in Bdemonstrates partial decompression of the mass effect with

herniation of infracted tissue through the skull defect (Coplin et al,2001).

101

CChhaapptteerr ((66)):: SSppiinnaall CCoorrddEEddeemmaa IInn

IInnjjuurryy aanndd RReeppaaiirr

102

SSppiinnaall CCoorrdd EEddeemmaa IInn IInnjjuurryy aannddRReeppaaiirr

IInnttrroodduuccttiioonn::The blood-spinal cord barrier (BSCB) regulates the fluid

microenvironment of the spinal cord within a narrow limit. The

details of structural and functional properties of the BSCB in normal

and pathological conditions are not well known in all details

(Leskovar et al, 2000).

Traumatic insults to the spinal cord disrupt the functional integrity

of the BSCB and results into an increased transport of several

substances from the vascular compartment to the spinal cord cellular

microenvironment. Breakdown of the BSCB thus appears to play

important roles in cell and tissue reaction as well as regeneration and

repair processes (Popovich et al, 1997).

An increased understanding of BSCB in spinal cord injury (SCI)

is important for the development of suitable therapeutic strategies to

minimize cell and tissue destruction and to enhance regeneration and

functional recovery (Sharma, 2004).

There are reasons to believe that the characteristics of the BSCB

are similar to that of the blood-brain barrier (BBB). The spinal cord

endothelial cells are connected with tight junctions and do not

exhibit vesicular transport. The spinal endothelial cells are

surrounded by a thick basement membrane like the BBB. However,

103

a minor difference in astrocytes-microvessel interactions is seen in

the superficial spinal cord microvessels. The large superficial vessels

of the spinal cord contain enough deposits of glycogen, not normally

seen in the brain microvessels. The functional significance of

glycogen deposits in relation with the barrier properties is not well

understood (James et al, 1997).

Interestingly, impairment of local circulation in the spinal cord

induces much less cell damage compared to the brain. A less marked

regional difference in the spinal cord microcirculation and/or

metabolism compared to the brain could be the main reason behind

this phenomenon (Stålberg et al, 1998).

In traumatic brain injuries, breakdown of the BBB results in

abnormal leakage of proteins leading to vasogenic edema formation

and brain pathology. Edematous swelling of brain in a closed

cranium compresses vital centers resulting in instant death.

However, in the spinal cord, the vertebral canal provides some space

to accommodate edematous expansion of the spinal cord up to some

extent (Mendelow et al, 2000).

104

EEppiiddeemmiioollooggyy ooff SSppiinnaall CCoorrdd IInnjjuurryy::In the United States of America, about 30 to 50 cases per million

populations are recorded per year that is quite comparable to Europe

and other continents. The common cause of SCI is due to motor

vehicle accidents followed by fall, penetrating injuries like gun shot,

knife wounds or sports injuries (Schwab & Bartholdi, 1996).

Majority of cases show injury to the cervical spinal cord or

thoracolumbar junctions. The victims of SCI are generally young

men of 20 to 30 years of age while only 20 to 30 % of cases involve

women (Holmes, 1915, coated from Sharma, 2005).

Quadriplegia followed by paraplegia is the main symptoms of

SCI. Complete injuries without any signs of voluntary motor or

sensory perception below the level of the lesion are seen in about

50% cases of the SCI victims. The other causes of paralysis

involving the spinal cord are multiple sclerosis, ischemia and

tumors. Currently, no suitable therapeutic strategies are effective in

improving the quality of life of SCI patients. Thus, exploration of

new pharmacological avenues with possibility of regeneration of the

damaged spinal cord axons is urgently needed. Knowledge on the

structure and function of the BSCB and the spinal cord

microenvironment in SCI is thus crucial for the development of

novel pharmacological tools to minimize cell and tissue injuries as

well as to enhance recovery (Sharma, 2000).

105

PPaatthhoopphhyyssiioollooggyy ooff SSppiinnaall CCoorrdd IInnjjuurryy::Pathophysiology of SCI is complex and includes several

immediate and late cell and tissue reactions. The progression and

persistence of these pathological changes mainly depends on the

severity of the primary lesion. Depending on the magnitude and

severity of the initial impact, microhaemorrhages and leakage of

erythrocytes are present in the perivascular space across

microvessels, arterioles, veins and venules as well as in the spinal

cord neuropil within 3 minutes (Sharma, 2005).

Damage to neuropil, swollen astrocytes, ruptured cell membranes

and basal lamina are frequent within 6 to 10 minutes after SCI.

Swollen endothelial cells with electron dense cytoplasm exhibiting

large numbers of vesicles (60 to 70 nm diameter) without widening

of the tight junctions are common at this time. In some microvessels,

the perivascular spaces contain proteinaceous fluid. The endothelial

balloons are evident in some microvessels 4 to 6 hours after injury

(Mautes & Noble, 2000).

A detailed account of BSCB permeability following spinal cord

transection and contusion is previously described by Noble and co-

workers. Extravasation of exogenous horseradish peroxidase (HRP)

is seen in 0.5 to 2.0 cm proximal and distal segments of the cord to

the transection site. The segment located 1 cm away from the lesion

site showed extravasation of HRP between 30 minutes and 3 hours

on day 1. A less pronounced increase in BSCB disruption is seen in

106

the proximal segment compared to the distal segment. The

permeability to HRP is restored within 14 days after injury (Noble,

1978, coated from Sharma, 2005).

Vesicular transport rather than widening of the tight junctions is

responsible for HRP extravasation in the transection and contusion

injuries. These observations suggest that the mechanisms of leakage

across the BSCB are similar in nature irrespective of the types of

injury (Sharma, 2004).

At the ultrastructural level, lanthanum tracer was mainly confined

within the lumen of the endothelial of normal rats. SCI resulted in

the occurrence of lanthanum filled vesicles within the endothelial

cell cytoplasm. Marked increase in the endothelial cell membrane

permeability to lanthanum is seen in several vascular profiles that

appear to be very specific. In some microvascular profiles, the

lanthanum is present in the basal lamina. However, the tight junction

remained intact to lanthanum in SCI. These observations suggest

that increased endothelial cell membrane permeability seems be one

additional way of vascular leakage (Sharma, 2000).

Spinal cord edema formation:After SCI, edema formation is apparent as early as 30 seconds and

becomes prominent within 2 to 5 minutes that could last up to 15

days. The labeled Evans blue albumin (EBA) spreads up to one

segment from the injury site. Traumatic injuries resulting in

permanent paraplegia increase tissue water content above and below

the lesion site. Adjacent spinal cord segments also exhibit leakage of

107

albumin and dextran as well as tissue damage. On the other hand,

transient paraplegia is not associated with extravasation of albumin

or dextran and/or increase in spinal cord water content (Sharma,

2003).

Edema, as measured by water content is seen as early as 5 minutes

after impact injury that persisted up to 15 days. The edema

formation is most prominent in the gray matter. On the other hand,

using specific gravity gradient column, about 127 % increase in

edema and volume swelling was observed near the impact site in the

gray matter compared to only 24 % increase in white matter after 1

hour injury. The regression of edema is evident after 9 days. This

indicates that progression, persistence and resolution of edema are

crucial for cell and tissue injury following SCI (Li & Tator, 1998).

Local microhaemorrhage and tissue necrosis near the lesion site

also influence increase in the water content. Increased tissue water

content in the adjacent non-traumatised segment, thus represents true

edema formation. Tissue pressure gradients develop within 1 or 2

hours after primary injury between the lesioned site and the remote

areas in both rostral and caudal directions. The tissue pressure

gradients influence spread of edema fluid across the spinal cord

(Sharma, 2002).

Profound edema development is seen within 30 min after SCI near

the lesion site that is progressive with time. Interestingly, the caudal

segments exhibited more pronounced edema development compared

to the rostral segments indicating that release of neurochemicals and

108

BSCB breakdown following SCI influences edema formation

(Mautes et al, 2000).

TTrreeaattmmeenntt SSttrraatteeggiieess iinn SSppiinnaall CCoorrddIInnjjuurryy::

There are reasons to believe that BSCB could be an important target

for the drugs used to treat SCI induced cell injury and sensory-motor

recovery. However, the current pharmacological strategies are not

well focused on the changes in the BSCB function after trauma in

relation to cord pathology or the functional outcome (Sharma,

2003).

The altered spinal cord microenvironment appears to be one of the

key factors in neuroprotection or sensory-motor recovery following

SCI. It is quite likely that drugs or therapeutic agents that offer

neuroprotection are able to minimize the BSCB disturbances. The

potential of these therapeutic agents in the treatment of SCI is the

subject of many researches. The main treatment strategies in spinal

cord injury can be summarized in (table 5) (Hagg & Oudega, 1998).

109

Table. 5: Treatment Strategies in Spinal Cord Injury:

1) Neuroprotective approach:directed against interrupting the cascade ofsecondary injury processes.limiting tissue damage.arrest or reverse sensory/motor function impairment.

2) Rehabilitating approach:directed against consequences of spinal cord injurystabilization of current status with traumatraining of reflexes and residual circuitsfor optimal living conditions

3) Regenerative approach:directed towards enhancement of axonal regenerationpurely experimental at this stageno experience in human spinal cord injury

(Sharma, 2003)

PPhhaarrmmaaccoollooggyy ooff tthhee BBSSCCBB iinn ssppiinnaall ccoorrdd

iinnjjuurryy::The pharmacological strategies in SCI are used to influence the

process of secondary injury cascade to limit tissue damage and to

improve sensory-motor function. Another pharmacological aspect in

SCI is to enhance axonal regeneration. This can either be achieved

using neurotrophic factors or blocking regeneration inhibiting

factors. There are many therapeutic aspects that can be used, and

will be summarized:

110

1) Neurotrophic factors:

Neurotrophic factors and their receptors are present in the

developing and adult spinal cord. The neurotrophin receptors

influence neuronal survival by modulation of neurotransmitters,

neuropeptides as well as their release in the spinal cord. The

receptors for both neurotrophins and cytokines are located on

neurons, glial cells, inflammatory cells, meninges, and blood vessels

in scar tissue. There are evidences that neurotrophins effect signaling

of cytokines (Oudega & Hagg, 1999).

Brain derived neurotrophic factor (BDNF) and insulin like growth

factor 1 (IGF-1) are members of neurotrophins family and induce

neuroprotection during ischemia and trauma. Exogenous supplement

of growth factors induces neuroprotection either by neutralizing the

influence of neurodestructive agents or by enhancing the influence

of neuroprotective substances. Pretreatment with BDNF or IGF-1

markedly attenuated the occurrence of gross visual swelling after

injury without influencing microhaemorrhages (Ruitenberg et al,

2003).

Attenuation of the BSCB permeability with neurotrophins

indicates their involvement in the secondary injury mechanisms

following trauma. A reduction in BSCB permeability reduces

leakage of plasma proteins and thus able to prevent vasogenic edema

formation (Lu & Waite, 1999).

111

2) Tumor necrosis factor alpha (TNF-) antiserum:

In the CNS, tumor necrosis factor alpha (TNF-) is a cytotoxic

cytokine that is upregulated within 1 to 6 hours following traumatic,

ischemic or hypoxic insults. Intrathecal administration of TNF-

antiserum attenuates nitric oxide (NO) production and induces

neuroprotection by neutralizing the effects of endogenous TNF-

(Lee et al, 2000).

3) Nitric oxide synthase antiserum:

Treatment with nitric oxide synthase (NOS) antiserum resulted in

a decrease in peptide or protein extravasation across the BSCB

following trauma. This indicates that NOS activation increases NO

production that disrupts the BSCB through intracellular signal

transduction. To further establish the therapeutic values of the NOS

antiserum, studies using its application at longer time intervals

following SCI on the BSCB breakdown and cell injury are needed

(Hooper et al, 2000).

4) Antioxidant compounds:

Microhaemorrhages and extravasation of blood components

caused by SCI is one of the important sources of oxidative stress and

generation of free radicals that disrupt myelin sheaths and induce

cell damage, hemoglobin is an important source of iron to catalyze

oxygen radicals and lipid peroxidation (Calbrese et al, 2000).

Treatment with one potent chain-breaking antioxidant compound

H-290/51 attenuated trauma induced BSCB disruption to Evans blue

112

albumin (EBA) and radioiodine tracers. These observations suggest

that lipid peroxidation and generation of free radicals contributes to

the BSCB breakdown in SCI (Mustafa et al, 1995).

A significant reduction in water content and mild perivascular

edema, swelling of nerve cells and myelin vesiculation at the

ultrastructural level in the drug treated group supports this idea

(Tong et al, 1998).

5) Prostaglandins:

The precursor of prostaglandins (PGs) arachidonic acid and its

metabolite are involved in the secondary injury processes.

Pretreatment with indomethacin, a potent inhibitor of

cyclooxygenase enzyme, significantly attenuated edema formation

and cell damage. These results support a role of PGs in the

endothelial cell membrane permeability. Whether the effects of PGs

on BSCB permeability are mediated by specific PG receptors, are

still unclear (Leskovar et al, 2000).

6) Bradykinin (BK):

Blockade of BK2 receptor antagonist slightly but significantly

reduced the breakdown of the BSCB to EBA, radioiodine and

lanthanum tracers. Edema formation and cell injury in the drug

treated traumatized cord are considerably reduced. These

observations demonstrate that bradykinin is involved in the

breakdown of the BSCB permeability probably through BK2

receptors (Bogar et al, 1999).

113

7) Opioid Peptides:

Opioid and non opioid neuropeptides, together with monoamines

and amino acids play integral roles in the neurotransmission in the

spinal cord. Intrathecal or systemic administration of selective -

opioid antagonist nor-binaltrophimine (nor-BNI) enhances

neurological recovery after spinal cord trauma suggests an

involvement of - opioid receptors in SCI (Tang et al, 2000).

The natural ligand of the - opioid receptors, dynorphin that is

well known to participate in the pathophysiology of SCI supports

this idea. Treatment with dynorphin A (1–17) antiserum improves

the neurological outcome after SCI, At 5 h the gross swellings of the

spinal cord, BSCB disruption and edema formation are significantly

reduced. Trauma induced cell injury; myelin vesiculation and

membrane disruption are also reduced by dynorphin antiserum

(Hauser et al, 2001).

8) Adrenergic receptor blockers:

On the basis of norepinephrine accumulation in the traumatized

cord, role of catecholamines in SCI was suggested by Osterholm and

Mathews. However, inhibition of catecholamines synthesis with -

methyltyrosine; or blockade of - adrenergic receptor with clonidine

yielded controversial results (Faden & Salzman, 1992).

Some trials which examined the influence of potent - and -

adrenergic receptor antagonists, phenoxybenzamine and propranolol,

respectively on edema formation and BSCB disruption in SCI

114

yielded that: pretreatment with - or - adrenergic receptor blockers

did not attenuate BSCB permeability and edema formation. Thus,

further studies using adrenoceptor agonists are needed to clarify the

involvement of catecholamines in SCI (Winkler et al, 1998).

115

SSuummmmaarryy

The concept of cerebral edema has been recognized for more

than 2000 years, yet an understanding of the complex physiology of

this condition has evolved only within the past 30 years.

Hippocrates noted that removal of the overlying skull bones

allowed the injured brain to swell outward, thus minimizing

compression of normal tissue trapped within the cranial vault.

The Monro–Kellie doctrine later recapitulated this concept,

affirming that when ‘‘water or other matter is effused or secreted

from the blood vessels ... a quantity of blood equal in bulk to the

effused matter, will be pressed out of the cranium.’’

This indiscriminate concept of brain swelling was cited in a

diverse range of clinical settings until 1967, when Igor Klatzo

defined the modern classification of edema based on

pathophysiology. Cerebral edema, according to Klatzo, was defined

as ‘‘an abnormal accumulation of fluid associated with volumetric

enlargement of the brain.’’

This entity was divided into vasogenic edema, characterized by

derangement of the blood–brain barrier (BBB), and cytotoxic

edema, related to intracellular swelling in the absence of changes at

the BBB. Klatzo emphasized that these two forms usually

coexisted.

116

In 1975, Robert Fishman added interstitial edema as a distinct

entity by describing the transependymal flow of cerebrospinal fluid

(CSF) into the periventricular white matter in individuals with

acute obstructive hydrocephalus; this form was later termed

hydrocephalic edema.

This classification is highly simplistic, given that it pertains to

complex pathophysiological and molecular mechanisms, but is

valuable as a simple therapeutic guide for treatment of cerebral

edema. Most brain insults involve a combination of these

fundamental subtypes of edema, although one can predominate

depending on the type and duration of injury.

Cytotoxic edema results from swelling of the cellular elements

(neurons, glia, and endothelial cells) because of substrate and

energy failure, and affects both gray and white matter. This edema

subtype is conventionally encountered in: cerebral ischemia,

traumatic brain injury, infections, and metabolic disorders

including kidney and liver failure.

Vasogenic edema that results from breakdown of the BBB due to

increased vascular permeability, as commonly encountered in:

hemorrhage, later stages of brain infarction, TBI, infections,

seizures, trauma, tumors, radiation injury and hypertensive

encephalopathy, predominantly affects white matter.

This edema subtype is responsive to both steroid administration

(notably edema associated with neoplasms) and osmotherapy.

Other causes of vasogenic edema include tissue hypoxia and water

117

intoxication that may be responsive to osmotherapy but resistant to

steroid administration.

Interstitial edema, a consequence of impaired absorption of CSF,

leads to increases in transependymal CSF flow, resulting in acute

hydrocephalus. This edema subtype is also not responsive to steroid

administration, and its response to osmotherapy is debatable.

In osmotic edema there is an osmotic gradient which is present

between plasma and the extracellular fluid. Edema may occur with

a number of hypo-osmolar conditions including: improper

administration of intravenous fluids leading to acute dilutional

hyponatremia, inappropriate antidiuretic hormone secretion,

excessive hemodialysis of uremic patients and diabetic

ketoacidosis.

Basic information about the types of edema is provided for better

understanding of the expression pattern of some of the newer

molecules implicated in the pathogenesis of brain edema. These

molecules include the aquaporins (AQP), matrix metalloproteinases

(MMPs) and growth factors such as vascular endothelial growth

factors (VEGF) A and B and the angiopoietins. The potential of

these agents in the treatment of edema is the subject of many

reviews.

Blood-spinal cord barrier (BSCB) plays an important role in the

regulation of the fluid microenvironment of the spinal cord. Trauma

to the spinal cord impairs the BSCB permeability to proteins

leading to vasogenic edema formation. Several endogenous

118

neurochemical mediators and growth factors contribute to trauma

induced BSCB disruption.

Studies carried out suggest that those drugs and neurotrophic

factors capable to attenuate the BSCB dysfunction following

trauma are neuroprotective in nature. Whereas, agents that do not

exert any influence on the BSCB disruption failed to reduce cell

injury. These observations are in line with the idea that BSCB

disruption plays an important role in the pathophysiology of spinal

cord injuries.

Neuroimaging by CT scans and magnetic resonance imaging can

be particularly useful in confirming intracranial compartmental and

midline shifts, herniation syndromes, ischemic brain injury, and

exacerbation of cerebral edema (sulcal effacement and obliteration

of basal cisterns).

The consequences of cerebral edema can be lethal and include

cerebral ischemia from compromised regional or global cerebral

blood flow (CBF) and intracranial compartmental shifts due to

intracranial pressure gradients that result in compression of vital

brain structures. The overall goal of medical management of

cerebral edema is to maintain regional and global CBF to meet the

metabolic requirements of the brain and prevent secondary

neuronal injury from cerebral ischemia.

Medical management of cerebral edema involves using a

systematic and algorithmic approach, from general measures

(optimal head and neck positioning for facilitating intracranial

119

venous outflow, avoidance of dehydration and systemic

hypotension, and maintenance of normothermia) to specific

therapeutic interventions (controlled hyperventilation,

administration of corticosteroids and diuretics, osmotherapy, and

pharmacological cerebral metabolic suppression).

120

DDiissccuussssiioonn::

Hence the significance of brain edema, which continues to be a

major cause of mortality after diverse types of brain pathologies, the

lack of effective treatment, remains a stimulus for continued interest

and research into the pathogenesis of this condition (Kempski,

2001).

Though there has been good progress in understanding of

pathophysiological mechanisms associated with cerebral edema

more effective treatment is required and is still awaited (Marmarou

et al, 2006).

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 (Abbott, 2004).

The treatment of cerebral edema remains largely empirical.

Options are relatively limited, and the mechanisms of action of most

of the therapeutic agents and interventions currently used are not

fully elucidated (Ahmed & Anish, 2007).

Research in the last decade has led to an appreciation of the

complexity of brain edema pathogenesis and to the awareness that

many molecules are involved acting simultaneously or at different

stages during the edema process (Johnston & Teo, 2000)

121

This suggests that effective treatment of brain edema cannot be

achieved by a single agent, but will require the administration of a

‘‘magic bullet’’ containing a variety of agents released at different

times during the course of edema in order to be successful

(Alejandro & Rabinstein, 2006)

Although protocols and algorithms exist to treat brain edema

associated with specific neurologic entities, these are not based on

rigorous scientific data (Kimelburg, 2004).

Current uncertainties and deficiencies must be resolved by

continuing research, fueled by growing understanding of the

pathophysiological processes responsible for the formation of the

different forms of brain edema (Nag, 2003) b.

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 (Kuroiwa et al,

2007).

Traumatic insults to the spinal cord disrupt the functional

integrity of the blood-spinal cord barrier (BSCB) and results into an

increased transport of several substances from the vascular

compartment to the spinal cord cellular microenvironment.

Transport of macromolecules like proteins from the vascular

compartment to the spinal cord microenvironment induces vasogenic

edema (Sharma, 2003).

New pharmacotherapeutic agents and compounds that reduce

trauma induced alterations in the BSCB and cell injury may

122

strengthen the effects of endogenous neuroprotective agents and

minimize the adverse influence of endogenous neurodestructive

elements. Thus, drugs, compounds or agents that are capable to

minimize trauma induced BSCB breakdown could be the promising

therapeutic agents for the treatment of SCI in the future (Sharma,

2005).

123

RReeffeerreenncceess::

Abbott A: Evidence for bulk flow of brain interstitial

fluid: significance for physiology and pathology. Neurochem Int

(2004) 45, 545 – 52.

Adams RH & Alitalo K: Molecular regulation of

angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol (2007)

8:464– 478. doi:10.1038/nrm2183.

Ahmed R & Anish B: Medical management of cerebral

edema. Neurosurg Focus (2007), 22 (5):E12.

Alejandro A. & Rabinstein: Treatment of Cerebral

Edema. The Neurologist (2006); 12: 59–73.

Amiry-Moghaddam M, Ottersen OP. The molecular

basis of water transport in the brain. Nat Rev Neurosci (2003); 4: 991–

1001.

Asahi M, Wang X, Mori T, et al: Effects of matrix

metalloproteinase-9 gene knock-out on the proteolysis of blood–

brain barrier and white matter components after cerebral ischemia. J

Neurosci (2001) 21:7724–7732.

Ayata C & Ropper AH: Ischaemic brain oedema. J

Clin Neurosci (2002) 9:113–124. doi:10.1054/jocn.2001.1031.

Badaut J, Hirt L, Granziera C, et al: Astrocyte-

specific expression of aquaporin-9 in mouse brain is increased after

124

transient focal cerebral ischemia. J Cereb Blood Flow Metab (2001)

21:477–482. doi:10.1097/00004647- 200105000-00001.

Ball AK & Clarke CE: Idiopathic intracranial

hypertension. Lancet Neurol (2006), 5, 433-42.

Ballabh P, Braun A, Nedergaard M: The blood brain

barrier: an overview. Structure regulation and clinical implication.

Neurobiol Dis (2004),16, 1-13.

Banasiak KJ, Burenkova O, Haddad GG. Activation

of voltage sensitive sodium channels during oxygen deprivation

leads to apoptotic neuronal death. Neuroscience (2004); 126: 31–44.

Bastin ME, Sinha S, Whittle IR, et al.: Measurements

of water diffusion and T1 values in peritumoural oedematous brain.

Neuroreport (2002); 13:1335–40.

Battison C, Andrews PJ, Graham C, et al:

Randomized, controlled trial on the effect of a 20% mannitol solution

and a 7.5% saline/6% dextran solution on increased intracranial

pressure after brain injury. Crit Care Med (2005) 33:196–202.

Berger S, Schurer L, Hartl R, et al.: Reduction of

post-traumatic intracranial hypertension by hypertonic/hyperoncotic

saline/dextran and hypertonic mannitol. Neurosurgery. (1995); 37:98

–107.

Bhardwaj A & Ulatowski JA: Hypertonic saline

solutions in brain injury. Curr Opin Crit Care (2004) 10:126–131.

Bloch O, Auguste KI, Manley GT, et al: Accelerated

progression of kaolin-induced hydrocephalus in aquaporin-4-

125

deficient mice. J Cereb Blood Flow Metab (2006) 26:1527–1537.

doi:10.1038/sj.jcbfm.9600306.

Bogar LJ, Bartula LL, Parkman HP, et al: Enhanced

bradykinin-stimulated prostaglandin release in the acutely inflamed

guinea pig gallbladder is due to new synthesis of cyclooxygenase 1

and prostacyclin synthase. J Surg Res (1999); 84: 71-76.

Boyd NL, Park H, Yi H, et al: Chronic shear induces

caveolae formation and alters ERK and Akt responses in endothelial

cells. Am J Physiol Heart Circ Physiol (2003) 285:H1113–H1122.

Broderick JP, Adams HP Jr, Barsan W, et al:

Guidelines for the management of spontaneous intracerebral

hemorrhage. A statement for healthcare professionals from a special

group of the Stroke Council, American Heart Association. (1999)

Stroke 30:905–915.

Bruno A, Williams LS, Kent TA: How important is

hyperglycemia during acute brain infarction? Neurologist (2004) 10:

195–200.

Bullock R, Chesnut RM, Clifton G, et al: Guidelines

for the management of severe head injury: Brain Trauma Foundation.

Eur J Emerg Med (1996) 3:109–127.

Bullock M, Chestnut R, Ghajar J, et al.: Guidelines

for the Surgical Management of Traumatic Brain Injury. Surgical

management of traumatic parenchymal lesions. Neurosurgery.

(2006); 58(3 suppl):S25-S46.

126

Buschmann U, Yonekawa Y, Fortunati M, et al:

Decompressive hemicraniectomy in patients with subarachnoid

hemorrhage and intractable intracranial hypertension. Acta Neurochir

(Wien). (2007); 149: 59-65.

Calbrese V, Bates TE, Giuffrida Stella AM.: NO

synthase and NOdependent signal pathways in brain aging and

neurodegenerative disorders: The role of oxidant/antioxidant balance.

Neurochem Res (2000); 25: 1315-341.

Candelario-Jalil E, Yang Y, Rosenberg GA: Diverse

roles of matrix metalloproteinases and tissue inhibitors of

metalloproteinases in neuroinflammation and cerebral ischemia.

Neuroscience.(2008).158:983 994.doi:10.1016/j.neuroscience06.

025

Carmona Suazo JA, Maas AI, van den Brink WA, et

al.: CO2 reactivity and brain oxygen pressure monitoring in severe

head injury. Crit Care Med. (2000); 28:3268 –3274.

Chang DI, Hosomi N, Lucero J, et al: Activation

systems for latent matrix metalloproteinase-2 are upregulated

immediately after focal cerebral ischemia. J Cereb Blood Flow

Metab (2003) 23:1408–1419.

Clifton GL, Miller ER, Choi SC, et al: Lack of effect

of induction of hypothermia after acute brain injury. N Eng J Med

(2001) 344:556–563.

Coplin WM, Cullen NK, Policherla PN, et al.: Safety

and feasibility of craniectomy with duraplasty as the initial surgical

127

intervention for severe traumatic brain injury. J Trauma. (2001);

50:1050 –1059.

Cosnard G, Duprez T, Grandin C, et al.: Diffusion

and perfusion-weighted MR imaging during the hyperacute phase of

stroke. J Radiol (2000) 81(8):858–869.

Coutts SB, Lev MH, Eliasziw M, et al.: ASPECTS on

CTA source images versus unenhanced CT: added value in

predicting final infarct extent and clinical outcome. Stroke (2004);

35:2472–6.

Czosnyka M, Czosnyka & Z Momjian S, et al:

Cerebrospinal fluid dynamics. Physiolog Measurement (2004) 25,

R51-76.

Demediuk P, Saunders RD, Anderson DK, et al.:

Early membrane lipid changes in laminectomized and traumatized

cat spinal cord. Neurochem Pathol (1989); 7: 79-89.

Dennis MS: Outcome after brain hemorrhage.

Cerebrovasc Dis (2003), 16, 9-13.

Diringer M.: Hyperventilation in head injury: what

have we learned in 43 years? Crit Care Med. (2002); 30:2142–2143.

Diringer MN & Zazulia AR: Osmotic therapy: fact or

fiction. Neurocrit Care(2004) 1:219–234.

Doerfler A, Engelhorn T, Heiland S, et al: Perfusion-

and diffusion-weighted magnetic resonance imaging for monitoring

decompressive craniectomy in animals with experimental

hemispheric stroke. J Neurosurg. (2002); 96:933-940.

128

Dolman D, Drndarski S, Abbott NJ, et al: Induction

of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary

brain microvessel endothelial cells in culture. J Neurochem (2005)

93:825–833. doi:10.1111/j.1471-4159.2005.03111.x.

Eccher M & Suarez JI: Cerebral edema and

intracranial pressure. Monitoring and intracranial dynamics, in

Suarez JI (ed): Critical Care Neurology and Neurosurgery. Totowa,

NJ: Humana Press, (2004), pp 47–100.

Faden AI & Salzman S.: Pharmacological strategies in

CNS trauma. Trends Pharmacol Sci (1992); 13: 29-35.

Ferrara N, Gerber HP, LeCouter J: The biology of

VEGF and its receptors. Nat Med (2003) 9:669–676.

doi:10.1038/nm0603-669.

Forster C: Tight junctions and the modulation of barrier

function in disease. Histochem Cell Biol (2008) 130:55–70. doi:

10.1007/s00418-008-0424-9.

Freshman SP, Battistella FD, Matteucci M, et al.:

Hypertonic saline (7.5%) versus mannitol: a comparison for

treatment of acute head injuries. J Trauma. (1993); 35:344 –348.

Furman CS, Gorelick-Feldman DA, Davidson KG, et

al: Aquaporin-4 square array assembly: opposing actions of M1 and

M23 isoforms. Proc Natl Acad Sci USA (2003) 100:13609–13614.

doi:10.1073/pnas.2235843100.

129

Furuse M & Tsukita S: Claudins in occluding

junctions of humans and flies. Trends Cell Biol: (2006) 16:181–188.

doi:10.1016/ j.tcb.2006.02.006.

Gadkary CS, Alderson P, Signorini DF: Therapeutic

hypothermia for head injury. Cochrane Database Syst Rev (2002) 1:

CD001048.

Gemma M, Cozzi S, Tommasino C, et al.: 7.5%

Hypertonic saline versus 20% mannitol during elective neurosurgical

supratentorial procedures. J Neurosurg Anesthesiol. (1997); 9:329 –

334.

Glantz MJ, Cole BF, Forsyth PA, et al: Practice

parameter: anticonvulsant prophylaxis in patients with newly

diagnosed brain tumors. Report of the Quality Standards

Subcommittee of the American Academy of Neurology (2000).

Neurology 54:1886–1893.

Glasr N, Barnett P, McCaslin D et al.: Risk factors for

cerebral edema in children with diabetic ketoacidosis. N Engl J Med

(2001); 344:264 9.

Hagg T & Oudega M.: Neurotrophic factors and CNS

regeneration. In: Stålberg E, Sharma HS, Olsson Y Eds, Spinal Cord

Monitoring. Basic Principles, Regeneration, Pathophysiology and

Clinical Aspects, Springer Wien New York (1998); 129-55.

Harukuni I, Kirsch J, Bhardwaj A: Cerebral

resuscitation: role of osmotherapy. J Anesth (2002) 16:229–237.

130

Hauser KF, Knapp PE, Turbek CS.: Structure-

activity analysis of dynorphin A toxicity in spinal cord neurons:

Intrinsic neurotoxicity of dynorphin A and its carboxyl-terminal,

nonopioid metabolites. Exp Neurol (2001); 168: 78-87.

Hawkins BT & Davis TP. The blood-brain barrier /

neuro - vascular unit in health and disease. Pharmacol Rev (2005);

57: 173–85.

Hawkins BT & Egleton RD: Pathophysiology of the

blood– brain barrier: animal models and methods. Curr Top Dev Biol

(2008) 80:277–309. doi:10.1016/S0070-2153(07)80007-X.

Hemphill JC, Beal MF, Gress DR.: Critical care in

neurology. In : Braunwald E, Fauci AS, Kasper DL, Hauser SL,

Longo DL, Jameson JL, editors. Harrison’s Principles of Internal

Medicine. 15th ed. New York: Mc Graw Hill, (2001):2491-8.

Holzer M, Bernard SA, Hachimi-Idrissi S, et al:

Hypothermia for neuroprotection after cardiac arrest: systematic

review and individual patient data metaanalysis. Crit Care Med

(2005) 33:414–418.

Hooper DC, Scott GS, Zborek A, et al.: Uric acid, a

peroxynitrite scavenger, inhibits CNS inflammation, and tissue

damage in a mouse model of multiple sclerosis. FASEB J (2000); 14:

691-98.

Jaillard A, Hommel M, Baird AE, et al.: Significance

of early CT signs in acute stroke: a CT scandiffusion MRI study.

Cerebrovasc Dis (2002); 13: 47 56.

131

James HE, Marshall LF, Reulen H-J, et al.: Brain

Edema X, Springer Wien, (1997) New York.

Johnston AJ, Steiner LA, Coles JP, et al. Effect of

cerebral perfusion pressure augmentation on regional oxygenation

and metabolism after head injury. Crit Care Med. (2005); 33:189 –

195.

Johnston IH & Teo C: Disorders of CSF

hydrodynamics. Cilds nerv syst (2000), 16, 776-99.

Kaal EC & Vecht CJ.: The management of brain

edema in brain tumors. Curr Opin Oncol. (2004); 16:593– 600.

Katayama Y & Kawamata T: Edema fluid

accumulation within necrotic brain tissue as a cause of the mass

effect of cerebral contusion in head trauma patients. Acta Neurochir

Suppl (Wien) (2003) 86:323–327.

Kempski O, von AU, Schurer L, et al: Intravenous

glutamate enhances edema formation after a freezing lesion. Adv

Neurol (1990) 52:219–223.

Kempski O: cerebral edema. Semin Nephrol (2001)

21:303–307. [PubMed: 11320499].

Kim DS & Garwood M: High field magnetic resonance

techniques for brain research. Curr Opin Neurobiol (2003) 13:612–

619.

Kimelburg HK: Water homeostasis in the brain: basic

concepts. Neuroscience (2004), 129, 851-60.

132

Korenkov AI, Pahnke J, Frei K, et al: Treatment with

nimodipine or mannitol reduces programmed cell death and infarct

size following focal cerebral ischemia. Neurosurg Rev (2000)

23:145–150.

Krieger DW, De Georgia MA, Abou-Chebl A, et al:

Cooling for acute ischemic brain damage (Cool Aid): an open pilot

study of induced hypothermia in acute ischemic stroke. Stroke (2001)

32:1847–1854.

Kuroiwa T, Miyasaka N, Fengyo Z, et al:

Experimental ischemic brain edema: morphological and magnetic

resonance imaging findings. Neurosurg Focus (2007) 22:E11.

doi:10.3171/foc.2007.22. 5.12.

Latour LL, Kang DW, Ezzeddine MA, et al:

Early blood-brain barrier disruption in human focal brain

ischemia. Ann Neurol (2004); 56: 468–77.

Lee YB, Yune TY, Bail SY, et al.: Role of tumor

necrosis factor-a in neural and glial apoptosis after spinal cord injury.

Exp Neurol (2000); 166: 190-95.

Leira R, Davalos A, Silva Y, et al.: Early neurologic

deterioration in intracerebral hemorrhage: predictors and associated

factors. Neurology. (2004); 63:461– 467.

Lemke DM & Hacein-Bey L. Cerebral venous sinus

thrombosis. J Neurosci Nurs. (2005); 37:258 –264.

Leskovar A, Moriarty LJ, Turek JJ, et al: Tha

macrophage in acute neural injury: Changes in cell number over time

133

and levels of cytokine prosuction in mammalian central and

peripheral nervous systems. J Exp Biol (2000); 203: 1783-795.

Li S & Tator Ch.: Spinal cord blood flow and evoked

potentials as outcome measures for experimental spinal cord injury.

In: Stålberg E, Sharma HS, Olsson Y, Eds., Spinal Cord Monitoring.

Basic Principles, Regeneration, Pathophysiology and Clinical

Aspects, Springer, Wien, New York (1998); pp 365 392.

Liang D, Bhatta S, Gerzanich V, et al: Cytotoxic

edema: mechanisms of pathological cell swelling. Neurosurg Focus

(2007) 22:E2. doi:10.3171/foc.22.5.3.

Lo EH, Dalkara T, Moskowitz MA: Mechanisms,

challenges and opportunities in stroke. Nat Rev Neurosci (2003)

4:399–415. doi:10.1038/nrn1106.

Longatti P, Basaldella L, Orvieto E, et al:

Aquaporin(s) expression in choroid plexus tumours. Pediatr

Neurosurg (2006) 42:228–233. doi:10.1159/000092359.

Lossinsky AS & Shivers RR: Structural pathways for

macromolecular and cellular transport across the blood–brain barrier

during inflammatory conditions. Histol Histopathol (2004) 19:535–

564 (Review).

Lu J & Waite P.: Advances in spinal cord regeneration.

Spine (1999); 24: 926-30.

Machein MR & Plate KH: VEGF in brain tumors. J

Neurooncol (2000) 50:109–120. doi:10.1023/A:1006416003964.

134

Marcella A. Madera, MD; Raj K. et al: Traumatic

brain injury. http://www.merckmanuals.com (2007).

Marion DW, Puccio A, Wisniewski SR, et al.: Effect

of hyperventilation on extracellular concentrations of glutamate,

lactate, pyruvate, and local cerebral blood flow in patients with

severe traumatic brain injury. Crit Care Med. (2002); 30:2619 –

2625.

Marmarou A, Signoretti S, Aygok G, et al: Traumatic

brain edema in diffuse and focal injury: cellular or vasogenic? Acta

Neurochir Suppl(2006);96:24–29. [PubMed: 16671417].

Marmarou A: A Review of progress in understanding

the pathophysiology and treatment of brain edema. Neurosurg Focus

(2007) 22:E1.

Marti HJ, Bernaudin M, Bellail A, et al: Hypoxia-

induced vascular endothelial growth factor expression precedes

neovascularization after cerebral ischemia. Am J Pathol (2000)

156:965–976.

Masuhr F, Mehraein S, Einhaupl K.: Cerebral venous

and sinus thrombosis. J Neurol. (2004); 251:11–23.

Mautes AE, Bergeron M, Sharp FR, et al.; Sustained

induction of heme oxygenase-1 in the traumatized spinal cord. Exp

Neurol (2000); 166: 254-65.

Mautes AE & Noble LJ.: Co-induction of HSP70 and

heme oxygenase-1 in macrophages and glia after spinal cord

contusion in the rat. Brain Res (2000); 883: 233-37.

135

Mayer SA & Rincon F: Treatment of intracerebral

hemorrhage. Lancet Neurol (2005), 4, 662-72.

Mendelow AD, Baethmann A, Czernicki Z, et al.:

Brain Edema XI, Springer Wien (2000), New York.

Meng S, Qiao M, Lin L, et al: Correspondence of

AQP4 expression and hypoxicischaemic brain oedema monitored by

magnetic resonance imaging in the immature and juvenile rat. Eur J

Neurosci (2004) 19:2261–2269. doi:10.1111/j.0953-

816X.2004.03315.x.

Milhorat TH, Clark RG, Hammock MK:

Experimental hydrocephalus. 2. Gross pathological findings in acute

and subacute obstructive hydrocephalus in the dog and monkey. J

Neurosurg (1970) 32:390–399.

Minshall RD, Sessa WC, Stan RV, et al: Caveolin

regulation of endothelial function. Am J Physiol Lung Cell Mol

Physiol (2003) 285:L1179–L1183.

Minshall RD & Malik AB: Transport across the

endothelium: regulation of endothelial permeability. Handb Exp

Pharmacol (2006) 107–144.

Mirski AM, Denchev ID, Schnitzer SM, et al.:

Comparison between hypertonic saline and mannitol in the reduction

of elevated intracranial pressure in a rodent model of acute cerebral

injury. J Neurosurg Anesthesiol. (2000); 12:334 –344.

136

Muizelaar JP, Marmarou A, Ward JD, et al: Adverse

effects of prolonged hyperventilation in patients with severe head

injury: a randomized clinical trial. J Neurosurg (1991) 75:731–739.

Mullins ME, Lev MH, Bove P, et al.: Comparison of

image quality between conventional and low-dose nonenhanced head

CT. AJNR Am J Neuroradiol (2004); 25:533–8.

Mustafa A, Sharma HS, Olsson Y, et al.: Vascular

permeability to growth hormone in the rat central nervous system

after focal spinal cord injury. Influence of a new antioxidant

compound H-290/51 and age. Neurosci Res (1995); 23: 185-94.

Nag S: The blood–brain barrier and cerebral

angiogenesis: lessons from the cold-injury model. Trends Mol Med

(2002) 8:38– 44. doi:10.1016/S1471-4914(01)02221-3.

Nag S, Eskandarian MR, Davis J, et al: Differential

expression of vascular endothelial growth factor-A (VEGF-A) and

VEGF-B after brain injury. J Neuropathol Exp Neurol (2002)

61:778–788.

Nag S: Pathophysiology of blood–brain barrier

breakdown. Methods Mol Med (2003) a 89:97–119.

Nag S: Blood–brain barrier permeability using tracers

and immunohistochemistry. Methods Mol Med (2003) b 89:133–144.

Nag S, Papneja T, Venugopalan R, et al: Increased

angiopoietin2 expression is associated with endothelial apoptosis and

blood–brain barrier breakdown. Lab Invest (2005) 85:1189– 1198.

doi:10.1038/labinvest.3700325.

137

Nag S: Structure and pathology of the blood–brain

barrier. In: Lathja A (ed) Handbook of neurochemistry and molecular

neurobiology. Springer, New York, (2007) pp 58–78.

Nathan BR & Scheld WM: New advances in the

pathogenesis and pathophysiology of bacterial meningitis. Curr

Infect Dis Rep (2000); 2:332-6.

Ng I, Lim J, Wong HB: Effects of head posture on

cerebral hemodynamics: its influences on intracranial pressure,

cerebral perfusion pressure, and cerebral oxygenation. Neurosurgery

(2004)54:593–597.

Nitta T, Hata M, Gotoh S, et al: Size-selective

loosening of the blood–brain barrier in claudin-5-deficient mice. J

Cell Biol (2003) 161:653–660. doi:10.1083/jcb.200302070.

Noble LJ & Wrathall JR.: Blood-spinal cord barrier

disruption proximal to a spinal cord transection in the rat: time

course and pathways associated with protein leakage. Exp Neurol

(1988); 99: 567-78.

Nusrat A, Parkos CA, Verkade P, et al: Tight

junctions are membrane microdomains. J Cell Sci (2000) 113(Pt

10):1771–1781.

Olsson Y, Sharma HS, Pettersson CÅV.: Effects of

pchlorophenylalanine on microvascular permeability changes in

spinal cord trauma. An experimental study in the rat using

131Isodium and lanthanum tracers. Acta Neuropathol (Berl) (1990);

79: 595-603.

138

Olsson Y, Sharma HS, Pettersson Å, et al:

Endogenous Release of Neurochemicals may increase Vascular

Permeability, induce Edema and Influence on Cell Changes in

Trauma to the Spinal Cord. Progress in Brain Research (1992); 91:

197-203.

Oshio K, Watanabe H, Song Y, et al: Reduced

cerebrospinal fluid production and intracranial pressure in mice

lacking choroid plexus water channel aquaporin- 1. FASEB (2005) J

19:76–78.

Otrock ZK, Makarem JA, Shamseddine AI: Vascular

endothelial growth factor family of ligands and receptors. Blood

Cells Mol Dis (2007) 38:258–268. doi:10.1016/j.bcmd.12.003

(Review).

Oudega M & Hagg T.: Neurotrophins promote

regeneration of sensory axons in the adult rat spinal cord. Brain Res

(1999); 818: 431-38.

PapadopoulosMC, Saadoun S, Binder DK, et al:

Molecular mechanisms of brain tumor edema. Journal Neuroscience

(2004) 129:1011–1020. doi:10.1016/j. neuroscience.2004. 05.044.

Papadopoulos MC & Verkman AS: Aquaporin-4 and

brain edema. Pediatr Nephrol (2007) 22:778–784.

doi:10.1007/s00467-006- 0411-0.

Papadopoulos MC & Verkman AS: Potential utility of

aquaporin modulators for therapy of brain disorders. Prog Brain Res

(2008) 170:589–601. doi:10.1016/S0079-6123(08)00446-9.

139

Parsons MW, Barber PA, Desmond PM, et al: Acute

hyperglycemia adversely affects stroke outcome: a magnetic

resonance and spectroscopy study. Ann Neurol (2002) 52:20–28.

Parton RG & Simons K: The multiple faces of

caveolae. Nat Rev Mol Cell Biol (2007) 8:185–194.

doi:10.1038/nrm2122.

Plumb J, McQuaid S, Mirakhur M, et al: Abnormal

endothelial tight junctions in active lesions and normal-appearing

white matter in multiple sclerosis. Brain Pathol (2002) 12:154–169.

Pollay M.: Blood-Brain Barrier, Cerebral Edema. In:

Wilkins RH, Rengachary SS, editors. Neurosurgery. 2nd ed. New

York: Mc Graw Hill Book Co., (1996); 335-44.

Popovich PG, Wei P, Stokes BT.: Cellular

inflammatory response after spinal cord injury in Sprague-Dawley

and Lewis rats. J Comp Neurol (1997); 377: 443-64.

Pouyssegur J, Dayan F, Mazure NM. Hypoxia

signalling in cancer and approaches to enforce tumour regression.

Nature (2006); 441: 437–43.

Powers WJ, Zazulia AR, Videen TO, et al.:

Autoregulation of cerebral blood flow surrounding acute (6 to 22

hours) intracerebral hemorrhage. Neurology. (2001); 57:18 –24.

Qureshi AI, Wilson DA, Traystman RJ.: Treatment of

elevated intracranial pressure in experimental intracerebral

hemorrhage: comparison between mannitol and hypertonic saline.

Neurosurgery. (1999); 44:1055–1063.

140

Qureshi AI & Suarez JI: Use of hypertonic saline

solutions in treatment of cerebral edema and intracranial

hypertension. Crit Care Med (2000) 28:3301–3313.

Raab S & Plate KH: Different networks, common

growth factors: shared growth factors and receptors of the vascular

and the nervous system. Acta Neuropathol (2007) 113:607–626. doi:

10.1007/s00401-007-0228-3.

Rabinstein AA: Found comatose, in Rabinstein AA,

Wijdicks EFM (eds): Tough Calls in Acute Neurology. Philadelphia:

Elsevier, (2004), pp 3–18.

Rabinstein AA: Treatment of brain edema. Neurologist

(2006)12: 59–73.

Ranjan P, Mishra AM & Kale R et al: Cytotoxic

edema is responsible for raised intracranial pressure in fulminant

hepatic failure: in vivo demonstration using DW-MRI in human

subjects. Metab Brain Dis (2005), 20, 181-92.

Rash JE, Davidson KG, Yasumura T, et al: Freeze

fracture and immunogold analysis of aquaporin-4 (AQP4) square

arrays, with models of AQP4 lattice assembly. Neuroscience (2004)

129:915–934. doi:10.1016/j.neuroscience, (2004).06.076.

Reiss Y, Machein MR, Plate KH: The role of

angiopoietins during angiogenesis in gliomas. Brain Pathol (2005)

15:311– 317.

Rizzo V, Morton C, DePaola N, et al: Recruitment of

endothelial caveolae into mechanotransduction pathways by flow

141

conditioning in vitro. Am J Physiol Heart Circ Physiol (2003)

285:H1720–H1729.

Roberto Cabeza & Alan Kingstone, Editors,

Handbook of Functional Neuroimaging of Cognition, Second

Edition, MIT Press, (2006), ISBN 0-262-03344-5.

Roberts I, Yates D, Sandercock P, et al: Effect of

intravenous corticosteroids on death within 14 days in 10008 adults

with clinically significant head injury (MRC CRASH trial):

randomised placebo controlled trial. Lancet (2004) 364:1321–1328.

Ropper AH, Gress DR, Diringer MN, et al:

Neurological and Neurosurgical Intensive Care. Philadelphia:

Lippincott, Williams & Wilkins (2004), pp 26–51.

Rosenberg GA.: Ischemic brain edema. Prog

cardiovasc Dis (1999); 42(3):209-16.

Rosenberg GA: Brain edema and disorders of

cerebrospinal fluid circulation. In: Bradley WG, Daroff RB, Ferichel

GM, Marsden CD, editors. Neurology in clinical practice. Vol 2.3rd

ed. Boston: Butterworth Heinmann(2000); 2:1545-59.

Rosenberg GA: Matrix metalloproteinases in

neuroinflammation. Glia, (2002), 39:279–291.

doi:10.1002/glia.10108.

Rosenberg GA & Yang Y: Vasogenic edema due to

tight junction disruption by matrix metalloproteinases in cerebral

ischemia. Neurosurg Focus (2007) 22:E4.

doi:10.3171/foc.2007.22.5.5.

142

Rosenblum WI: Cytotoxic edema: monitoring its

magnitude and contribution to brain swelling. J Neuropathol Exp

Neurol (2007) 66:771–778. doi:10.1097/nen.0b013e3181461965.

Rother J.: CT and MRI in the diagnosis of acute stroke

and their role in thrombolysis. Thromb Res, (2001); 103(Suppl 1):S1

25–33.

Roviezzo F, Tsigkos S, Kotanidou A, et al:

Angiopoietin-2 causes inflammation in vivo by promoting vascular

leakage. J Pharmacol Exp Ther (2005) 314:738–744.

doi:10.1124/jpet.105.086553.

Roy H, Bhardwaj S, Yla-Herttuala S: Biology of

vascular endothelial growth factors. FEBS Lett (2006) 580:2879–

2887. doi:10.1016/j.febslet.2006.03.087.

Saadoun S, Papadopoulos MC, Davies DC, et al:

Aquaporin-4 expression is increased in edematous human brain

tumors. J Neurol Neurosurg Psychiatry (2002) 72:262– 265.

doi:10.1136/jnnp.72.2.262.

Scarabino T, Nemore F, Giannatempo GM, et al.: 3.0

T imaging. Riv Neuroradiol (2004) 17:765–776.

Schell RM, Applegate RL II, Cole DJ: Salt, starch,

and water on the brain. J Neurosurg Anesthesiol (1996) 8:178–182.

Schilling L & Wahl M.: Mediators of cerebral edema.

Adv Exp Med Biol (1999); 474:123-41.

143

Schwab ME & Bartholdi D.: Degeneration and

regeneration of axons in the lesioned spinal cord. Phys Rev (1996);

76: 319-70.

Schwab S, Spranger M, Schwarz S, et al: Barbiturate

coma in acute hemispheric stroke: useful or obsolete? Neurology

(1997) 48: 1608–1613.

Schwarz S, Schwab S, Bertram M, et al.: Effects of

hypertonic saline hydroxyethyl starch solution and mannitol in

patients with increased intracranial pressure after stroke. Stroke.

(1998); 29:1550 –1555.

Schwarz S, Georgiadis D, Aschoff A, et al: Effects of

body position on intracranial pressure and cerebral perfusion in

patients with large hemispheric stroke. Stroke (2002) 33:497–501.

Scott A. Huettel, Allen W. Song, Gregory McCarthy:

Functional Magnetic Resonance Imaging, Sinauer Associates,

(2004), ISBN 0-87893-288-7.

Sharma HS, Olsson Y, Dey P K.: Early accumulation

of serotonin in rat spinal cord subjected to traumatic injury. Relation

to edema and blood flow changes. Neuroscience (1990); 36: 725-30.

Sharma HS.: Neurobiology of the CNS injury and

repair: new roles of amino acids, growth factors and neuropeptides.

Amino Acids (2002); 23: 217-19.

Sharma HS: Neurotrophic factors attenuate

microvascular permeability disturbances and axonal injury following

144

trauma to the rat spinal cord. Acta Neurochir (Wien) (2003); Suppl

86: 383- 88.

Sharma HS: Pathophysiology of the blood-spinal cord

barrier in traumatic injury. In: Sharma HS and Westman J Eds, The

Blood- Spinal Cord and Brain Barriers in Health and Disease.

Elsevier Academic Press, San Diego (2004); 437-518.

Sharma HS: Pathophysiology of Blood-Spinal Cord

Barrier in Traumatic Injury and Repair. Current Pharmaceutical

Design, (2005), 11, 1353-1389.

Silberstein C, Bouley R, Huang Y, et al: Membrane

organization and function of M1 and M23 isoforms of aquaporin-4 in

epithelial cells. Am J Physiol Renal Physiol (2004) 287:F501–F511.

doi:10.1152/ ajprenal.00439.2003.

Simma B, Burger R, Falk M, et al: A prospective,

randomized, and controlled study of fluid management in children

with severe head injury: lactated Ringer’s solution versus hypertonic

saline. Crit Care Med (1998) 26:1265–1270.

Simon RP & Beckman JS: Why pus is bad for the

brain. Neurology (2002); 58:167-8.

Simon J, Czechowsky D, Hill M, et al.: Fluid-

attenuated inversion recovery preparation: Not an improvement over

conventional diffusion-weighted imaging at 3 T in acute ischemic

stroke. AJNR (2004) 25:1653–1658.

145

Sinha S, Bastin ME, Wardlaw JM, et al: Effects of

dexamethasone on peritumoral oedematous brain: a DT-MRI study. J

Neurol Neurosurg Psychiatry (2004)75:1632 –1635.

Slivka AP & Murphy EJ: High-dose

methylprednisolone treatment in experimental focal cerebral

ischemia. Exp Neurol (2001) 167: 166–172.

Song L, Ge S, Pachter JS: Caveolin-1 regulates

expression of junction-associated proteins in brain microvascular

endothelial cells. Blood (2007) 109:1515–1523. doi:10.1182/blood-

2006-07-034009.

Stålberg E, Sharma HS, Olsson Y.: Spinal Cord

Monitoring. Basic Principles, Regeneration, Pathophysiology and

Clinical Aspects, Springer, Wien, New York (1998); pp 1-527.

Stanley J. & Swierzewski: Traumatic Brain Injury

(TBI) Prognosis. Http://www. HealthCommunities.com (2011).

Steiner T, Ringleb P, Hacke W.: Treatment options for

large hemispheric stroke. Neurology. (2001); 57(5 suppl 2):S61–S68.

Stummer W: Mechanisms of tumor-related brain

edema. Neurosurg Focus (2007) 22:E8. doi:10.3171/foc.2007.22.5.9.

Suarez JI. Treatment of acute brain edema. Rev Neurol

(2001); 32(3):275-81.

Subramaniam S & Hill MD.: Massive cerebral

infarction. Neurologist. (2005); 11:150 –160.

146

Sukriti Nag, Janet L. & Manias, et al: Pathology and

new players in the pathogenesis of brain edema. Acta Neuropathol

(2009), 118:197–217.

Sun MC, Honey CR, Berk C, et al: Regulation of

aquaporin-4 in a traumatic brain injury model in rats. J Neurosurg

(2003) 98:565–569.

Sypert GW: Stabilization and management of cervical

injuries. In: Pitt L H and Wagner F C Eds, Craniospinal Trauma,

New York, Thieme (1990); pp 363-70.

Tait MJ, Saadoun S, Bell BA, et al: Water movements

in the brain: role of aquaporins. Trends Neurosci (2008) 31:37–43.

doi:10.1016/j.tins.2007.11.003.

Takefuji S, Murase T & Sugimura Y: role of

microglia in the pathogenesis of osmotic- induced demyelination.

Exp Neurol (2007), 204, 88-92.

Tang Q, Lynch RM, Porreca F, et al: Dynorphin A

elicits an increase in intracellular calcium in cultured neurons via a

nonopioid, non-NMDA mechanism. J Neurophysiol (2000); 83:

2610- 615

Thenuwara K, Todd MM, Brian JE Jr: Effect of

mannitol and furosemide on plasma osmolality and brain water.

Anesthesiology (2002) 96:416–421

Toung TJ, Hurn PD, Traystman RJ, et al.: Global

brain water increases after experimental focal cerebral ischemia:

effect of hypertonic saline. Crit Care Med. (2002); 30:644–649.

147

Toung TJ, Chang Y, Lin J, et al.: Increases in lung

and brain water following experimental stroke: effect of mannitol

and hypertonic saline. Crit Care Med. (2005); 33:203–208.

Toung TJ, Chen CH, Lin C, et al: Osmotherapy with

hypertonic saline attenuates water content in brain and extracerebral

organs. Crit Care Med (2007)35:526–531.

Turksen K & Troy TC: Barriers built on claudins. J

Cell Sci (2004) 117:2435–2447. doi:10.1242/jcs.01235.

Unterberg AW, Stover J, Kress B, et al: Edema and

brain trauma. Neuroscience (2004) 129:1021–1029. doi:10.1016/

j.neuroscience.2004.06.046.

Van Itallie CM & Anderson JM: Claudins and

epithelial paracellular transport. Annu Rev Physiol (2006) 68:403–

429. doi:10.1146/annurev.physiol.68.040104.131404.

Vaquero J & Butterworth RF: Mechanisms of brain

edema in acute liver failure and impact of novel therapeutic

interventions. Neurol Res (2007) 29:683–690.

doi:10.1179/016164107X240099

Verkman AS: More than just water channels:

unexpected cellular roles of aquaporins. J Cell Sci (2005) 118:3225–

3232. doi:10.1242/jcs.02519.

Vespa PM, O’Phelan K, Shah M, et al: Acute seizures

after intracerebral hemorrhage: a factor in progressive midline shift

and outcome. Neurology (2003) 60:1441–1446.

148

Vialet R, Albanese J, Thomachot L, et al.: Isovolume

hypertonic solutes (sodium chloride or mannitol) in the treatment of

refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5%

saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med.

(2003); 31:1683–1687.

Victor M & Ropper AH: Disturbances of

cerebrospinal fluid and its circulation. Principles of Neurology. 7th

ed. New York: Mc Graw Hill, (2001) a; 655-75.

Victor M & Ropper AH: Cerebrovascular diseases.

Principles of Neurology. 7th ed. New York: Mc Graw Hill, (2001) b;

821-924.

Virgintino D, Robertson D, Errede M, et al:

Expression of caveolin-1 in human brain microvessels. Neuroscience

(2002) 115:145–152. doi:10.1016/ S0306-4522(02)00374-3.

VO KD, Lin W, Lee JM.: Evidence-based

neuroimaging in acute ischemic stroke. Neuroimaging Clin N Am

(2003); 13:167–83.

Volonte D, Galbiati F, Pestell RG, et al: Cellular stress

induces the tyrosine phosphorylation of caveolin-1 (Tyr14) via

activation of p38 mitogen-activated protein kinase and c-Src kinase.

J Biol Chem (2001) 276:8094–8103. doi:10.1074/ jbc.M009245200.

Vorbrodt AW & Dobrogowska DH: Molecular

anatomy of intercellular junctions in brain endothelial and epithelial

barriers: electron microscopist’s view. Brain Res Brain Res Rev

(2003) 42:221–242. doi:10.1016/S0165-0173(03)00177-2.

149

Vos CM, Geurts JJ, Montagne L, et al. Blood–brain

barrier alterations in both focal and diffuse abnormalities on

postmortem MRI in multiple sclerosis. Neurobiol Dis (2005);

20(3):953–60.

Wakai A, Roberts I, Schierhout G: Mannitol for acute

traumatic brain injury. Cochrane Database Syst Rev 1, (2007)

CD001049.

Wang X & Lo EH. Triggers and mediators of

hemorrhagic transformation in cerebral ischemia. Mol Neurobiol

(2003); 28: 229–44.

Ware ML, Nemani VM, Meeker M, et al: Effects of

23.4% sodium chloride solution in reducing intracranial pressure in

patients with traumatic brain injury: a preliminary study.

Neurosurgery (2005) 57:727–736.

Warth A, Simon P, Capper D, et al: Expression

pattern of the water channel aquaporin-4 in human gliomas is

associated with blood–brain barrier disturbance but not with patient

survival. J Neurosci Res (2007) 85:1336–1346.

doi:10.1002/jnr.21224.

Weed LH & McKibben PS: Experimental alteration of

brain bulk. Am J Physiol (1919) 48:531–555.

Williams TM & Lisanti MP: The caveolin genes: from

cell biology to medicine. Ann Med (2004) 36:584–595. doi:10.1080/

07853890410018899.

150

Winkler T, Sharma HS, Stålberg E, et al.: Spinal cord

bioelectrical activity, edema and cell injury following a focal trauma

to the spinal cord. An experimental study using pharmacological and

morphological approach. In: Stålberg E, Sharma HS, Olsson Y Eds,

Spinal Cord Monitoring. Basic Principles, Regeneration,

Pathophysiology and Clinical Aspects, Springer Wien New York

(1998); pp. 283-363.

Wolburg H, Noell S, Mack A, et al: Brain endothelial

cells and the glio-vascular complex. Cell Tissue Res (2008) 335:75–

96. doi:10.1007/s00441- 008-0658-9.

Xi G, Keep RF, Hoff JT: Pathophysiology of brain

edema formation. Neurosurg Clin N Am (2002) 13:371–383.

doi:10.1016/ S1042-3680(02)00007-4.

Xi G, Keep R, Hoff J.: Mechanisms of brain injury

after intracerebral haemorrhage. Lancet Neurol. (2006); 5:53–63.

Yamamoto N, Yoneda K, Asai K, et al: Alterations in

the expression of the AQP family in cultured rat astrocytes during

hypoxia and reoxygenation. Brain Res Mol Brain Res (2001) 90:26–

38. doi:10.1016/S0169- 328X(01)00064-X.

Yasser metwally: Vasogenic edema.

Http://yassermetwally.com (2009) Vasogenic edema.

Yla-Herttuala S, Rissanen TT, Vajanto I, et al:

Vascular endothelial growth factors: biology and current status of

clinical applications in cardiovascular medicine. J Am Coll Cardiol

(2007) 49:1015–1026. doi:10.1016/j.jacc.2006.09.053.

151

Zadeh G & Guha A: Neoangiogenesis in human

astrocytomas: expression and functional role of angiopoietins and

their cognate receptors. Front Biosci (2003) 8:e128–e137.

doi:10.2741/964.

Zador Z, Bloch O, Yao X, et al: Aquaporins: role in

cerebral edema and brain water balance. Prog Brain Res (2007)

161:185–194. doi:10.1016/S0079-6123(06)61012-1.

Zhang ZG, Zhang L, Croll SD, et al: Angiopoietin-1

reduces cerebral blood vessel leakage and ischemic lesion volume

after focal cerebral embolic ischemia in mice. Neuroscience (2002)

113:683–687. doi:10.1016/S0306-4522(02)00175-6.

Zlokovic BV: The blood–brain barrier in health and

chronic neurodegenerative disorders. Neuron (2008) 57:178–201.

doi:10.1016/j.neuron.2008.01.003.