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Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
Thesis section: brain edema
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Thesis section: brain edema

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Thesis section: brain edema
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  • 1. Central Nervous System Edema Essay In Neuropsychiatry Submitted for partial fulfillment of Master Degree By Mina Ibrahim Adly Ibrahim M.B.B.CH Supervisors ofProf. Mohammed Yasser Metwally Professor of Neuropsychiatry Faculty of Medicine-Ain Shams University www.yassermetwally.comProf. Naglaa Mohamed Elkhayat Professor of Neuropsychiatry Faculty of Medicine-Ain Shams University Dr. Ali Soliman Ali Shalash Lecturer of Neuropsychiatry Faculty of Medicine-Ain Shams University Faculty of Medicine Ain Shams University 2011
  • 2. ContentsSubject page1. Acknowledgment………………………………………………22. List of abbreviations……………………………………………33. List of figures…………………………………………………..64. List of tables…………………………………………………....85. Introduction and aim of the work……………………………....96. Chapter (1): Pathogenesis of cerebral edema…………………157. Chapter (2): Chemical Mediators Involved in The Pathogenesis Of Brain Edema…………………………………378. Chapter (3): Diagnosing cerebral edema……………………...539. Chapter (4): Cerebral Edema in Neurological Diseases………6910.Chapter (5): Treatment of Cerebral Edema…………………...7911. Chapter (6): Spinal Cord Edema In Injury and Repair……...10112. Summary…………………………………………....………11513. Discussion……..……………………………………………12014. References………..…………………………………………12315. Arabic summary……...………………………………………… 1
  • 3. Acknowledgment Thanks to merciful lord for all the countless gifts you haveoffered me, and thanks to my family for their love and support. It is a great pleasure to acknowledge my deepest thanks andgratitude to Prof. Mohammed Yasser Metwally, Professor ofNeuropsychiatry, Faculty of Medicine-Ain Shams University, forsuggesting the topic of this essay, and his kind supervision. It is a greathonour to work under his supervision. I would like to express my deepest thanks and sincere appreciationto 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 andappreciation to Dr. Ali Soliman Ali Shalash, Lecturer ofNeuropsychiatry, Faculty of Medicine-Ain Shams University, for hiskind endless help, generous advice and support during the study. Mina Ibrahim Adly 2011 2
  • 4. List of abbreviationsADC: 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. 3
  • 5. 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. 4
  • 6. 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. 5
  • 7. List of figuresFigure PageFigure 1: Gross image demonstrating edema in human brain compared with a normal one...………………………………..…….18Figure 2: White matter from an area of edema…………………....…19Figure 3: Illustrated picture of blood brain barrier…………………..20Figure 4: An axial CT scan with glioblastoma multiforme…….……21Figure 5: The cold injury site…………………..……………………23Figure 6: Endothelial phosphorylated Cav-1………………………...25Figure 7: expression of caveolins and tight junction proteins during BBB breakdown…..……………………………….………29Figure 8: Axial CT scans with whole right hemisphere infarction…..32Figure 9: An axial MR image of a 4 year old with hydrocephalus….34Figure 10: Pathways for water entry into and exit from brain……….42Figure 11: Temporal expression of growth factor proteins is shown during the period of BBB breakdown in the cold injury mode……………………………………………………..51Figure 12: Cerebral herniation syndromes..…………………………55Figure 13: CT scan of global brain edema...…………………………60Figure 14: CT scan showing brain edema caused by a tumor……….61Figure 15: An area which represents an infarct………………….…..61Figure 16: Intracranial hemorrhage depicted by MRI……………….63Figure 17: Periventricular FLAIR hyperintensity due to hydrocephalic edema………………………………………………….…….63 6
  • 8. Figure 18: MRI showing central pontine myelinolysis…...................63Figure 19: The cytotoxic component of acute cerebral ischemia is demonstrated by ADC hypointensity, whereas T2 weighted sequences may be unrevealing …….………………………..65Figure 20: MRI of status epilepticus reveals evidence of cytotoxic edema..............................................................................…...65Figure 21: Disruption of the BBB associated with a glioma….…….66Figure 22: Mass effect from infarction and midline shift. Hemicraniectomy performed with herniation through the skull defect…………………………………………….…100 7
  • 9. List of tables Table PageTable 1: Vasoactive agents that increase the blood–brain barrier permeability……………………..……………………….39Table 2: Summary of the clinical subtypes of herniation syndromes…………………………………………….…56Table 3: Summary of experimental studies comparing different formulations of hypertonic saline with mannitol 20%….…90Table 4: Theoretical potential complications of using hypertonic saline solutions………………..………………………………….93Table 5: Treatment Strategies in Spinal Cord Injury…………..…...109 8
  • 10. Introduction Surprising as it may sound cerebral edema is a fairly commonpathophysiological entity which is encountered in many clinicalconditions. Many of these conditions present as medical emergencies.By definition cerebral edema is the excess accumulation of water inthe intra-and/or extracellular spaces of the brain (Kempski, 2001). To explain the consequences of cerebral edema in the simplestterminology, 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. Sinceskull is like a rigid box which cannot be stretched, if there is excessivewater, the volume of brain as well as blood inside the skull iscompressed. Further increase in the intracranial pressure (ICP)eventually causes a reduction in cerebral blood flow throughout thebrain which can correspondingly cause extensive cerebral infarction. Ifthese changes continue further, it leads to the disastrous condition ofbrain herniation, which is the fore runner of irreversible brain damageand death (Rosenberg, 2000). Despite the classification of edema into distinct forms as:vasogenic, cytotoxic, hydrocephalic and osmotic, it is recognized thatin most clinical situations there is a combination of different types ofedema depending on the time course of the disease. For example, earlycerebral ischemia is associated with cellular swelling and cytotoxicedema; however, once the capillary endothelium is damaged there is 9
  • 11. BBB breakdown and vasogenic edema results. While in traumaticbrain injury both vasogenic and cytotoxic edema coexist (Marmarouet al, 2006). Vasogenic cerebral edema refers to the influx of fluid and solutesinto the brain through an incompetent blood brain barrier. This is themost common type of brain edema and results from increasedpermeability of the capillary endothelial cells; the white matter isprimarily affected. Breakdown in the BBB allows movement ofproteins from the intravascular space through the capillary wall intothe extracellular space. This type of edema is seen in: trauma, tumor,abscess, hemorrhage, infarction, acute MS plaques, and cerebralcontusion (Metwally, 2009). Cellular (cytotoxic) cerebral edema refers to a cellular swelling. It isseen in conditions like head injury, severe hypothermia,encephalopathy, pseudotumor cerebri and hypoxia. It results from theswelling of brain cells, most likely due to the release of toxic factorsfrom neutrophils and bacteria within minutes after an insult. Cytotoxicedema affects predominantly the gray matter (Liang et al, 2007). Interstitial edema is seen in hydrocephalus when outflow of CSF isobstructed and intraventricular pressure increases. The result ismovement of sodium and water across the ventricular wall into theparaventricular space. Interstitial cerebral edema occurring during 10
  • 12. meningitis is due to obstruction of normal CSF pathways (Abbott,2004). Osmotic cerebral edema occurs when plasma is diluted byhyponatremia, syndrome of inappropriate antidiuretic hormonesecretion, hemodialysis, or rapid reduction of blood glucose inhyperosmolar hyperglycemic state, the brain osmolality will thenexceed the serum osmolality creating an abnormal pressure gradientdown 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 blockedabsorption pathways force fluid to enter brain tissues. Cellular andblood vessel damage follows activation of an injury cascade whichbegins with glutamate release into the extracellular space. Calciumand sodium entry channels are opened by glutamate stimulation.Membrane ATPase pumps extrude one calcium ion exchange for 3sodium ions. Sodium builds up within the cell creating an osmoticgradient and increasing cell volume by entry of water (Marmarou,2007). It appears that injury in the spinal cord induce blood-spinal cordbarrier (BSCB) disruption. The BSCB breakdown involves cascade ofevents involving several neurochemicals like: serotonin,prostaglandins, neuropeptides and amino acids (Sharma, 2004). Serial neuroimaging by CT scans and magnetic resonance imagingcan be particularly useful in confirming intracranial compartmental 11
  • 13. and midline shifts, herniation syndromes, ischemic brain injury, andexacerbation of cerebral edema (sulcal effacement and obliteration ofbasal cisterns), and can provide valuable insights into the type ofedema present (focal or global, involvement of gray or white matter).CT scan provides an excellent tool for determination of abnormalitiesin brain water content. CT is an excellent method for following theresolution of brain edema following therapeutic intervention. MRIappears to be more sensitive than CT at detecting development ofcerebral edema (Kuroiwa et al, 2007). Management of cerebral edema involves using a systematic andalgorithmic approach, from general measures to specific therapeuticinterventions, and decopressive surgery. The general measuresinclude: elevation of head end of bed 15-30 degrees to promotecerebral venous drainage, fluid restriction, hypothermia, andcorrection 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 loopdiuretics after the osmotic agent infusion (Thenuwara et al, 2002).3. Corticosteroids: they lower intracranial pressure primarily invasogenic edema because of their effect on the blood vessel (Sinha etal, 2004). 12
  • 14. 4. Controlled hyperventilation: is helpful in reducing the raised ICPwhich falls within minutes of onset of hyperventilation (Mayer &Rincon, 2005). Cerebral edema, irrespective of the underlying origin of braininjury, is a significant cause of morbidity and death, and though therehas been good progress in understanding pathophysiologicalmechanisms associated with cerebral edema more effective treatmentis required and is still awaited (Rabinstein, 2006). 13
  • 15. Aim of the work  The aim of this review is to discuss different types andetiologies of brain edema and to overview recent management of thevarious chemical mediators involved in the pathogenesis of cerebraledema. 14
  • 16. Chapter (1): PathogenesisOf Cerebral Edema 15
  • 17. Pathogenesis Of Cerebral Edema  Introduction: Brain edema is defined as an increase in brain volume resultingfrom a localized or diffuse abnormal accumulation of fluid within thebrain parenchyma (Johnston & Teo, 2000). This definition excludesvolumetric enlargement due to cerebral engorgement which resultsfrom an increase in blood volume on the basis of either vasodilatationdue to hypercapnia or impairment of venous flow secondary toobstruction of the cerebral veins and venous sinuses (Nag, 2003) b. Initially, the changes in brain volume are compensated by adecrease in cerebrospinal fluid (CSF) and blood volume. In largehemispheric lesions, progressive swelling exceeds these compensatorymechanisms and an increase in the intracranial pressure (ICP) resultsin herniations of cerebral tissue leading to death (Wolburg et al,2008). Hence the significance of brain edema, which continues to be amajor cause of mortality after diverse types of brain pathologies suchas major cerebral infarcts, hemorrhages, trauma, infections andtumors. The lack of effective treatment for brain edema remains astimulus for continued interest and research into the pathogenesis ofthis condition (Marmarou, 2007). 16
  • 18.  General considerations: The realization that brain edema is associated with either extra- orintra-cellular accumulation of abnormal fluid led to its classificationinto vasogenic and cytotoxic edema. Vasogenic edema is associatedwith dysfunction of the blood–brain barrier (BBB) which allowsincreased passage of plasma proteins and water into the extracellularcompartment, while cytotoxic edema results from abnormal wateruptake by injured brain cells. Other types of edema described includehydrocephalic or interstitial edema and osmotic or hypostatic edema(Czosnyka et al, 2004). 17
  • 19.  Aetiopathogenesis of various types of cerebral edema: 1. Vasogenic edema: Brain diseases such as hemorrhage, infections, seizures, trauma,tumors, radiation injury and hypertensive encephalopathy areassociated with BBB breakdown to plasma proteins leading tovasogenic edema. Vasogenic edema also occurs in the later stages ofbrain infarction. Vasogenic edema may be localized or diffusedepending on the underlying pathology. The overlying gyri becomemore flattened, and the sulci are narrowed (Figure 1). When diffuseedema is present the ventricles are slit-like (Hemphill et al, 2001). Figure 1: 1b. Gross image demonstrating edema in human brain compared with a normal one (figure 1 a) (Hemphill et al, 2001). Breakdown of the BBB to plasma proteins can be demonstrated byimmunohistochemistry using antibodies to whole serum proteins, 18
  • 20. albumin, fibrinogen or fibronectin in human autopsy brain tissue orbrains of experimental animals (Kimelburg, 2004). The white matter is more edema-prone since it has unattachedparallel 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 linearpathways making the grey matter ECS much less subject to swelling.Light microscopy in acute edema shows vacuolation and pallor of thewhite matter (Figure 2a & b) (Ballabh et al, 2004). Figure 2: (figure 2a) Light microscopic appearance of normal white matter stained with hematoxylin–eosin and Luxol fast blue. (Figure 2b) White matterfrom an area of edema adjacent to a meningioma (not shown) shows myelin pallor and an increased number of astrocytes (arrowheads) (Ballabh et al, 2004). In long standing cases of edema there is fragmentation of themyelin sheaths which are phagocytosed by macrophages resulting inmyelin pallor. An astrocytic response is present in the areas of edema.mRNA levels are maximal on days 4–5 and they remain elevated up today 14 post-injury. Spatial mRNA expression follows the pattern ofpost-injury edema being present in the cortex adjacent to the lesion, 19
  • 21. and the ipsilateral and contralateral callosal radiations (Hawkins,2008).  The blood–brain barrier (BBB): It is well known that cerebral vessels differ from non-neural vesselsand have a structural, biochemical and physiological barrier, whichlimits the passage of various substances including plasma proteinsfrom blood into brain (Nag, 2003) b. Cellular components of the BBB include endothelium, pericytesand the perivascular astrocytic processes, which together with theirassociated neurons form the ‘‘neurovascular unit’’. The best studiedcell type is cerebral endothelium which has two distinctive structuralfeatures 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 theinterendothelial spaces. Breakdown of the BBB is assessed by tracers.Gadolinium DPTA is the most commonly used tracer in humanstudies (Figure 4). Figure 3: illustrated picture of blood brain barrier (Nag, 2003) b. 20
  • 22. Tracers like 125 Iodine-labeled serum albumin, Evans blue,horseradish peroxidase (HRP) and dextrans, having molecular weightsof 60,000–70,000 Da, are used in experimental animals. The diameterof the HRP molecule is 600 nm which is very close to the diameter ofalbumin which is 750 nm, making HRP a good tracer for proteinpermeability studies. Tracers having molecular weights less than3,000 Da such as lanthanum, small molecular weight dextrans, andsodium fluorescein or 14C sucrose are indicators of BBB dysfunctionto ions (Zlokovic, 2008). Although small amounts of water may also enter brain, themagnitude is not sufficient to produce edema. Therefore, studies usingthese tracers have no relevance to the BBB breakdown to plasmaproteins which is a key feature of vasogenic brain edema (Volonte etal, 2001). Figure 4: an axial CT scan post-gadolinium from a case diagnosed with glioblastoma multiforme showing a mass in the right hemisphere with midline shift. A serpiginous area of enhancement is present in the center of the mass indicating breakdown of the BBB (Zlokovic, 2008). 21
  • 23. Permeability properties of cerebral endothelium are not uniform inall brain vessels. In rodents, aside from regions outside the BBB, asignificant number of normal cerebral vessels are permeable to HRP.Thus, the demonstration of increased permeability in these areascannot be ascribed to pathology. Also, freeze fracture studies showthat there is variation in the number of interconnected strands thatmake up tight junctions in the different types of brain vessels, withcortical vessels having junctions of the highest complexity, whilejunctions of the postcapillary venules are least complex. The latterwould explain why increased permeability of the postcapillary venulesoccurs in inflammation (Nag, 2007).  The cold injury model: This model was developed by Klatzo to study the pathophysiologyof vasogenic edema and has been used extensively in studies. Aunilateral focal cortical freeze lesion is produced by placing the tip ofa cold probe cooled with liquid nitrogen on the dura for 45 seconds.There are variations in the method of producing the cold lesion whichmakes it difficult to compare the results obtained from differentlaboratories (Klatzo, 1958 coated from Sukriti Nag, et al, 2009). The ensuing edema was initially studied using exogenous tracerssuch as Evans blue and HRP. BBB breakdown to HRP was present at12 h, which was the earliest time point studied and the BBB wasrestored on day 6 post-injury. Similar results were obtained usingimmunohistochemistry to demonstrate endogenous serum protein 22
  • 24. extravasation using an antibody to serum proteins, fibrinogen orfibronectin (Lossinsky & Shivers, 2004). Two peaks of active BBB breakdown occur in the cold injurymodel. An initial phase which extends from 6 hours to day 2 affectsmainly arterioles and large venules at the margin of the lesion andleads to extravasation of plasma proteins at the lesion site (Figure 5a).There is spread of edema fluid through the ECS into the underlyingwhite matter of the ipsilateral and contralateral side (Figure 5b). Thesecond phase of BBB breakdown accompanies angiogenesis and ismaximal on day 4 (Figure 5c). Arterioles, veins and neovessels at thelesion site show extravasation of plasma proteins which remainconfined to the lesion site (Furuse & Tsukita, 2006). Figure 5: (figure 5a): the cold injury site on day 0.5 shows several vessels with BBB breakdown to fibronectin (arrowheads). (Figure 5b): On day 1, immunostaining with an antibody to serum proteins 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). 23
  • 25.  BBB breakdown in vasogenic edema: Ultrastructural studies demonstrate an increase in the number ofendothelial caveolae only in the vessels with BBB breakdown to HRPwithin minutes after the onset of pathological states such ashypertension, spinal cord injury, seizures, experimental autoimmuneencephalomyelitis, excitotoxic brain damage, brain trauma, and BBBbreakdown- induced by bradykinin, histamine, and leukotriene C4(Nag, 2002). These findings suggest that enhanced caveolae (figure 6) are themajor route by which early passage of plasma proteins occurs in braindiseases associated with vasogenic edema. Caveolae allow proteinpassage across endothelium via fluid-phase transcytosis andtransendothelial channels. These enhanced caveolae represent theresponse of viable endothelial cells to injury since both caveolarchanges and BBB breakdown are reversed 10 minutes after the onsetof acute hypertension induced by a single bolus of a pressor agent. Noalterations in tight junctions were noted in the studies mentionedabove (Parton & Simons, 2007). Convincing demonstration of tight junction breakdown has onlybeen reported following the intracarotid administration ofhyperosmotic agents using the tracer lanthanum, which is a marker ofionic permeability. Thus, junctional breakdown to proteins occurs latein the course of brain injury probably during end-stage disease andprecedes endothelial cell breakdown. Research in the last decade hasled to the isolation of novel proteins in both caveolae and tight 24
  • 26. junctions and studies are underway to define their role in brain injury(Minshall & Malik, 2006). Figure 6: a vein with BBB breakdown to fibronectin shows endothelial phosphorylated Cav-1 (PY14Cav-1) (Parton & Simons, 2007).  Caveolin-1 (Cav-1): The specific marker and major component of caveolae is Cav-1, anintegral membrane protein, which belongs to a multigene family ofcaveolin-related proteins that show similarities in structure but differin properties and distribution (Virgintino et al, 2002). Of the two major isoforms of Cav-1 only the -isoform ispredominant in the brain. Cav-2 has a similar distribution as Cav-1and non-neural endothelial cells express both Cav-1 and -2. Cav-1 hasbeen localized in human and murine cerebral endothelial cells. Theproperties of Cav-1 are the subject of many reviews (Boyd et al,2003). Brain injury is associated with increased expression of Cav-1. Timecourse studies in the rat cortical cold injury model demonstrate a 25
  • 27. threefold increase in Cav-1  expression at the lesion site on day 0.5post-injury. At the cellular level, a marked increase in endothelialCav-1 protein is present in vessels showing BBB breakdown tofibronectin (Rizzo et al, 2003). Further studies demonstrate that the endothelial Cav-1 in vesselswith BBB breakdown is phosphorylated. It is well established thatdilated vascular segments show enhanced permeability and leakprotein. Phosphorylation of Cav-1 is known to be an essential step forformation of caveolae (figure 6). Thus, phosphorylation of Cav-1 isessential for transcytosis of proteins across cerebral endotheliumleading to BBB breakdown and brain edema following brain injury(Minshall et al, 2003). In summary, caveolae and Cav-1 have a significant role in earlyBBB breakdown; hence, they could be potential therapeutic targets inthe control of early brain edema (Williams & Lisanti, 2004).  Tight junction proteins: Tight junctions are localized at cholesterol-enriched regions alongthe plasma membrane associated with Cav-1. Tight junctions areformed of three integral transmembrane proteins: occludin, theclaudin, and junctional adhesion molecule (JAM) families of proteins(Forster, 2008). The extracellular loops of these proteins originate from neighboringcells to form the paracellular barrier of the tight junction, which 26
  • 28. selectively excludes most blood borne substances from entering brain.Several accessory cytoplasmic proteins have also been isolated whichare necessary for structural support at the tight junctions. They includezonula occludens (ZO)-1 to -3, and cingulin (Nusrat et al, 2000). Occludin, the first tight junction protein to be identified is anapproximately 60-kDa tetraspan membrane protein with twoextracellular loops. High expression of occludin in brain endothelialcells as compared to nonneural endothelia provides an explanation forthe different properties of both these endothelia (Song et al, 2007). Claudins are 18- to 27-kDa tetraspan proteins with two extracellularloops, and they do not show any sequence similarity to occludin. Theclaudin family consists of 24 members in humans and exhibits distinctexpression patterns in tissue. Claudins may be the majortransmembrane proteins of tight junctions as occludin knockout miceare still capable of forming interendothelial tight junctions whileclaudin knockout mice are nonviable (Nitta et al, 2003). The JAMs belong to the immunoglobulin superfamily. JAM-A, thefirst member of the family to be isolated has been implicated in avariety of physiologic and pathologic processes involving cellularadhesion including tight junction assembly and leukocytetransmigration (Turksen & Troy, 2004). Occludin, claudins-3, -5 and -12, JAM-A and ZO-1 proteins havebeen localized in normal cerebral endothelium. Decreased expressionof the tight junction proteins in vessels with BBB breakdown in thecold injury model follows a specific sequence with transient decreases 27
  • 29. in expression of JAM-A on day 0.5 only, of claudin-5 on day 2 onlywhile occludin expression is attenuated from day 2 onwards andpersists up to day 6 (figure 7) (Plumb et al, 2002).  Resolution of edema: Much of our information about the resolution of vasogenic edema isderived from the earlier studies of the cortical cold injury model.During the period of BBB breakdown to plasma proteins there isprogressive increase in I 125-labeled albumin, paralleled by an increasein water content (Van Itallie & Anderson, 2006). Disappearance of serum proteins from the ECS coincides with thereturn of water content to normal values. Resolution of edema occursimmediately after closure of the BBB to proteins (figure 7). Thesestudies support previous observations that caveolae and Cav-1changes precede significant tight junction changes during early BBBbreakdown (Xi et al, 2002). Reduction of CSF pressure accelerates the clearance of edema fluidinto the ventricle. Recent evidence suggests that aquaporin 4 channelslocated in the ependyma and astrocytic foot processes (digestingserum proteins), have an important role in the clearance of theinterstitial water (Turksen & Troy, 2004). 28
  • 30. (Figure 7) Expression of caveolins and junction proteins duringBBB breakdown: Days post-lesion 0.5 2 4 6 BBB 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 BBB breakdown in the cold injury model. Increased expression of both caveolin-1 and phosphorylated caveolin-1 (PY14 Caveolin-1) was observed. Decreased expression of junctional adhesion molecule-A was observed on day 0.5 only andof claudin-5 on day 2 only, while decreased expression of occludin was present on day 2 and persisted throughout the period of observation (Vorbrodt, 2003). Other mechanisms for clearance of edema fluid include passage ofextravasated proteins via the abluminal plasma membrane ofendothelial cells back into blood. Edema fluid can also pass across theglia limitans externa into the CSF in the subarachnoid space and enterthe arachnoid granulations for clearance into the superior sagittalvenous sinus (Papadopoulos et al, 2004). 29
  • 31. Quantitative studies of the relative involvement of the variousroutes indicate that the clearance of edema by bulk flow into the CSFis restricted to the early phase of edema. Clearance by brainvasculature is small compared to that of CSF (Stummer, 2007). 2. Cytotoxic Edema: The most commonly encountered cytotoxic edema occurs incerebral ischemia, which may be focal due to vascular occlusion, orglobal due to transient or permanent reduction in brain blood flow.Other causes include traumatic brain injury, infections, and metabolicdisorders 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 ofastrocytes. Triethyl tin and hexachlorophene intoxications causeaccumulation of water in intramyelinic clefts and produce strikingwhite matter edema, while axonal swelling is a hallmark of exposureto hydrogen cyanide. Since toxins are not involved in many cases ofcytotoxic edema some prefer the term ‘‘cellular edema’’ rather thancytotoxic edema (Ranjan et al, 2005). Experimental models used to study cytotoxic edema include thefocal and global ischemia models and the water intoxication model. Incytotoxic edema astrocytes, neurons and dendrites undergo swellingwith a concomitant reduction of the brain ECS. This cellular swelling 30
  • 32. does not constitute edema which implies a volumetric increase ofbrain tissue (Lo et al, 2003). Astrocytes are more prone to pathological swelling than neuronsbecause 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 canswell up to five times their normal size, therefore glial swelling is themain finding in this type of edema (Rosenblum, 2007). Cytotoxic edema is best studied in focal ischemia models where aninterruption of energy supply due to decrease in blood flow below athreshold of 10 ml/100 g leads to failure of the ATP-dependent Napumps. This results in intracellular Na accumulation, with shift ofwater from the extracellular to the intracellular compartment tomaintain osmotic equilibrium. This can occur within seconds. The Nais accompanied by influx of Cl¯, H¯ and HCO3¯ ions (Unterberg et al,2004). These changes are reversible. However, ischemia of less than 6minutes results in irreversible brain damage forming the ‘‘ischemiccore’’. This infracted tissue is surrounded by a region referred to asthe ‘‘penumbra’’ where the blood flow is greater than 20 ml/100 g permin. Neurons and astrocytes in the penumbra undergo cytotoxicedema. If hypoxic conditions persist, death of these neurons and gliaresults in release of water into the ECS (Liang et al, 2007). Damage to endothelium leads to vasogenic edema which can bedemonstrated by computed tomography in human brain by 24–48 31
  • 33. hours after the onset of ischemic stroke (Figure 8a & b) (Ayata &Ropper, 2002). Figure 8a Figure 8bFigure 8: (figure 8a): Axial CT scans of a 52-year-old patient showing an area of decreased 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 to infarction associated with vasogenic edema (Ayata & Ropper, 2002). The vasogenic component of ischemic brain edema is biphasic. Thefirst opening of the BBB is hemodynamic in nature and occurs 3–4 hafter the onset of ischemia. There is marked reactive hyperemia whichdevelops in the previously ischemic area due to a rush of blood intovessels that are dilated by acidosis and devoid of autoregulation. Thisopening may be brief but it allows the entry of blood substances intothe tissue. The second opening of the BBB follows the release ofischemic occlusion and may be associated with a progressive increasein the infarct size (Rosenberg & Yang, 2007). 32
  • 34. Exudation of protein into the infarct area combined with an increasein osmolarity due to breakdown of cell membranes results in anincrease in local tissue pressure. This leads to depression of regionalblood flow below the critical thresholds for viability in penumbralregions and to further extension of the territory which undergoesirreversible tissue damage. Elimination routes for excess water may bethe same as those in vasogenic edema (Kuroiwa et al, 2007). 3. Hydrocephalic or interstitial edema: This is best characterized in noncommunicating hydrocephaluswhere there is obstruction to flow of CSF within the ventricularsystem or communicating hydrocephalus where the obstruction isdistal to the ventricles and results in decreased absorption of CSF intothe subarachnoid space. In hydrocephalus, a rise in the intraventricularpressure causes CSF to migrate through the ependyma into theperiventricular white matter, thus, increasing the extracellular fluidvolume (figure 9). The edema fluid consists of Na and water and hasthe same composition as CSF (Johnston & Teo, 2000). The white matter in the periventricular regions is spongy and onmicroscopy there is widespread separation of glial cells and axons.Astrocytic swelling is present followed by gradual atrophy and loss ofastrocytes (Abbott, 2004). In chronic hydrocephalus, increase in the hydrostatic pressurewithin the white matter results in destruction of myelin and axons and 33
  • 35. this is associated with a microglial response. The end result is thinningof the corpus callosum and compression of the periventricular whitematter. Other changes reported are destruction of the ependyma whichmay be focal or widespread, distortion of cerebral vessels in theperiventricular region with collapse of capillaries and occasionallythere 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 the lateral 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 intraventricularpressure is recorded, ependymal damage with backflow of CSF ispostulated to produce edema. Functional manifestations in these casesare minor unless changes are advanced when dementia and gaitdisorder become prominent (Ball & Clarke, 2006). 34
  • 36. 4. Osmotic edema: In this type of edema an osmotic gradient is present between plasmaand the extracellular fluid and the BBB is intact, otherwise an osmoticgradient could not be maintained. Edema may occur with a number ofhypo-osmolar conditions including: improper administration ofintravenous fluids leading to acute dilutional hyponatremia,inappropriate antidiuretic hormone secretion, excessive hemodialysisof uremic patients and diabetic ketoacidosis (Kimelburg, 2004). There is a decrease of serum osmolality due to reduction of serumNa and when serum Na is less than 120 mmol/L, water enters thebrain and distributes evenly within the ECSs of the grey and whitematter. Astrocytic swelling may be present. The spread of edemaoccurs by bulk flow along the normal interstitial fluid pathways.Following a 10% or greater reduction of plasma osmolarity, there is apronounced increase in interstitial fluid volume flow, and extracellularmarkers are cleared into the CSF at an increased rate (Katayama &Katayama, 2003). The formation of osmotic edema can lead to a significant increasein the rate of CSF formation without any contribution of the choroidplexuses. Since osmotic edema is vented rapidly, the increase in brainvolume tends to be modest. Experimentally, this type of edema isinduced following intraperitoneal infusion of distilled water. The BBBis not affected and cytotoxic mechanisms are not involved. Osmoticbrain edema can also occur when the plasma osmolarity is normal but 35
  • 37. tissue osmolarity is high in the core of the lesion as in brainhemorrhage, infarcts or contusions (Nag, 2003) a. 36
  • 38. Chapter (2): ChemicalMediators Involved in the Pathogenesis of Brain Edema 37
  • 39. Chemical Mediators Involvedin The Pathogenesis Of Brain Edema  Introduction: Brain edema continues to be a major cause of mortality afterdiverse types of brain pathologies such as major cerebral infarcts,hemorrhages, trauma, infections and tumors. The classification ofedema into vasogenic, cytotoxic, hydrocephalic and osmotic hasstood the test of time although it is recognized that in most clinicalsituations there is a combination of different types of edema duringthe course of the disease (Schilling & Wahl, 1999). It is well established that vaso-active agents can increase BBBpermeability and promote vasogenic brain edema (Table 1)(Yamamoto et al, 2001). Basic information about the types of edema is provided for betterunderstanding of the expression pattern of some of the newermolecules implicated in the pathogenesis of brain edema. Thesemolecules include the aquaporins (AQP), matrix metalloproteinases(MMPs) and growth factors such as vascular endothelial growthfactors (VEGF) A and B and the angiopoietins. The potential ofthese agents in the treatment of edema is the subject of manyreviews (Dolman et al, 2005). 38
  • 40. 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). 39
  • 41.  Aquaporins and brain edema: Aquaporins (AQP) are a growing family of molecular water-channel proteins that assemble in membranes as tetramers. Eachmonomer is 30 kDa and has six membrane-spanning domainssurrounding a water pore that allows bidirectional passage of water(Badaut et al, 2001). At least 13 AQPs have been found in mammals and more than300 in lower organisms. Expression of AQP 1, AQP3, AQP4,AQP5, AQP8 and AQP9 has been reported in rodent brain. OnlyAQP1 and AQP4 are reported to have a role in human brain edemaand will be discussed (Oshio et al, 2005).  Aquaporin1 (AQP1): Localization of AQP1 in the apical membrane of the choroidplexus epithelium suggests that it may have a role in CSF secretion.This could be supported by the finding that AQP1 is upregulated inchoroid plexus tumors, which are associated with increased CSFproduction. AQP1 is also expressed in tumor cells and peritumoralastrocytes in high grade gliomas (Longatti et al, 2006). Although AQP1 is present in endothelia of non-neural vessels, itis not observed in normal brain capillary endothelial cells. Braincapillary endothelial cells cultured in the absence of astrocytes andthose in brain tumors that are not surrounded by astrocytic end-feetdo express AQP1, suggesting that astrocytic end-feet may signal 40
  • 42. adjacent endothelial cells to switch off AQP1 expression (Verkman,2005). AQP1-null mice show a 25% reduction in the rate of CSFsecretion, reduced osmotic permeability of the choroid plexusepithelium and decreased ICP. These findings support the role ofAQP1 in facilitating CSF secretion into the cerebral ventricles by thechoroid plexuses and suggest that AQP1 inhibitors may be useful inthe treatment of hydrocephalus and benign intracranial hypertension,both of which are associated with increased CSF formation oraccumulation (Tait et al, 2008).  Aquaporin4 (AQP4): AQP4, the principal AQP in mammalian brain, is expressed inglia at the borders between major water compartments and the brainparenchyma (figure 10). AQP4 is expressed in the basolateralmembrane of the ependymal cells lining the cerebral ventricles andsubependymal astrocytes which are located at the ventricular CSFfluid– brain interface (Furman et al, 2003). Expression of AQP4 in astrocytic foot processes brings it in closeproximity to intracerebral vessels, and thus, the blood–braininterface. Water molecules moving from the blood pass through theluminal endothelial membranes by diffusion and across theastrocytic foot processes through the AQP4 channels. AQP4 is alsoexpressed in the dense astrocytic processes that form the glialimitans which is at the subarachnoid– CSF fluid interface (Rash etal, 2004). 41
  • 43. Figure 10: Pathways for water entry into and exit from brain are shown. The AQP4- 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 andM23, which can form homo- and hetero-tetramers, respectively. Thelocation of AQP 4 at the brain–fluid interfaces suggests that it isimportant for brain water balance and may play a key role in brainedema. AQP4 overexpression in human astrocytomas correlates withthe presence of brain edema on magnetic resonance imaging(Silberstein et al, 2004). However, decrease in AQP4 protein expression is associated withearly stages of edema in rodents subjected to permanent focal brainischemia and hypoxia-ischemia. In traumatic brain injury AQP4mRNA is decreased in the area of edema adjacent to a cortical 42
  • 44. contusion. AQP4-null mice provide strong evidence for AQP4involvement 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 involvedin the clearance of extracellular fluid from the brain parenchyma invasogenic edema (Meng et al, 2004). A number of models in which vasogenic edema is thepredominant form of edema, including the cortical cold injury,tumor implantation and brain abscess models, demonstrate that theAQP4-null mice have a significantly greater increase in brain watercontent and ICP than the wild-type mice suggesting that brain waterelimination is defective after AQP4 deletion (Papadopoulos &Verkman, 2007). Melanoma cells implanted into the striatum of wild-type andAQP4-null mice produce peritumoral edema and comparable sizedtumors in both groups after a week. However, the AQP4- null micehave a higher ICP and water content. This suggests that in vasogenicedema, excess water enters the brain ECS independently of AQP4,but exits the brain primarily through AQP4 channels into the CSFand via astrocytic foot processes into blood (Papadopoulos &Verkman, 2007). 43
  • 45. Cytotoxic edema: Swelling of astrocytic foot processes is a major finding incytotoxic edema and since AQP4 channels are located in theastrocytic foot processes, it was hypothesized that they may have arole in formation of cell swelling. This was found to be the casesince water intoxicated AQP4-null mice show a significant reductionin astrocytic foot process swelling, a decrease in brain water contentand 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 edemaand improved outcome and survival. These studies imply that AQP4has a significant role in water transport and development of cellularedema following cerebral ischemia (Zador et al, 2007).Hydrocephalic edema: Obstructive hydrocephalus produced by injecting kaolin in thecistern magna of AQP4-null mice show accelerated ventricularenlargement compared with wild-type mice. Reduced water permeability of the ependymal layer,subependymal astrocytes, astrocytic foot processes and glia limitansproduced by AQP4 deletion reduces the elimination rate of CSFacross these routes. Thus, AQP4 induction could be evaluated as anonsurgical treatment for hydrocephalus (Bloch et al, 2006). In summary, AQP4 has opposing roles in the pathogenesis ofvasogenic and hydrocephalic edema when compared to cytotoxic 44
  • 46. edema. Therefore, AQP4 activators or upregulators have thepotential to facilitate the clearance of vasogenic and hydrocephalicedema, while AQP4 inhibitors have the potential to protect the brainin cytotoxic edema. This is an area of ongoing research since noneof the AQP4 activators or inhibitors investigated thus far are suitablefor development for clinical use (Sun et al, 2003).  Matrix metalloproteinases (MMPs): The MMPs are zinc- and calcium-dependent endopeptidaseswhich are known to cleave most components of the extracellularmatrix including fibronectin, proteoglycans and type IV collagen.Activation of MMPs involves cleavage of the secreted proenzyme,while inhibition involves a group of four endogenous tissueinhibitors of metalloproteinases (TIMPs). The balance betweenproduction, activation, and inhibition prevents excessive proteolysisor inhibition (Asahi et al, 2001). Type IV collagenases are members of the larger MMP genefamily of proteolytic enzymes that have the ability of destroying thebasal lamina of vessels and thereby play a role in the development ofmany pathological processes including vasogenic edema in multiplesclerosis 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. 45
  • 47. Endothelial cells express mainly MMP-9; pericytes express MMP-3and -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 markedlyupregulated 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 temporaryischemia have shown that MMPs contribute to disruption of theBBB leading to vasogenic cerebral edema (Yang et al, 2007). Middle cerebral artery occlusion in rats for 90 min withreperfusion causes biphasic opening of the BBB in the piriformcortex with a transient, reversible opening at 3 h which correlateswith a transient increase in expression of MMP-2. This is associatedwith a decrease in claudin-5 and occludin expression in cerebralvessels. By 24 h the tight junction proteins are no longer observed inlesion vessels, an alteration that is reversed by treatment with theMMP inhibitor, BB-1101. The later BBB opening between 24 and48 h is associated with a marked increase of MMP-9 which isreleased in the extracellular matrix where it degrades multipleproteins, and produces more extensive blood vessel damage(Rosenberg & Yang, 2007). The role of MMPs in BBB breakdown is further supported by theobservation that treatment with MMP inhibitors or MMPneutralizing antibodies decreases infarct size and prevents BBB 46
  • 48. breakdown after focal ischemic stroke. The MMP inhibitors used sofar restore early integrity of the BBB in rodent ischemia models.Since these inhibitors block MMPs involved in angiogenesis andneurogenesis as well, they slow recovery. Therefore, the challenge isto identify agents that will protect the BBB and block vasogenicedema without interfering with recovery (Candelario-Jalil et al,2008).  Growth factors and brain edema:  Vascular endothelial growth factor-A (VEGF-A): VEGF, the first member of the six member VEGF family to bediscovered is now designated as VEGF-A. Initial reports describedthe potent hyperpermeability effect of VEGF-A on themicrovasculature of tumors hence its designation ‘vascularpermeability factor’. VEGF-A has a significant role in vascularpermeability and angiogenesis during embryonic vasculogenesis andin physiological and pathological angiogenesis (Adams & Alitalo,2007). There is agreement that vascular endothelial growth factorreceptor- 2 (VEGFR-2), which is present on endothelial cells, is themajor mediator of the mitogenic, angiogenic and permeability-enhancing effects of VEGF-A. The permeability inducing properties of VEGF-A have also beendemonstrated in the brain; Intracortical injections of VEGF-A 47
  • 49. produces BBB breakdown at the injection site. Normal adult cortexshows basal expression of VEGF-A mRNA and protein, while highexpression of VEGF-A mRNA and protein is present in normalchoroid plexus epithelial cells and ependymal cells (Ferrara et al,2003). Although several studies reported VEGF-A gene up regulation incerebral ischemia models, increased expression was related toangiogenesis and not to BBB breakdown. In non-neural vessels,VEGF-A is reported to cause vascular hyperpermeability by openingof interendothelial junctions and induction of fenestrae inendothelium (Marti et al, 2000). A single ultrastructural study reported interendothelial gaps andsegmental fenestrae-like narrowings in brain vessels permeable toendogenous albumin following a single intracortical injection ofVEGF-A. VEGF-A can also increase permeability by inducingchanges in expression of tight junction proteins. Reduced occludinexpression occurs in retinal and brain endothelial cells exposed toVEGF-A (Machein & Plate, 2000).  Vascular endothelial growth factor-B (VEGF-B): This member of the VEGF family displays strong homology toVEGF-A. Mice embryos (day 14) and adults show high expressionof VEGF-B mRNA in most organs with very high levels in the heartand the nervous system. Moderate down regulation of VEGF-Boccurs prior to birth and VEGF-B is the only member of the VEGF 48
  • 50. family that is expressed at detectable levels in the adult CNS (Nag etal, 2005). Constitutive expression of VEGF-B protein is present in theendothelium of all cerebral vessels including those of the choroidplexuses. Thus, VEGF-B has a role in maintenance of the BBB insteady states and VEGF-B may be protective against BBBbreakdown and edema formation (Nag et al, 2002).  Angiopoietin (Ang) family:Four members of this family have been isolated thus far anddesignated Ang1–4, Ang1 and 2 are best characterized. EndothelialAng1 is expressed widely in normal adult tissues, consistent with itplaying a constitutive stabilization role by maintaining normalendothelial cell to cell and cell to matrix interactions. Studies of therodent brain show constitutive expression of Ang1 protein inendothelium of all cerebral cortical vessels and only weakexpression of Ang2 (Raab & Plate, 2007). Functional studies indicate that Ang1 and Ang2 have reciprocaleffects in many systems. Ang1 has an antiapoptotic effect onendothelial cells, while Ang2 is reported to promote apoptosis.Presence of Ang1 is associated with smaller gaps in the endotheliumof postcapillary venules during inflammation. Ang1 is reported tostabilize interendothelial junctions. This demonstrates that Ang1 is apotent antileakage factor (Otrock et al, 2007). 49
  • 51.  Time course of growth factor expression post- injury: The cold injury model was used to study the temporal alterationsin expression of growth factors and their relation to BBB breakdown(figure 11). In the early phase post-injury up to day 2, there isincreased expression of VEGF-A protein, VEGFR-2 protein and asevenfold increase in Ang2 mRNA. During this period, vessels withBBB breakdown show endothelial immunoreactivity for VEGF-Aand Ang2 but not for VEGF-B or Ang1 (Reiss, 2005). On days 4 and 6 post-injury, there is progressive increase in Ang1and VEGF-B mRNA and protein and decrease in Ang2 and VEGF-A mRNA coinciding with maturation of neovessels and restorationof the BBB (Roviezzo et al, 2005). Increased expression of growth factors has been reported ingliomas. VEGF-A is overexpressed up to 50-fold in the peri-necrotictumor cells in glioblastomas, Increased expression of theangiopoietins has also been reported in glioblastomas. Highexpression of Ang1 has been reported in areas of high vasculardensity in all stages of glioblastoma progression while highexpression of Ang2 has been reported in endothelial cells inglioblastomas. In these studies a strong association is made betweenthese growth factors and tumor angiogenesis (Roy et al, 2006). 50
  • 52. Figure 11: Expression of growth factors during BBB breakdown: Days post-lesion 0.5 2 4 6 BBB breakdown VEGF-A VEGF-B VEGFR-2 Ang1 Ang2 Protein Expression Basal Increased DecreasedFigure 11: Temporal expression of growth factor proteins and their receptors is shown during the period of BBB breakdown in the cold injury model. Protein expression was determined by immunohistochemistry and/or immunofluorescence (Reiss, 2005). There is the potential of using growth factors to treat early andmassive edema associated with large hemispheric lesions which arelethal due to the effects of early edema. Potential candidates includeinhibitors of VEGF-A or administration of Ang1 or VEGF-B (Zadeh& Guha, 2003). 51
  • 53. Inhibitors of VEGF-A or recombinant Ang1 have been tried inrodent models of ischemia. Pretreatment of rodents with VEGF-Areceptor protein, which inactivates endogenous VEGF-A orrecombinant Ang1 attenuates BBB breakdown and edema associatedwith cerebral infarcts (Zhang, 2002). The long-term effects of administering these agents onangiogenesis and repair were not studied in these models. This mustbe assessed before these agents can be used for the treatment ofbrain edema (Yla-Herttuala et al, 2007). 52
  • 54. Chapter (3): Diagnosing cereb ra l ed ema 53
  • 55. Diagnosing cerebral edema  Introduction: Brain edema is a life-threatening complication following severalkinds of neurological and non-neurological conditions. Neurologicalconditions include: ischemic stroke and intracerebral hemorrhage,brain tumors meningitis, encephalitis of all etiologies and other braintraumatic and metabolic insults (Rosenberg, 1999). Non-neurological conditions include: diabetic ketoacidosis, lacticacidotic coma, hypertensive encephalopathy, fulminant viral hepatitis,hepatic encephalopathy, Reye’s syndrome systemic poisoning (carbonmonoxide and lead), hyponatraemia, opioid drug abuse anddependence, bites of certain reptiles and marine animals, and highaltitude cerebral edema (Glasr et al, 2001). Most cases of brain injury that result in elevated intracranialpressure (ICP) begin as focal cerebral edema. Consistent with theMonroe–Kellie doctrine as it applies to intracranial vault physiology,the consequences of cerebral edema can be lethal and include cerebralischemia from compromised cerebral blood flow and intracranialcompartmental shifts due to ICP gradients, resulting in compression ofvital brain structures (herniation syndromes; Table 2) (Harukuni et al,2002). Prompt recognition of these clinical syndromes and institution oftargeted therapies constitutes the basis of cerebral resuscitation. It is 54
  • 56. imperative to emphasize the importance of a patient displayingcerebral herniation syndrome (figure 12) without increments in globalICP; in these cases, elevations in ICP may or may not accompanycerebral 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 lobe glioma. (Figure12b): Coronal brain slices illustrating uncal herniation due tohematoma expansion. (figure12c): Compression of the cerebellar tonsils following elevated ICP. (Courtesy of Harry V. Vinters, M.D.) (Victor & Ropper, 2001) a. 55
  • 57. Table 2: Summary of the clinical subtypes of herniationsyndromes:Herniation Clinical ManifestationsSyndrome usually diagnosed using neuroimaging; cingulatesubfalcian gyrus herniates under the falx cerebrii (usuallyor cingulate anteriorly); may cause compression of ipsilateral anterior cerebral artery, resulting in contralateral lower extremity paresis downward displacement of one or both cerebralcentral hemispheres, resulting in compression oftentorial diencephalon and midbrain through tentorial notch; typically due to centrally located masses; impaired consciousness and eye movements; elevated ICP; bilateral flexor or extensor posturing most commonly observed clinically; usually due to lateral laterally located (hemispheric) masses (tumors andtranstentorial hematomas); herniation of the mesial temporal lobe, (uncal) uncus, and hippocampal gyrus through the tentorial incisura; compression of oculomotor nerve, midbrain, and posterior cerebral artery; depressed level of consciousness; ipsilateral papillary dilation and contralateral hemiparesis; decerebrate posturing; central neurogenic hyperventilation; elevated ICP herniation of cerebellar tonsils through foramentonsillar magnum, leading to medullary compression; most frequently due to masses in the posterior fossa; precipitous changes in blood pressure and heart rate, small pupils, ataxic breathing, disturbance of conjugate gaze and quadriparesisexternal due to penetrating injuries to the skull, loss of CSF and brain tissue; ICP may not be elevated due to dural opening (Harukuni et al, 2002) 56
  • 58.  Clinical Features: A high index of suspicion is very important. The features of cerebraledema add on to and often complicate the clinical features of theprimary underlying condition. Cerebral edema alone will not produceobvious clinical neurological abnormalities until elevation of ICPoccurs. Symptoms of elevation of intracranial pressure are headache,vomiting, papilledema, abnormal eye movements, neck pain orstiffness, cognitive decline, seizures, hemiparesis, dysphasia, otherfocal 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 tocompression or distortion of the dura mater and of the pain-sensitiveintracranial blood vessels. It is often paroxysmal, at first worse onwaking or after recumbency, throbbing in character, correspondingwith the arterial pressure wave. Exertion, coughing, sneezing,vomiting, straining, or sudden changes in posture accentuate it. Suchheadache is often frontal or occipital or both (Pollay, 1996). The vomiting that accompanies increased intracranial pressure oftenoccurs in the mornings when the headache is at its height, it is morecommon in children than in adults. It is generally attributed tocompression or ischemia of the vomiting center in the medullaoblongata (Hemphil et al, 2001). 57
  • 59. Similarly, the bradycardia, which is also common, results fromdysfunction in the cardiac centre but, in some patients withinfratentorial lesions, tachycardia eventually develops. Papilledemadevelops more rapidly with mass lesions in the posterior fossa becauseof their especial tendency to cause sudden obstructive hydrocephalus.Obstruction of CSF flow in the subarachnoid space and impairedabsorption both appear to be important factors in patients with tumors(Schilling, 1999). Breathing control is often impaired. Slow and deep respiratorymovements often accompany a sudden rise in intracranial pressuresufficient to impair consciousness. Later, breathing may becomeirregular, Cheyne–Stokes respiration, and periods of apnea thenalternate with phases during which breathing waxes and wanes inamplitude. Central neurogenic hyperventilation, or so-called ataxicbreathing, is less common effects of brainstem compression ordistortion but, in terminal coma, breathing is often rapid or shallow.These abnormalities of respiratory rate and rhythm may be due tocompression or distortion of the brainstem (Victor & Ropper, 2001) b. 58
  • 60.  Investigations: A. Computed Tomography (CT): CT technology may noninvasively illustrate the volumetric changesand alterations in parenchymal density resulting from cerebral edema.Expansion of brain tissue due to most forms of edema may be detectedon CT, although diffuse processes like fulminant hepatic failure maybe more difficult to discern. Diffuse swelling may be recognized by adecrease in ventricular size with compression or obliteration of thecisterns and cerebral sulci (figure 13) (Vo Kd et al, 2003). Cellular swelling associated with cytotoxic and ischemic edema canmanifest as subtle enlargement of tissue with obscuration of normalanatomic features, such as the differentiation between gray matter andwhite matter tracts (figure 14). Vasogenic edema may also cause tissueexpansion, although the associated density changes may be moreprominent (Coutts et al, 2004). In contrast, hydrocephalic edema may be suspected in cases inwhich ventricular expansion has occurred. Extensive volumetricchanges and the associated pressure differentials resulting in herniationmay be noted on CT as shifts in the location of various anatomiclandmarks (Rother, 2001). The increased water content associated with edema causes thedensity of brain parenchyma to decrease on CT (figure 15). Theattenuation effects of other tissue contents complicate precisecorrelation of water content with density on CT. Although slight 59
  • 61. decrements in tissue density result from cytotoxic and osmoticprocesses, more conspicuous areas of hypodensity result from theinflux of fluid associated with disruption of the BBB in vasogenicedema (Jaillard et al, 2002). Contrast CT improves the demonstration of infectious lesions andtumors that present with significant degrees of vasogenic edema. Thedifferentiation of specific forms of edema is limited with CT, but thismodality may provide sufficient information to guide therapeuticdecisions in many situations. CT may be inferior to MRI in thecharacterization of cerebral edema, but logistic constraints maypreclude MRI in unstable trauma patients, uncooperative patients, andpatients with contraindications due to the presence of metallic implantsor 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). 60
  • 62. Figure 14: CT scan showing imaging characteristics of brain edema caused by a tumor (Coutts et al, 2004).Figure 15 a&b: (figure 15a) an area of decreased density and loss of grey/white differentiation is present in the right insular region which represents an infarct. (Figure 15b): On day 3, a large area of decreased density involving almost the whole right hemisphere is present due to infarction associated with vasogenic edema (Jaillard et al, 2002). 61
  • 63. B. Magnetic Resonance Imaging (MRI): Volumetric enlargement of brain tissue due to edema is readilyapparent on MRI and the use of gadolinium, an MRI contrast agent,enhances regions of altered BBB. Differences in water content may bedetected on MRI by variations in the magnetic field generatedprimarily by hydrogen ions. T2-weighted sequences and fluid-attenuated inversion recovery (FLAIR) images reveal hyperintensity inregions of increased water content (figure 16). FLAIR imageseliminate the bright signal from CSF spaces and are therefore helpfulin characterizing periventricular findings such as hydrocephalic edema(figure 17) (Cosnard et al, 2000). These conventional MRI sequences are more sensitive in thedetection of lesions corresponding to hypodensities on CT. MRI is alsosuperior in the characterization of structures in the posterior fossa(figure 18). Recent advances in MRI technology make it possible tospecifically discern the type of edema based on signal characteristicsof a sampled tissue volume (Weber et al, 2000). This discriminatory capability resulted from the development ofdiffusion imaging techniques. The use of strong magnetic fieldgradients increases the sensitivity of the MR signal to the random,translational motion of water protons within a given volume element(Scarabino et al, 2004). 62
  • 64. 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). 63
  • 65. Cytotoxic edema and cellular swelling produce a net decrease in thediffusion of water molecules due to the restriction of movement,imposed by intracellular structures such as membranes andmacromolecules, and diminished diffusion within the extracellularspace due to shrinkage and tortuosity (figure 19). In contrast, theaccumulation of water within the extracellular space as the result ofvasogenic edema allows for increased diffusion (Scott et al, 2006). Diffusion-weighted imaging (DWI) sequences yield maps of thebrain, with regions of restricted diffusion appearing bright orhyperintense. The cytotoxic component of ischemic edema has beendemonstrated on DWI within minutes of ischemia onset (Simon et al,2004).Apparent diffusion coefficient (ADC) maps may be generated from aseries of DWI images acquired with varying magnetic field gradients.ADC elevations, resulting from vasogenic edema, appear hyperintenseon ADC maps, whereas decreases in ADC due to cytotoxic edemaappear hypointense (figure 20). These maps may be sampled tomeasure the ADC of a given voxel for multiple purposes, such asdifferentiating tumor from tumor associated edema (Yamasaki et al,2005). The development of perfusion-weighted imaging (PWI) with MRtechnology provided parametric maps of several hemodynamicvariables, including cerebral blood volume. Elevations in cerebralblood volume associated with cerebral edema are detectable by thistechnique. Simultaneous acquisition of multiple MRI sequences 64
  • 66. enables the clinician to distinguish various forms of cerebral edema.T2-weighted sequences and FLAIR images permit sensitive detectionof local increases in water content (Bastin et al, 2002). Figure 19 a, b&c: the cytotoxic component of acute cerebral ischemia is demonstrated by ADC hypointensity (a). The ischemic region appearshyperintense on DWI (b), whereas T2 weighted sequences may be unrevealing at this early stage (c) (Scott et al, 2006).Figure 20 a, b&c: MRI of status epilepticus reveals evidence of cytotoxic edema within cortical structures, illustrated by (a) T2-weighted and (b) DWIhyperintensity, with (c) mild hypointensity on ADC maps(Yamasaki et al, 2005) 65
  • 67. Gadolinium-enhanced T1- weighted sequences reveal sites of BBBleakage that may be present surrounding tumors (figure 21) orabscesses. DWI localizes abnormal areas of water diffusion, with ADCmaps differentiating various forms of edema. PWI can detect regionalelevation of cerebral blood volume (Kim & Garwood, 2003).The composite interpretation of these studies has revolutionized thediagnosis of cerebral edema. These images often reflect the combinedeffects of multiple types of edema. For instance, the cytotoxiccomponent 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 a glioma appears hyperintense on gadolinium-enhanced MRI (a). Peritumoralvasogenic edema is demonstrated by hyperintensity on T2-weighted sequences (b) and ADC maps (c) (Kim & Garwood, 2003). 66
  • 68. Serial imaging with this noninvasive modality also allows for thetemporal characterization of edema evolution. The relativecontributions of cytotoxic and vasogenic edema with respect to theADC during acute ischemic stroke and TBI have been investigated inthis manner. The main limitations of this technology logistically relateto cost, availability, contraindications, and its restricted use incritically ill individuals (Doerfler et al, 2002). C. Intracranial pressure monitoring: ICP monitoring is an important tool to monitor cases where cerebraledema is present or anticipated and is routinely done in all neurologyand neurosurgery ICUs. Unfortunately, the direct measurements ofICP and aggressive measures to counteract high pressures have notyielded uniformly beneficial results, and after two decades ofpopularity the routine use of ICP monitoring remains controversial(Bullock et al, 1996). The problem may be partly a matter of the timing of monitoring andthe proper selection of patients for aggressive treatment of raised ICP.Only if the ICP measurements are to be used as a guide to medicaltherapy and the timing of surgical decompression is the insertion of amonitor justified (Ayata & Ropper, 2002). Monitoring of ICP is helpful in patients in whom neurological statusis difficult to ascertain serially, particularly in the setting ofpharmacological sedation and neuromuscular paralysis. The BrainTrauma Foundation guidelines recommend ICP monitoring in patients 67
  • 69. with TBI, a GCS score of less than 9, and abnormal CT scans, or inpatients with a GCS score less than 9 and normal CT scans in thepresence of two or more of the following: age greater than 40 years,unilateral or bilateral motor posturing, or systolic blood pressuregreater than 90 mmHg (Suarez, 2001). No such guidelines exist for ICP monitoring in other brain injuryparadigms (ischemic stroke, ICH, cerebral neoplasm), and decisionsmade for ICP monitoring in this setting are frequently based on theclinical neurological status of the patient and data from neuroimagingstudies. Whether ICP monitoring adds much to the management ofpatients of stroke is still open to question, clinical signs and imagingdata on shift of brain tissue are probably more useful (Xi, et al 2006). 68
  • 70. Chapter (4): CerebralEdema in Neurological Diseases 69
  • 71. Cerebral Edema in Neurological Diseases  Introduction: Cerebral edema is associated with a wide spectrum of clinicaldisorders. Edema can either result from regional abnormalitiesrelated to primary disease of the central nervous system or be acomponent of the remote effects of systemic toxic–metabolicderangements. In either scenario, cerebral edema may be a lifethreatening 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. Thisvariability reflects the temporal evolution of a diverse combinationof edema types because most forms of cerebral edema have thecapacity to generate other types. The specific clinicalmanifestations are difficult to categorize by type and are betterdescribed by precipitating etiology. In other words, it is essential tooutline the prominent forms of edema that are present in a givenclinical scenario. The location of edema fluid determinessymptomatology. Focal neurologic deficits result from isolatedregions of involvement, whereas diffuse edema producesgeneralized symptoms such as lethargy (Amiry-Moghaddam &Ottersen, 2003). 70
  • 72. 1. Cerebrovascular Disease: Cerebral ischemia frequently causes cerebral edema. Tissuehypoxia that results from ischemic conditions triggers a cascade ofevents that leads to cellular injury. The onset of ischemic edemainitially manifests as glial swelling occurring as early as 5 minfollowing interruption of the energy supply. This cytotoxic phase ofedema occurs when the BBB remains intact, although continuedischemia leads to infarction and the development of vasogenicedema after 48–96 hours (Latour et al, 2004). Clinical symptoms are initially representative of neuronaldysfunction within the ischemic territory, although the spread ofedema may elicit further neurological deficits in patients with largehemispheric infarction. This clinical syndrome involves increasinglethargy, asymmetrical pupillary examination, and abnormalbreathing. The mechanism of neurologic deterioration appears toinvolve pressure on brain stem structures due to the mass effect ofinfarcted and edematous tissue. Elevation of ICP may begeneralized or display focal gradients that precipitate herniationsyndromes. Herniation may lead to compression and infarction ofother vascular territories, in turn initiating a new cycle of infarctionand edema (Hawkins & Davis, 2005). Intracerebral hemorrhage presents with focal neurologic deficits,headache, nausea, vomiting, and evidence of mass effect. Theedema associated with intracerebral hemorrhage is predominantlyvasogenic, climaxing 48–72 hours following the initial event. 71
  • 73. Secondary ischemia with a component of cytotoxic edema mayresult from impaired diffusion in the extracellular space of theperihemorrhage region. Other forms of hemorrhage, includinghemorrhagic transformation of ischemic territories andsubarachnoid hemorrhage may be associated with edema thatresults from the noxious effects of blood degradation products(Wang X & Lo, 2003). 2. Traumatic Brain Injury (TBI): Raised ICP attributed to cerebral edema is the most frequentcause of death in TBI. Focal or diffuse cerebral edema of mixedtypes may develop following TBI. Following contusion of thebrain, the damaged BBB permits the extravasation of fluid into theinterstitial space. Areas of contusion or infarction may release orinduce chemical mediators that can spread to other regions. Thesefactors activated during tissue damage are powerful mediators ofextravasation and vasodilation (Marcella et al 2007). TBI is associated with a biphasic pathophysiologic responseheralded by a brief period of vasogenic edema immediatelyfollowing injury, followed after 45–60 minutes by the developmentof cytotoxic edema. Vasogenic edema may be detected byneuroimaging modalities within 24–48 hours and reach maximalseverity between Days 4 and 8. Autoregulatory dysfunction is acommon sequela of TBI that may promote the formation ofhydrostatic edema in regions where the BBB remains intact. Recent 72
  • 74. efforts have also demonstrated a prominent role of cytotoxic edemain head-injured patients. Tissue hypoxia with ischemic edemaformation and neurotoxic injury due to ionic disruption contributeto this cytotoxic component. In addition, osmotic edema may resultfrom hyponatremia, and hydrocephalic edema may complicate theacute phase of TBI when subarachnoid hemorrhage or infectionspredominate. Diffuse axonal injury may produce focal edema inwhite matter tracts experiencing shear-strain forces duringacceleration/deceleration of the head (Stanley & Swierzewski,2011). 3. Infections: A combination of vasogenic and cytotoxic edema arises frommany infectious processes within the central nervous system. Otherforms of edema may also occur in infections, includinghydrocephalic edema secondary to CSF obstruction and osmoticedema due to SIADH. Numerous infectious agents have direct toxiceffects generating vasogenic edema through alteration of the BBBand cytotoxic edema from endotoxin-mediated cellular injury.Bacterial wall products stimulate the release of various endothelialfactors, resulting in excessive vascular permeability (Simon &Beckman, 2002). Cerebral edema is a critical determinant of morbidity andmortality in pediatric meningitis. Abscess formation or focalinvasion of the brain results in an isolated site of infection 73
  • 75. surrounded by a perimeter of edema encroaching on theneighboring parenchyma. This ring of vasogenic and cytotoxicedema may produce more symptoms than the actual focus ofinfection. Similar regions of focal or diffuse edema mayaccompany encephalitis, particularly viral infections such as herpessimplex encephalitis (Nathan & Scheld, 2000). 4. Cerebral Venous Sinus Thrombosis: A major life-threatening consequence of cerebral venous sinusthrombosis is cerebral edema. Two different kinds of cerebraledema can develop. The first, cytotoxic edema is caused byischemia, which damages the energy-dependent cellular membranepumps, leading to intracellular swelling. The second type,vasogenic edema, is caused by a disruption in the blood–brainbarrier and leakage of blood plasma into the interstitial space(Masuhr et al, 2004). The clinical manifestations of cerebral venous thrombosis arehighly variable. Individuals may be asymptomatic, and others maysuffer a progressive neurologic deterioration with headaches,seizures, focal neurologic deficits, and severe obtundation leadingto death (Lemke & Hacein-Bey, 2005). 74
  • 76. 5. Neoplastic Disease: The detrimental effects of cerebral edema considerably influencethe morbidity and mortality associated with brain tumors. Tumor-associated edema continues to be a formidable challenge,producing symptoms such as headache and focal neurologic deficitsand, considerably altering the clinical outcome (partial resection,chemotherapeutic agents and radiation have also been shown toencourage the formation of edema). The predominant form oftumor-associated edema is vasogenic, although cytotoxic edemamay occur through secondary mechanisms, such as tumorcompression of the local microcirculation or tissue shifts withherniation. Individuals with hydrocephalus can also develophydrocephalic edema because of ventricular outflow obstruction(Pouyssegur et al, 2006). 6. Seizures: Prolonged seizure activity may lead to neuronal energy depletionwith eventual failure of the Na+/K+ ATPase pump and concomitantdevelopment of cytotoxic or ischemic edema. Unlike ischemiaproduced by occlusion of a cerebral artery, a more heterogeneouscellular population is affected. The reactive hyperemic responsedriven by excessive metabolic demands increases the hydrostaticforces across a BBB already damaged by the vasogenic componentof ischemic edema. The disruption of normal ionic gradients,extracellular accumulation of excitotoxic factors, and lactic acidosis 75
  • 77. further exacerbate vasogenic edema. Consequently, cessation ofseizure activity usually results in the complete resolution ofcerebral edema (Vespa et al, 2003). 7. Multiple Sclerosis: One of the crucial stages in the evolution of a multiple sclerosislesion 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 inflammatoryresponse. Although BBB breakdown imaged as focal enhancementin T1- weighted MRI after gadolinium DTPA injection is the goldstandard of lesion detection during the course of the disease, thedeposition of contrast agent in the CNS has been shown to correlatewith clinical disability (Vos et al, 2005). 8. Hydrocephalus: Isolated hydrocephalic edema may result from acute obstructivehydrocephalus with impairment of CSF drainage. Transependymalpressure gradients result in edema within periventricular whitematter tracts. The rapid disappearance of myelin lipids underpressure causes the periventricular white matter to decrease involume. The clinical manifestations may be minor, unlessprogression to chronic hydrocephalus becomes apparent with 76
  • 78. symptoms including dementia and gait abnormalities (Abbott,2004). 9. Hypertensive Encephalopathy: This potentially reversible condition presents with rapidlyprogressive neurological signs, headache, seizures, altered mentalstatus, and visual disturbances. The pathogenesis of edemaformation is controversial but is thought to involve elevatedhydrostatic forces due to excessive blood pressure, with lesserdegrees of involvement attributed to vasogenic edema andsecondary ischemic components. The rate of blood pressureelevation is a critical factor, because hypertensive encephalopathyusually develops during acute exacerbations of hypertension. Earlyrecognition and treatment of hypertensive encephalopathy mayreverse cerebral edema, preventing permanent damage to the BBB,and ischemia, although severe cases may be fatal (Johnston et al,2005). 10. Hyperthermia: The pathophysiology of this rare cause of cerebral edema is poorlyunderstood. Although the fatal consequences of heat stroke have beenrecognized since ancient times, the underlying mechanisms awaitclarification. Scant pathologic material suggests a combination ofcytotoxic and vasogenic components, secondary to an increase inBBB permeability due to the release of multiple chemical factors and 77
  • 79. direct cytotoxic damage. Age and physiologic state of the individualappear to be important determinants of clinical outcome inhyperthermic injury (Bruno et al, 2004). 78
  • 80. Chapter (5): Treatment of C e r e b r al E d e m a 79
  • 81. Treatment of Cerebral Edema  Introduction: Cerebral edema is frequently encountered in clinical practice incritically ill patients with acute brain injury from diverse origins andis a major cause of increased morbidity and death in this subset ofpatients. The consequences of cerebral edema can be lethal andinclude cerebral ischemia from compromised regional or globalcerebral blood flow (CBF) and intracranial compartmental shifts dueto intracranial pressure gradients that result in compression of vitalbrain structures (Rabinstein, 2004). The overall goal of treatment of cerebral edema is to maintainregional and global CBF to meet the metabolic requirements of thebrain and prevent secondary neuronal injury from cerebral ischemia(Broderick et al, 1999). Treatment of cerebral edema involves using a systematic andalgorithmic approach, from general measures (optimal head and neckpositioning for facilitating intracranial venous outflow, avoidance ofdehydration and systemic hypotension, and maintenance ofnormothermia) to specific therapeutic interventions (controlledhyperventilation, administration of corticosteroids and diuretics,osmotherapy, and pharmacological cerebral metabolic suppression),and decompressive surgery (Wakai et al, 2007). 80
  • 82. I. General measures for treating Cerebral edema: Several general measures that are supported by principles of alteredcerebral physiology and clinical data from patients with brain injuryshould be applied to patients with cerebral edema. The primary goalof these measures is to optimize cerebral perfusion, oxygenation, andvenous drainage; minimize cerebral metabolic demands; and avoidinterventions that may disturb the ionic or osmolar gradient betweenthe brain and the vascular compartment (Ahmed & Anish, 2007). 1. Optimizing head and neck positions: Finding the optimal neutral head position in patients with cerebraledema is essential for avoiding jugular compression and impedance ofvenous outflow from the cranium, and for decreasing CSF hydrostaticpressure. In normal uninjured patients, as well as in patients withbrain 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 withischemic stroke, however, because it may compromise perfusion toischemic tissue at risk. It is also imperative to avoid the use ofrestricting devices and garments around the neck (such as devicesused to secure endotracheal tubes), as these may lead to impairedcerebral venous outflow via compression of the internal jugular veins(Ropper et al, 2004). 81
  • 83. 2. Ventilation and oxygenation: Hypoxia and hypercapnia are potent cerebral vasodilator andshould be avoided in patients with cerebra edema. It is recommendedthat any patients with Glasgow coma scale (GCS) scores less than orequal to 8 and those with poor upper airway reflexes be intubatedpreemptively for airway protection. This strategy is also applicable topatients with concomitant pulmonary disease, such as aspirationpneumonitis, pulmonary contusion, and acute respiratory distresssyndrome (Eccher & Suarez, 2004). Avoidance of hypoxemia and maintenance of PaO2 atapproximately 100 mmHg are recommended. Careful monitoring ofclinical neurological status, ICP is recommended in mechanicallyventilated patients with cerebral edema with or without elevations inICP. Blunting of upper airway reflexes (coughing) with endobronchiallidocaine before suctioning, sedation, or, rarely, pharmacologicalparalysis may be necessary for avoiding increases in ICP (Schwarz etal, 2002). 3. Seizure prophylaxis: Anticonvulsants (predominantly phenytoin) are widely usedempirically in clinical practice in patients with acute brain injury ofdiverse origins, including traumatic brain injury (TBI), subarachnoidhemorrhage (SAH), and intracranial hemorrhage (ICH), although datasupporting their use are lacking (Vespa et al, 2003). 82
  • 84. Early seizures in TBI can be effectively reduced by prophylacticadministration of phenytoin for 1 or 2 weeks without a significantincrease in drug-related side effects. The use of prophylacticanticonvulsants in ICH can be justified, as subclinical seizure activitymay cause progression of shift and worsen outcome in critically illpatients with ICH. Yet the benefits of prophylactic use ofanticonvulsants in most causes leading to brain edema remainunproven, and caution is advised in their use (Glantz et al, 2000). 4. Management of fever and hyperglycemia: Numerous experimental and clinical studies have demonstrated thedeleterious effects of fever on outcome following brain injury, whichtheoretically result from increases in oxygen demand. Therefore,normothermia is strongly recommended in patients with cerebraledema, irrespective of underlying origin. Acetaminophen (325–650mg orally, or rectally every 4–6 hours) is the most common, and thesafest agent used, and is recommended to avoid elevations in bodytemperature (Bruno et al, 2004). Evidence from clinical studies in patients with ischemic stroke,subarachnoid hemorrhage, and TBI suggests a strong correlationbetween hyperglycemia and worse clinical outcomes. Hyperglycemiacan exacerbate brain injury and cerebral edema. Significantlyimproved outcome has been reported in general ICU patients withgood glycemic control; although larger studies focused on specificbrain injury paradigms are forthcoming. Nevertheless, currentevidence suggests that rigorous glycemic control may be beneficial in 83
  • 85. 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 thebrain edema. In trauma and stroke patients, blood pressure should besupported to maintain adequate perfusion, avoiding sudden rises andvery high levels of hypertension. Keeping cerebral perfusion pressureabove 60–70 mm Hg is generally recommended after traumatic braininjury (Johnston et al, 2005). 6. Nutritional support and fluid management: Prompt maintenance of nutritional support is imperative in allpatients with acute brain injury. Unless contraindicated, the enteralroute of nutrition is preferred. Special attention should be given to theosmotic content of formulations Low serum osmolality must beavoided in all patients with brain swelling since it will exacerbatecytotoxic edema. This objective can be achieved by strictly limitingthe intake of hypotonic fluids. In fact, there is clear evidence that freewater should be avoided in patients with head injuries and brainedema (Leira et al, 2004). In patients with pronounced, prolonged serum hyperosmolality, thedisorder must be corrected slowly to prevent rebound cellularswelling. Fluid balance should be maintained neutral. Negative fluidbalance has been reported to be independently associated with adverseoutcomes in patients with severe brain trauma. Avoiding negative 84
  • 86. cumulative fluid balance is essential to limit the risk of renal failure inpatients receiving mannitol (Powers et al, 2001). II. Specific measures for managing Cerebral edema: 1. Controlled hyperventilation: Based on principles of altered cerebral pathophysiology associatedwith brain injury, controlled hyperventilation remains the mostefficacious therapeutic intervention for cerebral edema, particularlywhen the edema is associated with elevations in ICP (Carmona et al,2000). A decrease in PaCO2 by 10 mmHg produces proportionaldecreases in regional CBF, resulting in rapid ICP reduction. Thevasoconstrictive effect of respiratory alkalosis on cerebral arterioleshas been shown to last for 10 to 20 hours, beyond which vasculardilation may result in exacerbation of cerebral edema and reboundelevations in ICP (Mayer & Rincon, 2005). Overaggressive hyperventilation may actually result in cerebralischemia. Therefore, the common clinical practice is to lower andmaintain PaCO2 by 10 mmHg to a target level of approximately 30–35 mmHg for 4 to 6 hours, although identifying the correct strategyfor achieving this goal is unclear in terms of adjusting tidal volumesand respiratory rate (Marion et al, 2002). 85
  • 87. It should be noted that controlled hyperventilation is to be used as arescue or resuscitative measure for a short duration until moredefinitive therapies are instituted and maintained. Caution is advisedwhen reversing hyperventilation gradually over 6 to 24 hours, toavoid cerebral hyperemia and rebound elevations in ICP secondary toeffects of reequilibration (Diringer, 2002). 2. Osmotherapy use:  Historical perspective: The earliest description of the use of osmotic agents dates back to1919, Weed and McKibben observed that intravenous administrationof a concentrated salt solution resulted in an inability to withdrawCSF from the lumbar cistern due to a collapse of the thecal sac. Thisobservation was followed by a set of experiments in an animal modelin which they demonstrated (under direct visualization via acraniotomy) egress of the brain away from the cranial vault withintravenous infusion of hypertonic saline solutions and herniation ofbrain 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 anosmotic agent. Its use was short-lived and is of historic interest onlybecause of several untoward side effects (nausea, vomiting, diarrhea,and coagulopathy). The interest in elevating plasma oncotic pressureas a strategy to ameliorate cerebral edema with the use ofconcentrated human plasma proteins, which appeared briefly in 1940, 86
  • 88. was short-lived due to several concerns, including cost, short half-life,cardiopulmonary effects, and allergic reactions. Glycerol was possiblythe second osmotic agent to be used clinically and is still used(Alejandro & Rabinstein, 2006). Mannitol, an alcohol derivative of simple sugar mannose, wasintroduced in 1960 and has since remained the major osmotic agent ofchoice in clinical practice. Its long duration of action and relativestability in solution has enhanced its use over the years (Dennis,2003). Renewed interest in hypertonic saline solutions reappeared in the1980s, in these studies; cerebral effects of these solutions wereinvestigated in well-controlled experimental studies in animal modelsof acute brain injury. These studies continue to provide evidence forthe potential use of these solutions in the clinical domains (Harukuniet al, 2002).  Therapeutic basis and goal of osmotherapy: Put simply, the fundamental goal of osmotherapy is to create anosmotic gradient to cause egress of water from the brain extracellular(and possibly intracellular) compartment into the vasculature, therebydecreasing intracranial volume. A serum osmolality in the range of300 to 320 mOsm/L has traditionally been recommended for patientswith acute brain injury who demonstrate poor intracranialcompliance; however, values greater than 320 mOsm/L can beattained with caution, without apparent untoward side effects(Korenkov et al, 2000). 87
  • 89. An ideal osmotic agent is one that produces a favorable osmoticgradient, is inert and nontoxic, is excluded from an intact BBB, andhas minimal systemic side effects. Mannitol has remained the majorosmotic agent of choice in clinical practice. Its long duration of action(4–6 hours) and relative stability in solution have enhanced its useover the years (Battison et al, 2005). The extraosmotic properties of mannitol have been studiedextensively and may provide additional beneficial effects in braininjury, including decreases in blood viscosity, resulting in increases inCBF and CPP, free radical Scavenging and inhibition of apoptosis(Qureshi et al, 2000). Like mannitol, hypertonic saline also possesses uniqueextraosmotic properties, including modulation of CSF production andresorption, accentuation of tissue oxygen delivery, and modulation ofinflammatory and neurohumoral responses (arginine-vasopressin andatrial natriuretic peptide) following brain injury that may act togetherto ameliorate cerebral edema (Bhardwaj et al, 2004).  Comparison between mannitol and hypertonic saline: Few studies have made direct comparisons between mannitol andhypertonic saline (table 3). In a prospective, randomized comparisonof 2.5 ml/kg of either 20% mannitol (1400 mOsm/kg) or 7.5%hypertonic saline (2560 mOsm/ kg) in patients undergoing electivesupratentorial procedures, ICP and intraoperative clinical assessmentof brain swelling were similar in both treatment groups (Toung et al,2005). 88
  • 90. In a prospective, randomized trial of hypertonic saline withhydroxyethyl starch, hypertonic saline was shown to be moreeffective than equiosmolar doses of mannitol in lowering elevatedICP and augmenting CPP in patients with ischemic stroke (Mirski etal, 2000). Likewise, intravenous bolus injection of 10% hypertonic saline wasshown to be effective in lowering ICP in patients with ischemic strokewho failed to show such a response to conventional doses ofmannitol. More recently, in a small prospective study, isovolemicintravenous infusion of 7.5% hypertonic saline was more effective inthe control of ICP following TBI, compared with mannitol treatment(Vialet et al, 2003). In summary, the literature supports the use of hypertonic saline as atherapy to decrease ICP in patients following TBI and stroke and tooptimize intravascular fluid status in patients with SAH-inducedvasospasm. However, no definite conclusions can be drawn at presentbecause the studies involved a wide range of saline concentrations,and equiosmolar solutions were not consistently used. Furthercarefully designed studies comparing the 2 agents are needed beforesuperiority of one of them can be firmly postulated (Ware et al,2005). 89
  • 91. Table 3: Summary of experimental studies comparing different formulations of hypertonic saline (HS) with mannitol 20% (M) (Toung et al, 2005). Study: Experimental HS Formulation & Results: Model: Mode of Infusion:Gemma (50/Elective 7.5% NaCl No differences in CSF pressureet al, 1997 neurosurgery) BolusSchwarz (9/Ischemic 75 g/L NaCl plus 60 g/L HS lowered ICP moreet al, 1998 infarction with hydroxyethyl effectively M increased raised ICP) starch (2570 mOsm/L) CPP more effectively. Serial bolusesVialet et (20/TBI with 7.5% NaCl HS had lower rate ofal, 2003 coma and raised Serial boluses failure to drop ICP. ICP)Battison (9/TBI) 7.5% NaCl plus 6% HS produced greater and et al, dextran-70* longer ICP reductions.2005 Two boluses of HS and MMirski et Focal cryogenic 11 mOsm/kg NaCl* Greater and longer ICPal, 2000 lesion in rats Bolus reduction with HS. Similar brain water content.Tuong et Temporary MCA 7.5%NaCl/acetate HS attenuated maximalal, 2005 occlusion (2 h) in Continuous edema in both rats hemispheres less robustly than MTuong et Permanent MCA 5% And 7.5% NaCl/acetate HS (both concentrations)al, 2002 occlusion in rats Continuous reduced lung and brain water content more effectively than M.Zornow Focal cryogenic 3.2% NaCl Similar ICP reduction. et al, lesion in rabbits Bolus Similar MAP response.1990Freshman ICP elevation by 7.5% NaCl Similar ICP reduction.et al, 1993 epidural balloon Bolus Similar brain water inflation in sheep content. CPP, cerebral perfusion pressure; MAP, mean arterial pressure; MCA, middle cerebral artery. *Equiosmolar doses of mannitol 20% (osmolarity 1160 mOsm/L) and HS were used 90
  • 92.  Treatment protocol for osmotherapy: The conventional osmotic agent mannitol, when administered at adose of 0.25 to 1.5 g/kg by intravenous bolus injection, usually lowersICP, with maximal effects observed 20 to 40 minutes following itsadministration. Repeated dosing of mannitol may be instituted every 6hours and should be guided by serum osmolality to a recommendedtarget value of approximately 320 mOsm/L; higher values result inrenal 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 cerebraledema with or without elevations in ICP. Hypertonic saline solutionsof 2, 3, or 7.5% contain equal amounts of sodium chloride andsodium acetate (50:50) to avoid hyperchloremic acidosis. Potassiumsupplementation (20–40 meq/L) is added to the solution as needed(Ahmed & Anish, 2007). Continuous intravenous infusions are begun through a centralvenous catheter at a variable rate to achieve euvolemia or slighthypervolemia (1–2 ml/ kg/hr). A 250-ml bolus of hypertonic salinecan be administered cautiously in select patients if more aggressiveand rapid resuscitation is warranted. Normovolemic fluid status ismaintained, guided by central venous pressure (Battison et al, 2005). The goal in using hypertonic saline is to increase serum sodiumconcentration to a range of 145 to 155 mEq/L (serum osmolalityapproximately 300–320 mOsm/L), but higher levels can be targetedcautiously. This level of serum sodium is maintained for 48 to 72 91
  • 93. hours until patients demonstrate clinical improvement or there is alack of response despite achieving the serum sodium target (Toung etal, 2002). During withdrawal of therapy, special caution is emphasized due tothe possibility of rebound hyponatremia leading to exacerbation ofcerebral edema. Serum sodium and potassium are monitored every 4to 6 hours, during both institution and withdrawal of therapy. Chestradiographs are obtained to find evidence of pulmonary edema fromcongestive heart failure, especially in elderly patients (Mirski et al,2000). Intravenous bolus injections (30 ml) of 23.4% hypertonic salinehave been used in cases of intracranial hypertension refractory toconventional ICP-lowering therapies; repeated injections of 30 mlboluses 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 etal, 2004).  Potential complications of osmotherapy: Safety concerns with mannitol include hypotension, hemolysis,hyperkalemia, renal insufficiency, and pulmonary edema. Clinicalexperiences suggest that the side-effect profile of hypertonic saline issuperior to mannitol, but some theoretical complications that are 92
  • 94. 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 salinetherapy, typically occurs when rapid corrections in serum sodiumarise from a chronic hyponatremic state to a normonatremic orhypernatremic state. Experimental studies suggest that for myelininjury to occur, the degree of rapid change in serum sodium is muchgreater from a normonatremic to a hypernatremic state (change of 93
  • 95. approximately 40 mEq/L), but further study with neuroimagingtechniques is required (Takefuji et al, 2007).3. Loop diuretics: The use of loop diuretics (commonly furosemide) for the treatmentof cerebral edema, particularly when used alone, remainscontroversial. Combining furosemide with mannitol produces aprofound diuresis; however, the efficacy and optimum duration of thistreatment remain unknown (Steiner et al, 2001). If loop diuretics are used, rigorous attention to systemic hydrationstatus is advised, as the risk of serious volume depletion is substantialand cerebral perfusion may be compromised. A common strategyused to raise serum sodium rapidly is to administer an intravenousbolus of furosemide (10 to 20 mg) to enhance free water excretionand 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 weakdiuretic and modulates CSF production, does not have a role incerebral edema that results from acute brain injuries; however, it isfrequently used in outpatient practice, particularly for the treatment ofcerebral edema associated with pseudo tumor cerebrii (Eccher &Suarez, 2004).4. Corticosteroid administration: The main indication for the use of steroids is for the treatment ofvasogenic edema associated with brain tumors or accompanying brain 94
  • 96. irradiation and surgical manipulation. Although the precisemechanisms of the beneficial effects of steroids in this paradigm areunknown, steroids decrease tight-junction permeability and, in turn,stabilize the disrupted BBB (Rabinstein, 2006). Glucocorticoids, especially dexamethasone, are the preferredsteroidal agents, due to their low mineralocorticoid activity; the usualinitial dose is 10 mg intravenously or by mouth, followed by 4 mgevery 6 hours. This is equivalent to 20 times the normal physiologicproduction 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 perday, may be used with chances of success in more refractory cases.After several days of use, steroids should be tapered gradually toavoid potentially serious complications from recurrent edema andadrenal suppression (Kaal & Vecht, 2004). The therapeutic role of steroids in TBI and stroke has been studiedextensively. In TBI, steroids failed to control elevations in ICP or toshow any benefit in outcome, and they may even be harmful. Instroke, steroids have failed to show any substantial benefit despitesome success in animal models. Given the deleterious side effects ofsteroid use (peptic ulcers, hyperglycemia, impairment of woundhealing, psychosis, and immunosuppression), until further studies arepublished, caution is advised in the use of steroids for cerebral edemaunless absolutely indicated (Roberts et al, 2004). 95
  • 97. Glucocorticoids are also useful to treat brain edema in cases ofbacterial meningitis. Edema in these patients develops as part of theinflammatory reaction triggered by the lysis of bacterial cell wallsinduced by antibiotics. Inflammation is mediated through theincreased production of cytokines and chemokines by microglia,astrocytes, and macrophages. Interleukin-1 (IL-1) and tumor necrosisfactor (TNF) increase vascular permeability both directly andindirectly by increasing leukocyte adherence to the endothelium(Sinha et al, 2004). Apart from previously mentioned mechanisms, glucocorticoidsexert a depressant effect on both the synthesis and translation of IL-1and TNF mRNA. The timing of glucocorticoid use may be critical asthe maximal reduction in the production of these inflammatorycytokines occurs only if therapy is started prior to the release of thebacterial cell wall components (Slivka & Murphy, 2001).5. Pharmacological coma: Barbiturates were introduced since the 1960s, and have gainedacceptance for the treatment of cerebral edema associated withintractable elevations in ICP. Barbiturates lower ICP, principally via areduction in cerebral metabolic activity, resulting in a coupledreduction in CBF and CBV (Mayer & Rincon, 2005). Yet their use in clinical practice is not without controversy. Inpatients with TBI, barbiturates are effective in reducing ICP, but havefailed to show evidence of improvement in clinical outcome. 96
  • 98. Evidence is limited for the utility of barbiturate treatment in cerebraldiseases that include space-occupying lesions such as tumor and ICH(Schwab et al, 1997). When used in the acute setting, pentobarbital, a barbiturate with anintermediate physiological half-life (approximately 20 hours) is thepreferred agent rather than phenobarbital. The recommended regimenentails a loading intravenous bolus dose of pentobarbital (3–10mg/kg), followed by a continuous intravenous infusion (0.5–3.0mg/Kg/hr, serum levels of 3 mg/dL) (Alejandro & Rabinstein, 2006). Several adverse effects of barbiturates that limit their clinical useare to be noted, including sustained lowering of systemic bloodpressure and CPP, cardiodepression, immunosuppression, andsystemic hypothermia. Perhaps the most important limitation withbarbiturate coma treatment is the inability to track subtle changes in apatient’s clinical neurological status, which necessitates frequentserial neuroimaging (Ropper et al, 2004).6. Hypothermia: Induced hypothermia has generated enormous interest as a potentialneuroprotective intervention in patients with acute brain insults.Sound experimental data provide a solid foundation to the clinicalevaluation of hypothermia to treat acute brain ischemia and traumaticinjury (Krieger et al, 2001). Different cooling methods are currently available, includingexternal (ice packs, iced gastric lavage, water or air circulating 97
  • 99. blankets, cooling vest) and endovascular means. The superiority ofendovascular cooling is probable but still under evaluation. Targetcore temperature is usually 32–34°C, measured with thermistorsplaced inside the urinary bladder (Clifton et al, 2001). Shivering must be prevented using deep sedation andneuromuscular paralysis when necessary; the combination of oralbuspirone and intravenous meperidine. Hypothermia is usuallymaintained for 12–72 hours, followed by a period of controlledrewarming over 12–24 hours (Gadkary et al, 2002). Induction of hypothermia is associated with several potentialcomplications. The most frequent and dangerous are sepsis(particularly from pneumonia), cardiac arrhythmias and hemodynamicinstability (often seen during rewarming), coagulopathy (especiallythrombocytopenia), and electrolyte disturbances (potassium,magnesium, calcium, phosphate) (Holzer et al, 2005). 98
  • 100. III. Surgical interventions: In patients with ICP elevation, cerebrospinal fluid drainage is a fastand highly effective treatment measure. This assertion holds true evenin the absence of hydrocephalus. Unfortunately, external ventriculardrainage carries a substantial risk of ventriculitis, even under the bestcare. Controlled lumbar drainage may be a safe alternative, though itsuse should be accompanied by extreme caution (Buschmann et al,2007). A comprehensive and updated discussion on the value ofhemicraniectomy to treat ischemic brain edema associated withmassive hemispheric strokes has been recently published. While it isclear that hemicraniectomy can be lifesaving, its beneficial impact onthe long-term functional outcome of survivors remains unproven. Anexample of this surgical intervention is presented in (Figure 22)(Coplin et al, 2001). In patients with critical intracranial hypertension after head traumawho fail to respond to all other therapeutic measures, craniectomywith duraplasty may be a valuable alternative. Hemicraniectomy maybe preferable in patients with focal lesions, such as hemorrhagiccontusions. Good long-term functional outcomes have been reportedin 25–56% of young patients after this surgery (Bullock, 2006). Although the optimal timing and indications for this interventionare not well established, the expeditious decision by an experiencedneurosurgeon to proceed with holocraniectomy in a young patient 99
  • 101. with massive intractable traumatic brain edema should probably notbe 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 the swollen infarction with early hemorrhagic transformation and shift of midline structures. Hemicraniectomy was promptly performed without complications. Postoperative CT scan shown in B demonstrates partial decompression of the mass effect with herniation of infracted tissue through the skull defect (Coplin et al, 2001). 100
  • 102. Chapter (6): Spinal Cord E d ema I n Injury and Repair 101
  • 103. Spinal Cord Edema In Injury and Repair  Introduction: The blood-spinal cord barrier (BSCB) regulates the fluidmicroenvironment of the spinal cord within a narrow limit. Thedetails of structural and functional properties of the BSCB in normaland pathological conditions are not well known in all details(Leskovar et al, 2000). Traumatic insults to the spinal cord disrupt the functional integrityof the BSCB and results into an increased transport of severalsubstances from the vascular compartment to the spinal cord cellularmicroenvironment. Breakdown of the BSCB thus appears to playimportant roles in cell and tissue reaction as well as regeneration andrepair processes (Popovich et al, 1997). An increased understanding of BSCB in spinal cord injury (SCI)is important for the development of suitable therapeutic strategies tominimize cell and tissue destruction and to enhance regeneration andfunctional recovery (Sharma, 2004). There are reasons to believe that the characteristics of the BSCBare similar to that of the blood-brain barrier (BBB). The spinal cordendothelial cells are connected with tight junctions and do notexhibit vesicular transport. The spinal endothelial cells aresurrounded by a thick basement membrane like the BBB. However, 102
  • 104. a minor difference in astrocytes-microvessel interactions is seen inthe superficial spinal cord microvessels. The large superficial vesselsof the spinal cord contain enough deposits of glycogen, not normallyseen in the brain microvessels. The functional significance ofglycogen deposits in relation with the barrier properties is not wellunderstood (James et al, 1997). Interestingly, impairment of local circulation in the spinal cordinduces much less cell damage compared to the brain. A less markedregional difference in the spinal cord microcirculation and/ormetabolism compared to the brain could be the main reason behindthis phenomenon (Stålberg et al, 1998). In traumatic brain injuries, breakdown of the BBB results inabnormal leakage of proteins leading to vasogenic edema formationand brain pathology. Edematous swelling of brain in a closedcranium compresses vital centers resulting in instant death.However, in the spinal cord, the vertebral canal provides some spaceto accommodate edematous expansion of the spinal cord up to someextent (Mendelow et al, 2000). 103
  • 105.  Epidemiology of Spinal Cord Injury: In the United States of America, about 30 to 50 cases per millionpopulations are recorded per year that is quite comparable to Europeand other continents. The common cause of SCI is due to motorvehicle 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 orthoracolumbar junctions. The victims of SCI are generally youngmen of 20 to 30 years of age while only 20 to 30 % of cases involvewomen (Holmes, 1915, coated from Sharma, 2005). Quadriplegia followed by paraplegia is the main symptoms ofSCI. Complete injuries without any signs of voluntary motor orsensory perception below the level of the lesion are seen in about50% cases of the SCI victims. The other causes of paralysisinvolving the spinal cord are multiple sclerosis, ischemia andtumors. Currently, no suitable therapeutic strategies are effective inimproving the quality of life of SCI patients. Thus, exploration ofnew pharmacological avenues with possibility of regeneration of thedamaged spinal cord axons is urgently needed. Knowledge on thestructure and function of the BSCB and the spinal cordmicroenvironment in SCI is thus crucial for the development ofnovel pharmacological tools to minimize cell and tissue injuries aswell as to enhance recovery (Sharma, 2000). 104
  • 106.  Pathophysiology of Spinal Cord Injury: Pathophysiology of SCI is complex and includes severalimmediate and late cell and tissue reactions. The progression andpersistence of these pathological changes mainly depends on theseverity of the primary lesion. Depending on the magnitude andseverity of the initial impact, microhaemorrhages and leakage oferythrocytes are present in the perivascular space acrossmicrovessels, arterioles, veins and venules as well as in the spinalcord neuropil within 3 minutes (Sharma, 2005). Damage to neuropil, swollen astrocytes, ruptured cell membranesand basal lamina are frequent within 6 to 10 minutes after SCI.Swollen endothelial cells with electron dense cytoplasm exhibitinglarge numbers of vesicles (60 to 70 nm diameter) without wideningof the tight junctions are common at this time. In some microvessels,the perivascular spaces contain proteinaceous fluid. The endothelialballoons are evident in some microvessels 4 to 6 hours after injury(Mautes & Noble, 2000). A detailed account of BSCB permeability following spinal cordtransection 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 tothe transection site. The segment located 1 cm away from the lesionsite showed extravasation of HRP between 30 minutes and 3 hourson day 1. A less pronounced increase in BSCB disruption is seen in 105
  • 107. the proximal segment compared to the distal segment. Thepermeability to HRP is restored within 14 days after injury (Noble,1978, coated from Sharma, 2005). Vesicular transport rather than widening of the tight junctions isresponsible for HRP extravasation in the transection and contusioninjuries. These observations suggest that the mechanisms of leakageacross the BSCB are similar in nature irrespective of the types ofinjury (Sharma, 2004). At the ultrastructural level, lanthanum tracer was mainly confinedwithin the lumen of the endothelial of normal rats. SCI resulted inthe occurrence of lanthanum filled vesicles within the endothelialcell cytoplasm. Marked increase in the endothelial cell membranepermeability to lanthanum is seen in several vascular profiles thatappear to be very specific. In some microvascular profiles, thelanthanum is present in the basal lamina. However, the tight junctionremained intact to lanthanum in SCI. These observations suggestthat increased endothelial cell membrane permeability seems be oneadditional way of vascular leakage (Sharma, 2000).  Spinal cord edema formation: After SCI, edema formation is apparent as early as 30 seconds andbecomes prominent within 2 to 5 minutes that could last up to 15days. The labeled Evans blue albumin (EBA) spreads up to onesegment from the injury site. Traumatic injuries resulting inpermanent paraplegia increase tissue water content above and belowthe lesion site. Adjacent spinal cord segments also exhibit leakage of 106
  • 108. albumin and dextran as well as tissue damage. On the other hand,transient paraplegia is not associated with extravasation of albuminor dextran and/or increase in spinal cord water content (Sharma,2003). Edema, as measured by water content is seen as early as 5 minutesafter impact injury that persisted up to 15 days. The edemaformation is most prominent in the gray matter. On the other hand,using specific gravity gradient column, about 127 % increase inedema and volume swelling was observed near the impact site in thegray matter compared to only 24 % increase in white matter after 1hour injury. The regression of edema is evident after 9 days. Thisindicates that progression, persistence and resolution of edema arecrucial for cell and tissue injury following SCI (Li & Tator, 1998). Local microhaemorrhage and tissue necrosis near the lesion sitealso influence increase in the water content. Increased tissue watercontent in the adjacent non-traumatised segment, thus represents trueedema formation. Tissue pressure gradients develop within 1 or 2hours after primary injury between the lesioned site and the remoteareas in both rostral and caudal directions. The tissue pressuregradients influence spread of edema fluid across the spinal cord(Sharma, 2002). Profound edema development is seen within 30 min after SCI nearthe lesion site that is progressive with time. Interestingly, the caudalsegments exhibited more pronounced edema development comparedto the rostral segments indicating that release of neurochemicals and 107
  • 109. BSCB breakdown following SCI influences edema formation(Mautes et al, 2000).  Treatment Strategies in Spinal Cord Injury:There are reasons to believe that BSCB could be an important targetfor the drugs used to treat SCI induced cell injury and sensory-motorrecovery. However, the current pharmacological strategies are notwell focused on the changes in the BSCB function after trauma inrelation to cord pathology or the functional outcome (Sharma,2003). The altered spinal cord microenvironment appears to be one of thekey factors in neuroprotection or sensory-motor recovery followingSCI. It is quite likely that drugs or therapeutic agents that offerneuroprotection are able to minimize the BSCB disturbances. Thepotential of these therapeutic agents in the treatment of SCI is thesubject of many researches. The main treatment strategies in spinalcord injury can be summarized in (table 5) (Hagg & Oudega, 1998). 108
  • 110. Table. 5: Treatment Strategies in Spinal Cord Injury: 1) Neuroprotective approach: directed against interrupting the cascade of secondary injury processes. limiting tissue damage. arrest or reverse sensory/motor function impairment. 2) Rehabilitating approach: directed against consequences of spinal cord injury stabilization of current status with trauma training of reflexes and residual circuits for optimal living conditions 3) Regenerative approach: directed towards enhancement of axonal regeneration purely experimental at this stage no experience in human spinal cord injury (Sharma, 2003)  Pharmacology of the BSCB in spinal cord injury: The pharmacological strategies in SCI are used to influence theprocess of secondary injury cascade to limit tissue damage and toimprove sensory-motor function. Another pharmacological aspect inSCI is to enhance axonal regeneration. This can either be achievedusing neurotrophic factors or blocking regeneration inhibitingfactors. There are many therapeutic aspects that can be used, andwill be summarized: 109
  • 111. 1) Neurotrophic factors: Neurotrophic factors and their receptors are present in thedeveloping and adult spinal cord. The neurotrophin receptorsinfluence neuronal survival by modulation of neurotransmitters,neuropeptides as well as their release in the spinal cord. Thereceptors for both neurotrophins and cytokines are located onneurons, glial cells, inflammatory cells, meninges, and blood vesselsin scar tissue. There are evidences that neurotrophins effect signalingof cytokines (Oudega & Hagg, 1999). Brain derived neurotrophic factor (BDNF) and insulin like growthfactor 1 (IGF-1) are members of neurotrophins family and induceneuroprotection during ischemia and trauma. Exogenous supplementof growth factors induces neuroprotection either by neutralizing theinfluence of neurodestructive agents or by enhancing the influenceof neuroprotective substances. Pretreatment with BDNF or IGF-1markedly attenuated the occurrence of gross visual swelling afterinjury without influencing microhaemorrhages (Ruitenberg et al,2003). Attenuation of the BSCB permeability with neurotrophinsindicates their involvement in the secondary injury mechanismsfollowing trauma. A reduction in BSCB permeability reducesleakage of plasma proteins and thus able to prevent vasogenic edemaformation (Lu & Waite, 1999). 110
  • 112. 2) Tumor necrosis factor alpha (TNF-) antiserum: In the CNS, tumor necrosis factor alpha (TNF-) is a cytotoxiccytokine 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 inducesneuroprotection by neutralizing the effects of endogenous TNF-(Lee et al, 2000). 3) Nitric oxide synthase antiserum: Treatment with nitric oxide synthase (NOS) antiserum resulted ina decrease in peptide or protein extravasation across the BSCBfollowing trauma. This indicates that NOS activation increases NOproduction that disrupts the BSCB through intracellular signaltransduction. To further establish the therapeutic values of the NOSantiserum, studies using its application at longer time intervalsfollowing SCI on the BSCB breakdown and cell injury are needed(Hooper et al, 2000). 4) Antioxidant compounds: Microhaemorrhages and extravasation of blood componentscaused by SCI is one of the important sources of oxidative stress andgeneration of free radicals that disrupt myelin sheaths and inducecell damage, hemoglobin is an important source of iron to catalyzeoxygen radicals and lipid peroxidation (Calbrese et al, 2000). Treatment with one potent chain-breaking antioxidant compoundH-290/51 attenuated trauma induced BSCB disruption to Evans blue 111
  • 113. albumin (EBA) and radioiodine tracers. These observations suggestthat lipid peroxidation and generation of free radicals contributes tothe BSCB breakdown in SCI (Mustafa et al, 1995). A significant reduction in water content and mild perivascularedema, swelling of nerve cells and myelin vesiculation at theultrastructural level in the drug treated group supports this idea(Tong et al, 1998). 5) Prostaglandins: The precursor of prostaglandins (PGs) arachidonic acid and itsmetabolite are involved in the secondary injury processes.Pretreatment with indomethacin, a potent inhibitor ofcyclooxygenase enzyme, significantly attenuated edema formationand cell damage. These results support a role of PGs in theendothelial cell membrane permeability. Whether the effects of PGson BSCB permeability are mediated by specific PG receptors, arestill unclear (Leskovar et al, 2000). 6) Bradykinin (BK): Blockade of BK2 receptor antagonist slightly but significantlyreduced the breakdown of the BSCB to EBA, radioiodine andlanthanum tracers. Edema formation and cell injury in the drugtreated traumatized cord are considerably reduced. Theseobservations demonstrate that bradykinin is involved in thebreakdown of the BSCB permeability probably through BK2receptors (Bogar et al, 1999). 112
  • 114. 7) Opioid Peptides: Opioid and non opioid neuropeptides, together with monoaminesand amino acids play integral roles in the neurotransmission in thespinal cord. Intrathecal or systemic administration of selective -opioid antagonist nor-binaltrophimine (nor-BNI) enhancesneurological recovery after spinal cord trauma suggests aninvolvement of - opioid receptors in SCI (Tang et al, 2000). The natural ligand of the - opioid receptors, dynorphin that iswell known to participate in the pathophysiology of SCI supportsthis idea. Treatment with dynorphin A (1–17) antiserum improvesthe neurological outcome after SCI, At 5 h the gross swellings of thespinal cord, BSCB disruption and edema formation are significantlyreduced. Trauma induced cell injury; myelin vesiculation andmembrane disruption are also reduced by dynorphin antiserum(Hauser et al, 2001). 8) Adrenergic receptor blockers: On the basis of norepinephrine accumulation in the traumatizedcord, role of catecholamines in SCI was suggested by Osterholm andMathews. However, inhibition of catecholamines synthesis with -methyltyrosine; or blockade of - adrenergic receptor with clonidineyielded 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 113
  • 115. yielded that: pretreatment with - or - adrenergic receptor blockersdid not attenuate BSCB permeability and edema formation. Thus,further studies using adrenoceptor agonists are needed to clarify theinvolvement of catecholamines in SCI (Winkler et al, 1998). 114
  • 116. Summary The concept of cerebral edema has been recognized for morethan 2000 years, yet an understanding of the complex physiology ofthis condition has evolved only within the past 30 years.Hippocrates noted that removal of the overlying skull bonesallowed the injured brain to swell outward, thus minimizingcompression 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 secretedfrom the blood vessels ... a quantity of blood equal in bulk to theeffused matter, will be pressed out of the cranium.’’ This indiscriminate concept of brain swelling was cited in adiverse range of clinical settings until 1967, when Igor Klatzodefined the modern classification of edema based onpathophysiology. Cerebral edema, according to Klatzo, was definedas ‘‘an abnormal accumulation of fluid associated with volumetricenlargement of the brain.’’ This entity was divided into vasogenic edema, characterized byderangement of the blood–brain barrier (BBB), and cytotoxicedema, related to intracellular swelling in the absence of changes atthe BBB. Klatzo emphasized that these two forms usuallycoexisted. 115
  • 117. In 1975, Robert Fishman added interstitial edema as a distinctentity by describing the transependymal flow of cerebrospinal fluid(CSF) into the periventricular white matter in individuals withacute obstructive hydrocephalus; this form was later termedhydrocephalic edema. This classification is highly simplistic, given that it pertains tocomplex pathophysiological and molecular mechanisms, but isvaluable as a simple therapeutic guide for treatment of cerebraledema. Most brain insults involve a combination of thesefundamental subtypes of edema, although one can predominatedepending on the type and duration of injury. Cytotoxic edema results from swelling of the cellular elements(neurons, glia, and endothelial cells) because of substrate andenergy failure, and affects both gray and white matter. This edemasubtype is conventionally encountered in: cerebral ischemia,traumatic brain injury, infections, and metabolic disordersincluding kidney and liver failure. Vasogenic edema that results from breakdown of the BBB due toincreased vascular permeability, as commonly encountered in:hemorrhage, later stages of brain infarction, TBI, infections,seizures, trauma, tumors, radiation injury and hypertensiveencephalopathy, 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 116
  • 118. intoxication that may be responsive to osmotherapy but resistant tosteroid administration. Interstitial edema, a consequence of impaired absorption of CSF,leads to increases in transependymal CSF flow, resulting in acutehydrocephalus. This edema subtype is also not responsive to steroidadministration, and its response to osmotherapy is debatable. In osmotic edema there is an osmotic gradient which is presentbetween plasma and the extracellular fluid. Edema may occur witha number of hypo-osmolar conditions including: improperadministration of intravenous fluids leading to acute dilutionalhyponatremia, inappropriate antidiuretic hormone secretion,excessive hemodialysis of uremic patients and diabeticketoacidosis. Basic information about the types of edema is provided for betterunderstanding of the expression pattern of some of the newermolecules implicated in the pathogenesis of brain edema. Thesemolecules include the aquaporins (AQP), matrix metalloproteinases(MMPs) and growth factors such as vascular endothelial growthfactors (VEGF) A and B and the angiopoietins. The potential ofthese agents in the treatment of edema is the subject of manyreviews. Blood-spinal cord barrier (BSCB) plays an important role in theregulation of the fluid microenvironment of the spinal cord. Traumato the spinal cord impairs the BSCB permeability to proteinsleading to vasogenic edema formation. Several endogenous 117
  • 119. neurochemical mediators and growth factors contribute to traumainduced BSCB disruption. Studies carried out suggest that those drugs and neurotrophicfactors capable to attenuate the BSCB dysfunction followingtrauma are neuroprotective in nature. Whereas, agents that do notexert any influence on the BSCB disruption failed to reduce cellinjury. These observations are in line with the idea that BSCBdisruption plays an important role in the pathophysiology of spinalcord injuries. Neuroimaging by CT scans and magnetic resonance imaging canbe particularly useful in confirming intracranial compartmental andmidline shifts, herniation syndromes, ischemic brain injury, andexacerbation of cerebral edema (sulcal effacement and obliterationof basal cisterns). The consequences of cerebral edema can be lethal and includecerebral ischemia from compromised regional or global cerebralblood flow (CBF) and intracranial compartmental shifts due tointracranial pressure gradients that result in compression of vitalbrain structures. The overall goal of medical management ofcerebral edema is to maintain regional and global CBF to meet themetabolic requirements of the brain and prevent secondaryneuronal injury from cerebral ischemia. Medical management of cerebral edema involves using asystematic and algorithmic approach, from general measures(optimal head and neck positioning for facilitating intracranial 118
  • 120. venous outflow, avoidance of dehydration and systemichypotension, and maintenance of normothermia) to specifictherapeutic interventions (controlled hyperventilation,administration of corticosteroids and diuretics, osmotherapy, andpharmacological cerebral metabolic suppression). 119
  • 121. Discussion: Hence the significance of brain edema, which continues to be amajor cause of mortality after diverse types of brain pathologies, thelack of effective treatment, remains a stimulus for continued interestand research into the pathogenesis of this condition (Kempski,2001). Though there has been good progress in understanding ofpathophysiological mechanisms associated with cerebral edemamore effective treatment is required and is still awaited (Marmarouet al, 2006). Certainly, the “ideal” agent for the treatment of cerebral edema-one that would selectively mobilize and / or prevent the formation ofedema fluid with a rapid onset and prolonged duration of action, andwith 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 mostof the therapeutic agents and interventions currently used are notfully elucidated (Ahmed & Anish, 2007). Research in the last decade has led to an appreciation of thecomplexity of brain edema pathogenesis and to the awareness thatmany molecules are involved acting simultaneously or at differentstages during the edema process (Johnston & Teo, 2000) 120
  • 122. This suggests that effective treatment of brain edema cannot beachieved by a single agent, but will require the administration of a‘‘magic bullet’’ containing a variety of agents released at differenttimes during the course of edema in order to be successful(Alejandro & Rabinstein, 2006) Although protocols and algorithms exist to treat brain edemaassociated with specific neurologic entities, these are not based onrigorous scientific data (Kimelburg, 2004). Current uncertainties and deficiencies must be resolved bycontinuing research, fueled by growing understanding of thepathophysiological processes responsible for the formation of thedifferent forms of brain edema (Nag, 2003) b. Probably in the days to come we can look forward to neweragents specifically acting on the various chemical mediatorsinvolved in the pathogenesis of cerebral edema (Kuroiwa et al,2007). Traumatic insults to the spinal cord disrupt the functionalintegrity of the blood-spinal cord barrier (BSCB) and results into anincreased transport of several substances from the vascularcompartment to the spinal cord cellular microenvironment.Transport of macromolecules like proteins from the vascularcompartment to the spinal cord microenvironment induces vasogenicedema (Sharma, 2003). New pharmacotherapeutic agents and compounds that reducetrauma induced alterations in the BSCB and cell injury may 121
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