Brain EdemaFrom the Laboratory Bench to the Bedside

Hong Kong Neurosurgical SocietyMonthly Wednesday Morning Meeting

8th December 2010Peter Woo

Chairman: Dr. KY Chan

Pathophysiology The Role of Corticosteroids

Trauma StrokeTumors

Novel therapies

Pathophysiology

Swelling vs. Edema

Swelling: ↑ volume occupied by a given mass e.g. by a tumor, blood or edema.

Addition of a new constituent into the extracellular space of the brain i.e. requires active blood flow.

Simard JM et al. Brain oedema in focal ischemia: molecular physiology and theoretical implications. Lancet Neurol 2007;6:258-268

Excessive accumulation of absolute cerebral tissue water content in the intracellular and/or extracellular spaces1.

ECS: 12-19% of brain volume2

1 Pollay M. Blood-brain barrier, cerebral edema. In: Wilkins RH, Rengachary SS, editors. Neurosurgery 2nd ed. New York: McGraw Hill Book Co., 1996;335-442 Go KG. The normal and pathological physiology of brain water. Adv Tech Stand Neurosurg 1997;23:47-142 3 Klatzo I. Presidential address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 1967 26:1-144 Fishman RA et al. Brain edema. N Eng J Med 1975;293(14):706-11

Vasogenic Cytotoxic Interstitial (hydrocephalic)4

Klatzo et al, 19673

Brain Edema

Starling’s Law and Brain Edema

Permeability pore

Driving forceHydrostatic pressure gradient

Osmotic pressure gradient+

Ion channels + Reverse pinocytosisEndothelial tight juncitons

Hydrostatic pressure gradient

Causes of Brain EdemaVasogenic Cytotoxic Hydrocephalic

(“Interstitial”)

Brain tumor Vascular Early hypoxia Early ischemia

Obstructive

Vascular Late hypoxia Late ischemia

Traumatic Communicating

Traumatic Infection

Infection Meningitis Encephalitis Abscess

Metabolic Hyponatremia Hyperammonemia Hyperbilirubinemia Diabetic ketoacidosis Uremia

Starling’s Principle of Edema Formation

• The driving force: the sum of the hydrostatic and the osmotic pressure gradients.

• The permeability pore: the passages through and between the BBB endothelial cells.

Starling EH et al. On the absorption of fluids from connective tissue spaces. J Physiol 1896;19:312-26

Vasogenic edema

Interstitial edema

Cytotoxic edema

↑ intraventricular pressureTrans-ependymal movementParaventricular tissue Extracellular

Commonest type↑ BBB permeability / BBB breakdownTrans-endothelial movementWhite matterExtra-cellular

Failed ATP-ion pumpBreakdown of ion gradientsTrans-membranous movement Grey matter first Intracellular-Extracellular

Vasogenic Edema

• Primary disturbance: endothelial dysfunction

• Increased vascular permeability of the BBB.

Incompetent BBB

Influx of solutes and fluid through an incompetent BBB into the extracellular space

Marmarou A et al. Distinguishing between cellular and vasogenic edema in head injured patients with focal lesions using magnetic resonance imaging. Acta Neurochir Suppl 2000; 76:349-351

Tumor-related Brain Edema

Capillary ultrastructural abnormalities

Paracrine signal pathwaysVEGFNO PGE2

Macrophage infiltration

Aquaporin expression

Stummer W. Mechanisms of tumor-related brain edema. Neurosurgical Focus 2007;22(5):E8 1-7

Normal Capillary Ultrastructure

Normal tight junction

Smooth basal lamina

Shibita S. Ultrastruture of capillary walls in human brain tumors. Acta Neuropathol 1989; 78:561-571.

Normal

Normal TJ

Smooth BL

Normal sealing strands

Irregular BL

Endothelial hyperplasia + infolding

Elongated irregular sealing strands

Fenestrations

GBM

↑ Pinocytic vesicles

Meningioma

Thinned endothelium + fenestrations

Fenestrations

Thinned endothelium + fenestrations

Increased number of pinocytic vesicles

Metastatic Tumor

↓ junctional adhesion molecules

FISH studies for GBM microvessels

1 Wolburg H et al. Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 2003;105(6):586-592 2 Papadopoulos MC et al. Loss of occludin expression: possible cause of brain tumour oedema. Soc Br Neurol Surg Meeting, Glasgow, Scotland, 2000 (Abstr.)

Decreased expression of function of adhesion proteins leads to tight junction opening and edema in astrocytomas and GBM1.Adenocarcinomas do not express occludin2.

Control

Control GBM

GBM

Paracrine Signal Pathways: VEGFVEGF binds to VEGFR-1 and -2

Tyrosine kinase mediated downstream cell signaling

↓Stimulates tumor cell mitosis,

angiogenesis and vascular permeability

VEGF 1000 times more potent than histamine1

Upregulation of VEGF in edema associated tumors: GBM, meningiomas and metastases2

Phosphorylation of occludin impairing its function3

Topical application of VEGF induces endothelial fenestration4

1 Machein MR et al. VEGF in brain tumors. Journal of Neuro-oncology 2000; 50:109-1202 Nishikawa R et al. Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 1998 96:453-462 3 Stummer W. Mechanisms of tumor-related brain edema. Neurosurgical Focus 2007;22(5):E8 1-74 Roberts WG et al. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 1997;57:765-772

Phosphorylation of TJ Proteins

Papadopoulos MC et al. Emerging mechanisms of brain tumor oedema. Br J Neurosurg 2001;15(2): 101-108

Differing VEGF Associations for Meningiomas and Gliomas*

Meningioma Glioma

Correlation with VEGF mRNA and peri-tumoral

edemaY Y

VEGF expression associated with tumor grade N

Y(High grade x50 more

than low grade)

VEGF expression regulation PDGF, EDGF, Estrogen Hypoxia

VEGF cell expression All tumor cells Peri-necrotic tumor cells * References section

AquaporinsTransmembrane channel proteins highly selective for the transport of H2O.

Bidirectional flow.

H2O transport by osmotic and hydrostatic gradients.

Positively charged arginine AA

Agre P et al. The aquaporin water channels. Proc Am Thorac Soc 2006;3(1):5–13.

Distribution of Cerebral Aquaporins

Amiry-Moghaddam et al. The molecular basis of water transport in the brain. Nature Reviews Neuroscience 2003;4:991-1001.

Aquaporin-4Endothelial astrocytic foot processes

Amiry-Moghaddam et al. The molecular basis of water transport in the brain. Nature Reviews Neuroscience 2003;4:991-1001.

AQP-4

AQP-4 Upregulation

Normal brain tissue

High grade glioma

Metastatic adenocarcincoma

Saadoun S et al. Peritumoral edema in meningiomas. A radiological and histological study. J Neurol Neurosurg Psy 2002;72:262-65.

Papadopoulos MC et al. Aquaporin-4 facilitates resorption of excess fluid in vasogenic brain edema. FASEB J 2004;18:1291-1293

Aquaporin-4 ameliorates Vasogenic Edema?

Bulk-flow in Tumor-related EdemaTumor associated edema propagates by bulk flow instead of simple diffusion.

White matter resistance < grey matter

∴ finger-like projections throughout white matter.

Reulen HJ et al. Role of pressure gradients and bulk flow in dynamics of vasogenic edema. J Neurosurg 1977;46:24-35

Rate of edema fluid accumulation: 0.5-3.2ml/hour or 14-78ml/day Speed of edema spread: 1.9mm/hour

Reulen HJ et al. Peritumoral brain edema. A keynote address. Adv Neurol 1990;52:307-315

Papadopoulos MC et al. Aquaporin-4 and brain edema. Pedia Nephrol 2007;22:778-84.

Brain Edema Fluid Resorptive Mechanisms medicated by AQP-4

Meningiomas and Peritumoral Edema

Up to 60% are associated with BE11.Risk factors2:

SizeLocationHistological subtype

1 Bradac GB et al. Peritumoral edema in meningiomas. A radiological and histological study. Neuroradiology 1986;28:304-3122 Bitzer M et al. Role of hydroceynamic procceses in the process of peritumoral edema in meningiomas. J Neurosurg 2000;93:594-6043 Tamiya T et al. Peritumoral brain edema in intracranial meningiomas. Effects of radiological and histological factors. Neurosurgery 2001;45(5)1046-1052

Disintegration of the arachnoid layer between the tumor-brain interface3

Pial-cortical blood supply to tumor (? VEGF)3

Meningiomas and Peritumoral Edema

Proposed mechanisms: Ischemia1

Venous congestion2

Excretory-secretory phenomena3

Hydrodynamic processes with leptomeningeal disintegration4

1 Tatagiba M et al. Peritumoral blood flow in intracranial meningiomas. Neurosurgery 1991;28:401-4042 Hiyama H et al. Meningiomas associated with peritumoral venous stasis: three types on cerebral angiogram. Acta Neurochir 1994;129:31-38 3 Phillippon J et al. Cerebral edema associated with meningiomas: possible role of a secretary-excretory phenomenon. Neursurgery. 1984;14:295-3014 Ito et al. Peritumoral edema in meningiomas: a contrast enhanced CT study. Acta Neurochir Suppl. 1994;60:361-364

Meningiomas and Peritumoral Edema

↑Tumor osmotic pressure

Pial blood supply

Secretory substances: VEGF

Rare group of WHO Grade I meningiomas (3%): secretory Epithelial differention with intracellular inclusions of CCK, CEA, alpha-1 antitrypsinIncidence of surrounding edema 80% Edema encompassed the entire hemisphere in 64% of cases

Proubst-Cousin S et al. Secretory meningioma. Clinical, histological and immunohistochemical findings in 31 cases. Cancer 1997;79:2003-2017

“...arguably the greatest translational research contribution in the history of neurosurgery.1”

1 McClelland S III et al. Genesis of the use of corticosteroids in the treatment and prevention of brain edema. Neurosurgery 2008; 62(4):965- 968.2 Prados et al. Studies on cerebral edema. Reaction of the brain to exposure to air; physiologic changes. Arch Neurol Psychiatry 1945; 54:290-300.

Dr. Joseph H. Galicich1958

1st year neurosurgical residentUniversity of Minnesota

Mice: Circadian periodicity in brain uptake of

fluorescein vs. reciprocal of adrenal corticosteroid rhythm.

Dogs and Galicich himself:40mg dexamethasone via:

Oral Intracarotid Intravenous

Intramuscular

GALICICH, J. H. & FRENCH, L. A. 1961. Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Pract Dig Treat, 12, 169-74.

GALICICH, J. H., FRENCH, L. A. & MELBY, J. C. 1961. Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet, 81, 46-53.

October 1959: Semicomatose hemiparetic patient with

recurrent temporal GBM→ improved limb power

Initial regimen:10mg Q6hDose-response curve: maximum

improvement with 4mg Q6h

Cortisol levels same

Mechanisms of Action

• Not yet understood. • ↓ edema formation. No effect on

absorption. • Increases capillary permeability within 1

hour.1

• Reaches full effect within 24-72 hours.2

1 SHAPIRO, W. R., HIESIGER, E. M., COONEY, G. A., BASLER, G. A., LIPSCHUTZ, L. E. & POSNER, J. B. 1990. Temporal effects of dexamethasone on blood-to-brain and blood-to-tumor transport of 14C-alpha-aminoisobutyric acid in rat C6 glioma. J Neurooncol, 8, 197-204.

2 KAAL, E. C. & VECHT, C. J. 2004. The management of brain edema in brain tumors. Curr Opin Oncol, 16, 593-600.

Promotion of BBB Stability Astrocytes and Pericytes

HEISS, J. D., PAPAVASSILIOU, E., MERRILL, M. J., NIEMAN, L., KNIGHTLY, J. J., WALBRIDGE, S., EDWARDS, N. A. & OLDFIELD, E. H. 1996. Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J Clin Invest, 98, 1400-8.

MACHEIN, M. R., KULLMER, J., RONICKE, V., MACHEIN, U., KRIEG, M., DAMERT, A., BREIER, G., RISAU, W. & PLATE, K. H. 1999. Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol Appl Neurobiol, 25, 104-12.

KIM, H., LEE, J. M., PARK, J. S., JO, S. A., KIM, Y. O., KIM, C. W. & JO, I. 2008. Dexamethasone coordinately regulates angiopoietin-1 and VEGF: a mechanism of glucocorticoid-induced stabilization of blood-brain barrier. Biochem Biophys Res Commun, 372, 243-8.

CHAN, P. H., FISHMAN, R. A., CARONNA, J., SCHMIDLEY, J. W., PRIOLEAU, G. & LEE, J. 1983. Induction of brain edema following intracerebral injection of arachidonic acid. Ann Neurol, 13, 625-32.

↓ VEGF↑Angiopoietin-1 Extra-GR pathways?

Arachidonic acid cascade Peroxidative damage to

cell membranesInhibits phospholipase A2

AA

VECHT, C. J., HOVESTADT, A., VERBIEST, H. B., VAN VLIET, J. J. & VAN PUTTEN, W. L. 1994. Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day. Neurology, 44, 675-80.

Single center double-blind RCT96 patients with 8 weeks FU

Low dose (4mg/day) vs. high dose (16mg/day)

After 1 week: 4mg/day is as effective as 16mg/day in patients, with no impending signs of brain herniation, in terms of KPS.

Novel TherapiesCorticotrophin-releasing factor (CRF)

Direct effect on BBB.No ↑ in systemic adrenal corticosteroids.1

Symptom improvement with reduced edema on MRI.2

1 TJUVAJEV, J., KOLESNIKOV, Y., JOSHI, R., SHERINSKI, J., KOUTCHER, L., ZHOU, Y., MATEI, C., KOUTCHER, J., KREEK, M. J. & BLASBERG, R. 1998. Anti-neoplastic properties of human corticotropin releasing factor: involvement of the nitric oxide pathway. In Vivo, 12, 1-10.

2 VILLALONA-CALERO, M. A., ECKARDT, J., BURRIS, H., KRAYNAK, M., FIELDS-JONES, S., BAZAN, C., LANCASTER, J., HANDER, T., GOLDBLUM, R., HAMMOND, L., BARI, A., DRENGLER, R., ROTHENBERG, M., HADOVSKY, G. & VON HOFF, D. D. 1998. A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema. Ann Oncol, 9, 71-7.

4 PORTNOW, J., SULEMAN, S., GROSSMAN, S. A., ELLER, S. & CARSON, K. 2002. A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomas. Neuro Oncol, 4, 22-5.

5 DEL MAESTRO, R. F., MEGYESI, J. F. & FARRELL, C. L. 1990. Mechanisms of tumor-associated edema: a review. Can J Neurol Sci, 17, 177-83.

VEGF inhibitors

COX-2 inhibitorsRofecoxib as effective as dexamethasone in decreasing BBB permeability.4

Indomethacin improved KPS in 40% of patients.5

Stroke-related Brain Edema

Severe hypoxiaNear critical hypoxia

Normoxia

Ionic edema occurs in the peri-infarct tissues i.e. in areas of perfused but severely ischemic tissues (“penumbra”).Relatively little edema within the infarct core.

[Na+] 142[K+] 5

[Ca-] 103

[Na+] 138[K+] 5

[Ca-] 105Extracellular space

Blood

Cell ATP

[Na+]

[K+]

[Na+] 14[K+] 157[Ca-] 0

[Na+]

[K+]

What cell is this? glial neuron?

H2O

Cytotoxic edema = Cellular edema = Oncosis = Oncotic

volume increase

Ionic edema

[Na+]

[Ca-]

H2O

↑↑↑

Edema and the Ischemic Brain

Cytotoxic edema Vasogenic

Primary drivers: [Na+] Secondary participants:

H2O, [Ca-]

Cytotoxic edema

Cell

[Na+]

KLEFFNER, I., BUNGEROTH, M., SCHIFFBAUER, H., SCHABITZ, W. R., RINGELSTEIN, E. B. & KUHLENBAUMER, G. 2008. The role of aquaporin-4 polymorphisms in the development of brain edema after middle cerebral artery occlusion. Stroke, 39, 1333-5.

↑ Aquaporin H2O

ATP

[Na+]

[K+]

↑ Sulfonylurea receptor-1 (SUR-1) regulated NCCa-ATP channel

SIMARD, J. M., CHEN, M., TARASOV, K. V., BHATTA, S., IVANOVA, S., MELNITCHENKO, L., TSYMBALYUK, N., WEST, G. A. & GERZANICH, V. 2006. Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med, 12, 433-40.

↑ Transient receptor potential channel (TRPC)

AARTS, M. M. & TYMIANSKI, M. 2005. TRPMs and neuronal cell death. Pflugers Arch, 451, 243-9.

Ionic

↑ NKCC

LIANG, D., BHATTA, S., GERZANICH, V. & SIMARD, J. M. 2007. Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus, 22, E2.

Scanning Electron Microscopy of Freshly Isolated Rat Astrocytes after NaN3-induced ATP depletion

Control 5 min 25 minSIMARD, J. M., CHEN, M., TARASOV, K. V., BHATTA, S., IVANOVA, S., MELNITCHENKO, L., TSYMBALYUK, N., WEST, G. A. & GERZANICH, V. 2006. Newly expressed

SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med, 12, 433-40.

Cell

Blood

[Na+]

[Na+]

H2O

Neuron / astrocyte Necrotic Cell Death

↑ Extracellular volumeIonic edema

[Na+] electrical gradient still preserved ∵ICS >> ECS[K+] bound to -ve charged intracellular proteins

[K+]=Protein-

Young et al. Ionic water shifts in injured central nervous system tissues. In: Salzman SK, Faden AI, eds. The Neurobiology of Central Nervous System Trauma. New York: Oxford University Press;1994,123-30

Vasogenic Cytotoxic edema IonicIonic

Ionic edema involves abnormal [Na+] transport with normal exclusion of protein by the “intact” BBB.Precedes vasogenic edema by >6 hours.

GOTOH, O., ASANO, T., KOIDE, T. & TAKAKURA, K. 1985. Ischemic brain edema following occlusion of the middle cerebral artery in the rat. I: The time courses of the brain water, sodium and potassium contents and blood-brain barrier permeability to 125I-albumin. Stroke, 16, 101-9.

Ionic Vasogenic

Endothelial dysfunction: breakdown of the BBB allowing passage of macromolecules e.g. albumin.

Brain Edema Imaging Techniques

Edema/ MRI sequence DWI ADC

Cytotoxic

Vasogenic

↑

↑ ↑

↓

SEVICK, R. J., KANDA, F., MINTOROVITCH, J., ARIEFF, A. I., KUCHARCZYK, J., TSURUDA, J. S., NORMAN, D. & MOSELEY, M. E. 1992. Cytotoxic brain edema: assessment with diffusion-weighted MR imaging. Radiology, 185, 687-90.

Ischemia-induced Vasogenic Edema

Endothelial cell retraction1

Thrombin

Uncoupling of TJ : interendothelial gaps

VEGF

Phosphorylation of TJ proteins2

Basement membrane degradation3

MMP-9 MMP-2

1 HUA, Y., WU, J., KEEP, R. F., HOFF, J. T. & XI, G. 2003. Thrombin exacerbates brain edema in focal cerebral ischemia. Acta Neurochir Suppl, 86, 163-6.

3 ROMANIC, A. M., WHITE, R. F., ARLETH, A. J., OHLSTEIN, E. H. & BARONE, F. C. 1998. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke, 29, 1020-30.

2 VAN BRUGGEN, N., THIBODEAUX, H., PALMER, J. T., LEE, W. P., FU, L., CAIRNS, B., TUMAS, D., GERLAI, R., WILLIAMS, S. P., VAN LOOKEREN CAMPAGNE, M. & FERRARA, N. 1999. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest, 104, 1613-20.

Brain

Blood

Ischemia-induced Vasogenic Edema

Permeability pore

Driving forceHydrostatic pressure gradient

Osmotic pressure gradient+

BBB breakdown

Systemic BP ICP

All osmotically active molecules

Timing of Decompressive Craniectomy ?

“...surgical decompression reduces case fatality and poor outcome... within 48 hours of stroke

onset....no evidence...when it is delayed up to 96 hours after stroke onset.”

HOFMEIJER, J., KAPPELLE, L. J., ALGRA, A., AMELINK, G. J., VAN GIJN, J. & VAN DER WORP, H. B. 2009. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurol, 8, 326-33.

Early Decompressive Craniectomy ?

Ionic edema stage BBB intact

Hydrostatic pressure less important for edema

formation

Vasogenic edema stageBBB violated ↓ICP →↑CPP

Hydrostatic pressure major contributor to edema

formation

Intracerebral Hemorrhage

THIEX, R. & TSIRKA, S. E. 2007. Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus, 22, E6.

Few hours

24-48 hours

Hematoma retraction

Coagulation cascadeThrombin induced BBB disruption

RBC lysis Hb and other degradation products

Inflammatory reaction

CBF in the ICH vicinity remains close to normal1.

1 XI, G., HUA, Y., BHASIN, R. R., ENNIS, S. R., KEEP, R. F. & HOFF, J. T. 2001. Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke, 32, 2932-8.

2 YANG, G. Y., BETZ, A. L., CHENEVERT, T. L., BRUNBERG, J. A. & HOFF, J. T. 1994. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg, 81, 93-102.

3 NATH, F. P., KELLY, P. T., JENKINS, A., MENDELOW, A. D., GRAHAM, D. I. & TEASDALE, G. M. 1987. Effects of experimental intracerebral hemorrhage on blood flow, capillary permeability, and histochemistry. J Neurosurg, 66, 555-62.

Peri-hematomal Edema Not Associated with Ischemia

Peri-hematomal edema zone ATP levels up to 8

hours after ictus: normal4.

4 WAGNER, K. R., XI, G., HUA, Y., KLEINHOLZ, M., DE COURTEN-MYERS, G. M. & MYERS, R. E. 1998. Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hemorrhage. J Neurosurg, 88, 1058-65.

0

12.5

25

37.5

50

0 1 2 3 4

Nath FP et al., 1987Yang GY et al., 1994

Ischemic Threshold 15-20

Time, hoursC

BF, m

l/100

gm/m

in

2

3

Loss of cellular homeostasis <10

Thrombin induced interendothelial gaps.Release of Fe2+ released from heme. Catalyst for lipid perioxidation ➝ free radical damage to endothelial cells

Peri-hematomal Edema

Vasogenic Cytotoxic

Degradation products Hb inhibits Na/K ATPase activity.Bilirubin disrupts ion transport and mitochondrial activity.

Oxy-hb: vasospasm

SADRZADEH, S. M., ANDERSON, D. K., PANTER, S. S., HALLAWAY, P. E. & EATON, J. W. 1987. Hemoglobin potentiates central nervous system damage. J Clin Invest, 79, 662-4.

XI, G., HUA, Y., BHASIN, R. R., ENNIS, S. R., KEEP, R. F. & HOFF, J. T. 2001. Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke, 32, 2932-8.

HUANG, F. P., XI, G., KEEP, R. F., HUA, Y., NEMOIANU, A. & HOFF, J. T. 2002. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg, 96, 287-93.

Iron chelator Can cross the BBB ↓ Hb induced Na/K ATPase inhibition ↓ Fe induced lipid peroxidation

↓ ICH brain edema in rats after intra-peritoneal deferoxamine infusion

HUANG, F. P., XI, G., KEEP, R. F., HUA, Y., NEMOIANU, A. & HOFF, J. T. 2002. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg, 96, 287-93.

REGAN, R. F. & PANTER, S. S. 1993. Neurotoxicity of hemoglobin in cortical cell culture. Neurosci Lett, 153, 219-22.

Subarachnoid HemorrhageGlobal cerebral edema7-12% of SAH Significant independent predictor of mortality and poor outcome (adjusted OR 2.5). Death at 3 months 40% vs. 18%1. RBC degradation componentsHyponatremia

1 CLAASSEN, J., CARHUAPOMA, J. R., KREITER, K. T., DU, E. Y., CONNOLLY, E. S. & MAYER, S. A. 2002. Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome. Stroke, 33, 1225-32.

No strong evidence

SAH

Global Ischemia

↑ICP

↓CBF

Cytotoxic edemaIonic edema

BBB breakdown

Vasogenic edema

Vasospasm

“3H” therapy(loss of autoregulation)

MOCCO, J., PRICKETT, C. S., KOMOTAR, R. J., CONNOLLY, E. S. & MAYER, S. A. 2007. Potential mechanisms and clinical significance of global cerebral edema following aneurysmal subarachnoid hemorrhage. Neurosurg Focus, 22, E7.

Steroids for Stroke?

1 DAVIS, S. M. & DONNAN, G. A. 2004. Steroids for stroke: another potential therapy discarded prematurely? Stroke, 35, 230-1.2 QIZILBASH N et al. Corticosteroids for acute ischemic stroke (Cochrane Review) The Cochrane Library, Issue 1, 2003. Oxford: Update Software; 2003. 3 POUNGVARIN, N. 2004. Steroids have no role in stroke therapy. Stroke, 35, 229-30.

Arguments For...

Animal studies1: Cats: MCA infarction volume ↑ x6-fold size in controls.Rats: pretreatment ↓ brain H2O content in global ischemia.

Cochrane Review2:Only 7 out of 22 studies. Only 453 patients.No uniform assessment.No trials conducted since 1986.

For ICH, only 3 studies.Only 159 patients.

Arguments Against...

Cochrane Review:Several RCTsNo beneficial effect. ↑ risk of complications.

Death within 1 year

Traumatic Brain Injury-related Edema

Brain Contusion

Delayed (several days)ICP static Peri-contusional area: white matter

Early (within 12-48 hours)↑ ICPContusion center

Rapid edema formation / “Malignant cerebral edema”

KAWAMATA, T., MORI, T., SATO, S. & KATAYAMA, Y. 2007. Tissue hyperosmolality and brain edema in cerebral contusion. Neurosurg Focus, 22, E5.

BRUCE, D. A., ALAVI, A., BILANIUK, L., DOLINSKAS, C., OBRIST, W. & UZZELL, B. 1981. Diffuse cerebral swelling following head injuries in children: the syndrome of "malignant brain edema". J Neurosurg, 54, 170-8.

But often not severe enough to cause early

mass effect

But often delayed 24-48h after injury

Cell[Idiogenic osmoles-]

Blood

Cytotoxic edema Vasogenic Cytotoxic edema Ionic

[Na+], [K+], [Cl-]

Contusion: ↑ tissue osmolality But [Na+], [K+], [Cl-] not altered

up till 12 hours post-trauma

Rapid disruption of the cell membrane

Homogenization of ICS and ECS contents

Products of cellular metabolism e.g. FFA

H2O

KAWAMATA, T., MORI, T., SATO, S. & KATAYAMA, Y. 2007. Tissue hyperosmolality and brain edema in cerebral contusion. Neurosurg Focus, 22, E5.KATAYAMA, Y. & KAWAMATA, T. 2003. Edema fluid accumulation within necrotic brain tissue as a cause of the mass effect of cerebral contusion in head trauma patients. Acta

Neurochir Suppl, 86, 323-7.KAWAMATA, T., KATAYAMA, Y., AOYAMA, N. & MORI, T. 2000. Heterogeneous mechanisms of early edema formation in cerebral contusion: diffusion MRI and ADC mapping

study. Acta Neurochir Suppl, 76, 9-12.

Other Mechanisms for TBI related-Edema

CellCell

[K+]

[Na+]

Ischemia:↓ ATP

Traumatic membrane depolarization:

Neurotransmitter release

[Glutamate][K+] [K+]

KATAYAMA Y. et al. Oedema fluid formation within contused brain tissue as a cause of medically uncontrollable elevation of intracranial pressure: the role of surgical therapy. Acta Neurochir Suppl (Wien) 51:308-310, 1990

PATRO A. et al Pathophysiology and treatment of traumatic brain edema. Indian Journal of Neurotrauma 2009, 6;1: 11-16

Blood

[PG]

PG release from injured vessels / platelets:

↑ capillary permeabilityVasoconstriction → ischemia

Indomethacin COX-2 inhibitor → limits vasogenic edema?*

* MOHANTY S, et al. Cerebral edema and blood brain and blood CSF barriers in experimental brain trauma: Effect of Indomethacin-a prostaglandin synthetase inhibitor. Ind J Physiol Pharma 1980; 24:90-96

[Na+]

[Na+]

Aquaporin-4 in TBI EdemaRole unknown

Contusion core: ? ↑1 OR ↓2

Peri-contusional tissue: ? ↓1 OR ↑2

New drug target? Acetazolamide reversibly inhibits AQP-4 → limits cytotoxic edema.3

1 SUN, M. C., HONEY, C. R., BERK, C., WONG, N. L. & TSUI, J. K. 2003. Regulation of aquaporin-4 in a traumatic brain injury model in rats. J Neurosurg, 98, 565-9.

2 ZHAO, J., MOORE, A. N., CLIFTON, G. L. & DASH, P. K. 2005. Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J Neurosci Res, 82, 499-506.

3 XU, M., SU, W. & XU, Q. P. 2010. Aquaporin-4 and traumatic brain edema. Chin J Traumatol, 13, 103-10.

Steroids for TBI?

Largest multi-center, international RCT. 239 centers, 49 countries. IV methylpredisolone vs. placebo.Loading dose of 2gm over 1 h then 48h maintenance dose. Increased risk of death at 2 weeks (RR 1.18, p=0.001)1 and 6 months (RR 1.15, p= 0.001).2

No increased risk of disability at 6 months. 1 ROBERTS, I. et al. 2004. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-

controlled trial. Lancet, 364, 1321-8.2 EDWARDS, P., et al. 2005. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.

Lancet, 365, 1957-9.3 ALDERSON P et al. : Corticosteroids for acute traumatic brain injury. Cochrane Database Syst Rev 2:CD000196, 2000.

General Management of Brain Edema

Proper head and neck position

Airway protection and ventilation

Meticulous BP control

Normothermia

Tight glucose control / nutritional support

Pain control and sedation

Seizure prophylaxis

Osmotherapy: mannitol; the hypertonic saline debate

Loop diuresis

Cerebral metabolic suppression

DAS, A., BANIK, N. L. & RAY, S. K. 2008. Modulatory effects of acetazolomide and dexamethasone on temozolomide-mediated apoptosis in human glioblastoma T98G and U87MG cells. Cancer Invest, 26, 352-8.

XU, M., SU, W. & XU, Q. P. 2010. Aquaporin-4 and traumatic brain edema. Chin J Traumatol, 13, 103-10.

Intra-axial Brain Tumors

Ischemic Stroke Brain Contusion

Predominant edema type

Vasogenic Ionic-vasogenic Ionic-vasogenic

Time transition from Ionic to Vasogenic edema (hours) N.A. >6 >24-48

Primary disturbance

Inter-endothelial gapping

↓cellular [Na+] extrusion

↑ contusion tissue osmolality.

Idiogenic proteins

Pathophysiology Hydrostatic pressure Osmotic-hydrostatic pressure

Osmotic-hydrostatic pressure

VEGF

AQP-4Dexamethasone

Acetazolamide /

ConclusionsBrain edema, irrespective of underlying origin, is a major cause of mortality and death.

Full understanding of the pathophysiology of brain edema has yet to be achieved.

An ideal agent that selectively prevents the formation or promotes the absorption of edema fluid with minimal side effects has yet to be discovered.

Agents targeting VEGF and AQP-4 are possible candidates.

ReferencesDifferent VEGF Associations for Meningiomas and Gliomas

Kalkanis SN et al. Correlation of vascular endothelial growth factor messenger RNA expression with peritumoral vasogenic edema in meningiomas. J of Neurosurg 1996;85:1095-1101Machein MR et al. VEGF in brain tumors. Journal of Neuro-oncology 2000; 50:109-120Plate KH et al. Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature 1992;359:845-848Shweiki D et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992;359:843-845