Chapter 4

Raised intracranial pressure and brain edema

VILLE LEINONEN1*, RITVAVANNINEN2, AND TUOMAS RAURAMAA3

1Department of Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland and Department of Neurosurgery,NeuroCenter, Kuopio University Hospital, Kuopio, Finland

2Department of Radiology, Institute of Clinical Medicine, University of Eastern Finland and Department of Radiology,Kuopio University Hospital, Kuopio, Finland

3Department of Pathology, Institute of Clinical Medicine, University of Eastern Finland and Department of Pathology,Kuopio University Hospital, Kuopio, Finland

Abstract

Acutely increased intracranial pressure (ICP) is a life-threatening neurosurgical emergency. Optimal man-agement strategy is selected according to the causative process. Typical causes are intracranial bleeds liketraumatic subdural, epidural, or intracerebral hematoma (ICH); spontaneous ICH, intraventricular hemor-rhage, subarachnoid hemorrhage, and hydrocephalus.When occurringwithout significant brain injury andtreated effectively before herniation, a full recovery can be expected. In intraparenchymal injuries a fullrecovery is unlikely since dead cells in the central nervous system leave an “empty hole,” to be replaced bycerebrospinal fluid. The clinical recovery is based on the surviving cells that are able to make new syn-apses. Surgery may decrease ICP by removing significant mass effect. In all conditions, when notableinjury of brain parenchyma occurs, brain edemamay gradually increase ICP and further worsen the clinicalcondition. This is seen typically in large brain infarctions when the formation of brain edema may lead toincreased ICP for hours and days. Brain edema is traditionally classified as vasogenic or cytotoxic butaccording to current knowledge is rather a continuum, starting with cytotoxic cell swelling followedby ionic edema and then vasogenic edema. Here we review the causes of increased ICP, including mech-anisms of brain edema, with clinical examples.

Classic symptoms of increased intracranial pressure(ICP) are headache, nausea, vomiting, and eventuallydecreased consciousness. Normal ICP depends on pos-ture, ranging from 5 to 15 mmHg in the supine andfrom –5 to +5 mmHg in the erect posture.

Brain edema is a pathologic state of abnormallyincreased accumulation of fluid within the brain paren-chyma. It can be caused by brain injury due to severalpotential reasons, such as ischemic or hemorrhagicstroke, trauma, infection, or tumor. Brain edema causesimpaired nerve function, may increase ICP, and eventu-ally may lead to tentorial (uncal), foramen magnum, orsubfalcine herniation. The herniation causes direct com-pression of brain tissue and compresses the vessels,

which leads to further ischemia and eventually death(Fig. 4.1).

CLASSIFICATION

Brain edema is traditionally classified as vasogenic orcytotoxic (Klatzo, 1967) but seems to be rather a contin-uum initiated by cytotoxic cell swelling followed byionic edema and then by vasogenic edema (Simardet al., 2007; Fig. 4.2). Vasogenic edema is characterizedby extravasation and extracellular accumulation of fluidin brain parenchyma due to disruption of the blood–brainbarrier (BBB). Cytotoxic edema is characterized by cellswelling due to intracellular accumulation of fluid and

*Correspondence to: Ville Leinonen, Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, P.O. Box 100, 70029KYS, Finland. Tel: +358-447172303, E-mail: ville.leinonen@kuh.fi

Handbook of Clinical Neurology, Vol. 145 (3rd series)NeuropathologyG.G. Kovacs and I. Alafuzoff, Editorshttp://dx.doi.org/10.1016/B978-0-12-802395-2.00004-3Copyright © 2018 Elsevier B.V. All rights reserved

sodium ions. Pathophysiologic time windows of the for-mation and recovery of vasogenic and cytotoxic edemaare variable and can occur in sequential fashion, e.g.,after ischemic stroke during the first day a rapidly recov-ering cytotoxic edema is seen followed by vasogenicedema during the next 2–3 days, lasting for several days(Simard et al., 2007).

Cytotoxic edema

In cytotoxic edema, excessive intracellular accumulationof fluid and sodium ions leads to cell swelling. Cytotoxicedema is typically caused by traumatic brain injury (TBI:Unterberg et al., 2004; Marmarou, 2007), intracerebralhemorrhage (Kuramatsu et al., 2013; Mracsko andVeltkamp, 2014; Leasure et al., 2016), acute liver failure(Wendon and Lee, 2008; Rabinstein, 2010), and in theprimary phase after ischemia (Simard et al., 2007;Kahle et al., 2009).

In general, cytotoxic edema is linked with cell death.Cerebral ischemia decreases blood flow, which dimin-ishes glucose supply, leading to decreased intracellularadenosine triphosphate (ATP) production (Liang et al.,2007; Kahle et al., 2009). The lack of ATP leads to failureof the intra-/extracellular sodium transport system andthen excessive intracellular accumulation of sodiumions, which leads to cell swelling by abnormal flow ofextracellular fluid into the cells (Liang et al., 2007;Kahle et al., 2009). Then the body accelerates the outflowof sodium ions from blood to improve decreased extra-cellular sodium and fluid without BBB disruption(Kahle et al., 2009). In the ischemic core of an acuteinfarction, the ultimate consequence of cytotoxic edemais oncotic death of neurons. In the endothelial cells

oncotic death results in complete loss of capillary integ-rity and in extravasation of blood – i.e., hemorrhagicconversion.

In acute liver failure, toxic waste, such as ammonia,which is usually removed by hepatic metabolism, accu-mulates. In central nervous system (CNS) cells they causeoxidative stress and mitochondrial dysfunction, leading toastrocytic dysfunction and swelling (Wendon and Lee,2008; Rabinstein, 2010).

Ionic edema (osmotic edema)

In ionic edema, the osmolality of brain exceeds that ofserum and the abnormal pressure gradient leads to exces-sive water intake into brain parenchyma (Simard et al.,2007). Dilution of plasma decreases serum osmolalityand can be caused by hyponatremia due to, e.g., syn-drome of inappropriate antidiuretic hormone or exces-sive water intake.

Vasogenic edema

In vasogenic edema, changes in capillary permeabilitycause extravasation of fluid and plasma proteins, suchas albumin, into the brain parenchyma. The excessiveaccumulation of extracellular fluid increases brain vol-ume and then ICP. Vasogenic edema is typically causedby CNS tumors like glioblastoma (Papadopoulos et al.,2004b; Ishihara et al., 2008; Wolburg et al., 2012) andmeningioma (Nakano et al., 2002), infections (Saadounet al., 2003), inflammatory diseases (Argaw et al., 2012),and in the secondary phase after ischemia (Simard et al.,2007). Areas within the infarct core will contain littleor no excess electrolytes before equilibration, whereas

Fig. 4.1. Tentorial herniation and brain swelling in a 4-year-old boy with a previously benign posterior fossa cyst treated with

shunting. The acute symptoms started with vomiting and fluctuating consciousness, and rapidly progressed with convulsions

and decreasing saturation and resulted in death.

26 V. LEINONEN ET AL.

the penumbral areas adjacent to infarct corewill contain anexcess of electrolytes and water.

The BBB is formed by astrocytes and pericytestogether with adhesion proteins producing tight junc-tions between perivascular brain endothelial cells(Ballabh et al., 2004; Abbott et al., 2006; Wolburget al., 2009). Brain ischemia reperfusion causes exci-totoxicity and oxidative stress through mitochon-drial dysfunction (Cheng et al., 2012; Walker andTesco, 2013), induces migration of leukocytes(Weiss et al., 2009) and activation of microglia andastrocytes (Nedergaard and Dirnagl, 2005), leadingto excessive release of cytokines, chemokines, and

vascular permeability factors (Dimitrijevic et al.,2007; Argaw et al., 2009) – all of which lead to dis-ruption of the BBB.

Ischemia-induced changes in capillary permeabilityform three distinct phases: ionic edema, vasogenicedema, and hemorrhagic conversion. In acute infarctionthe rapidity of transition from one phase to anotherdepends on collateral circulation and thus, the durationand depth of hypoxia prior to reperfusion by thrombect-omy or venous thrombolysis. The core that wascompletely ischemic with no collaterals is more likelyto undergo hemorrhagic conversion than the hypoxicpenumbra.

Fig. 4.2. Normal capillary and neuron, cytotoxic edema and ionic edema – cell swelling due to intracellular accumulation of

fluid, and vasogenic edema – disrupted blood–brain barrier leading to extravasation of serum protein and fluid. (Modified from

Simard JM, Kent TA, Chen M, et al. (2007) Brain oedema in focal ischaemia: molecular pathophysiology and theoretical

implications. Lancet Neurol 6: 258–268.)

RAISED INTRACRANIAL PRESSURE AND BRAIN EDEMA 27

HIGH-ALTITUDE CEREBRAL EDEMA

In high-altitude cerebral edema, the BBB is disrupted byhypoxia, leading to mitochondrial dysfunction (Songet al., 2016).

Interstitial edema

Interstitial edema is related to transependymal flowof cere-brospinal fluid (CSF) in hydrocephalus (Papadopoulosand Verkman, 2013).

EPIDEMIOLOGY

Since brain edema is not an easily determined simple dis-ease but a divergent continuum caused by various etiol-ogies, the epidemiology is difficult to define. A usefuldefinition of the epidemiology is based on the incidenceof potential etiologies of brain edema. Brain edema isalways present to some extent in TBI, various CNStumors, CNS infections, brain ischemia, and intracere-bral hemorrhage. The epidemiology of these disordersis beyond the scope of this review.

CLINICAL PHENOTYPES AND IMAGING

Symptoms of acutely increased ICP include typicallyheadache, nausea, vomiting, and eventually coma. Fre-quent symptoms are also visual disturbance (gaze pare-sis, reduced vision) and dizziness. Acutely increasedICP causes compensatory elevation of blood pressureto maintain cerebral blood flow, which, associated withirregular respiration due to brainstem compression andbradycardia (Cushing reflex), precedes imminent herni-ation. In addition to increased ICP due tomass effect withthe consequences mentioned above, brain edema maycause local impairment in nerve function. High-altitudecerebral edema is characterized by nonspecific patho-physiologic symptoms including progressive headache,loss of coordination, psychiatric changes, disturbancesof consciousness, and eventually coma (Wilson et al.,2009; B€artsch and Swenson, 2013).

Traumatic brain injury

TBI induces first cytotoxic edema followed by ionic andfinally vasogenic edema. The process is complex and dif-ferent phases may occur in parallel in variously injuredbrain areas. ICP may be temporarily decreased by man-nitol and hyperventilation but both produce only a short-term effect andmay provoke a rebound reaction. Anotherhyperosmotic solution used clinically is hypertonic(7.5%) saline, which seems to be more beneficial thanmannitol (Rickard et al., 2014). TBI causes often alsohyponatremia, which further aggravates the edema.Another means of decreasing ICP is sedation and

drainage of CSF. Usually the final option is decompres-sive craniectomy (DCE; Figs 4.3 and 4.4).

Hemorrhagic stroke

Intracerebral hemorrhage causes immediate, direct, irre-versible injury to the brain (Qureshi et al., 2009). Withinhours and days, cytotoxic, ionic, and eventually vaso-genic edema surrounding the hematoma (Fig. 4.5) mayincrease the mass effect and hamper the outcome(Urday et al., 2016). In case of superficial large hema-toma with significant mass effect in noneloquent areas,surgical decompression of the hematoma may improvethe outcome (Mendelow et al., 2005; Mendelow,2015), especially in cerebellar lesions – see below.

Subarachnoid hemorrhage (SAH) induces acuteglobal ischemia. SAH and its treatment may also causeglobal mild vasogenic edema in white matter and deepgray matter that is undetectable on T2-weightedmagnetic resonance (MR) images but is detectable bymeasuring the apparent diffusion coefficient (ADC)value in the subacute stage (Liu et al., 2007). Further-more, the vasospasm, occurring often days after theprimary bleed, may cause ischemic lesions thatinduce vasogenic edema (Cahill et al., 2006; Caneret al., 2012).

Ischemic stroke

In acute ischemia (Fig. 4.6), first a cytotoxic (cellular)edema is observed in a few hours but is transformedrather rapidly during the first day due to transcapillarymovement. With cytotoxic edema, tissue swelling doesnot occur because there is no new constituent from theintravascular space added. However, after cytotoxicedema formation, the outflow of Na+ from blood vesselsis accelerated. This causes extracellular fluid accumula-tion, known as ionic edema. Ionic edema is followed byvasogenic edema, and both lead to swelling of the brain.

Fig. 4.3. Malignant brain edema during decompressive cra-

niectomy for severe traumatic brain injury.

28 V. LEINONEN ET AL.

Vasogenic edema lasts for several days or even weeks.Thus, after ischemic stroke, the patient may further dete-riorate due to edema, typically 1–3 days after the primaryinsult. At that point the only effective treatment in largemiddle cerebral artery infarction is DCE (Fig. 4.7), whichshould be done prior to severe clinical deterioration(Hofmeijer et al., 2009). The significance of the optimaltiming of DCE is supported by experimental studies ofthe different phases of edema formation. In the earlyphase during the ionic edema stage, DCE enhances therestoration of tissue perfusion but may aggravate edemaformation in the later phase during vasogenic edema bydecreasing tissue pressure, leading to increasing hydro-static gradient (Hofmeijer et al., 2004).

Another potential surgical entity is cerebellar infarc-tion (Figs 4.8 and 4.9), where the edema may compressthe fourth ventricle, causing obstructive hydrocephalus,which can be treated by a ventriculostomy procedure. Itis noteworthy that, in addition to the obstructive hydro-cephalus, the cerebellar mass lesion may directly com-press the brainstem and thus require microsurgicalposterior fossa decompression. In that procedure, theinfarcted cerebellar tissue (often extruding like“toothpaste”) is resected with a small craniotomy orcraniectomy. Such surgery can be life-saving and thefunctional outcome good, since the patient may recover

Fig. 4.5. Computed tomography of an expansive spontaneous

frontotemporal intracerebral hematoma indicating a mild ede-

matic rim surrounding the hematoma.

Fig. 4.4. (A) First computed tomography (CT) 2 hours after head trauma indicating right-sided acute subdural hematoma and

traumatic subarachnoid hemorrhage (Glasgow Coma Scale 3 on admission). (B) T2-weighted and (C) fluid-attenutated inversion

recovery magnetic resonance images 3 days after trauma showing high-signal intensity areas indicative of edema and scattered

intracerebral areas of low-signal intensity representing contusion hemorrhage. (D) CT indicating expansive edemawith subfalcine

herniation 7 days after trauma leading to right-sided decompressive craniectomy (DCE). CT in the first postoperative day after

DCE (8 days after trauma) (E).

RAISED INTRACRANIAL PRESSURE AND BRAIN EDEMA 29

well from the cerebellar injury without devastatingneurologic defects.

Tumors

Vasogenic brain edema may occur in the surroundingcerebral parenchyma in both benign and malignantCNS tumors. Edema is related to nearly all malignanttumors, both metastatic and primary, like gliomas, espe-cially glioblastoma. A typical benign tumor-inducingedema is meningioma (Fig. 4.10). However, especiallysmall meningiomas often occur without any detectableedema. In tumors, the initial symptoms are often accom-panied by edema and therefore can be temporarily alle-viated by corticosteroids. Total resection of the tumorwill gradually reverse the edema but partial resectionmay sometimes aggravate it. Corticosteroids are usuallycontinued, especially in malignant tumors, if radiationtherapy is indicated since that may often temporarilyaggravate the edema.

Infections

Vasogenic edema appears also in relation to infections,especially in brain abscess (Fig. 4.11) but also in menin-gitis (Fig. 4.12). Therefore, corticosteroids are oftenadded with antimicrobial treatment. However, bacterialmeningitis generates energy failure that drives water

flow from blood into the brain cells, causing cytotoxicedema (Papadopoulos and Verkman, 2013).

Chronically increased ICP

When ICP increases gradually over weeks and months,compensatory mechanisms can adapt the brain to thechanges until a certain break point is reached. The adap-tive effect depends on the time window available. Thesame mass effect appearing in seconds (e.g., SAH)may lead to instant headache and unconsciousness; inhours (e.g., acute subdural hematoma) to rapidlyincreasing headache and focal symptoms (beforeunconsciousness); and in weeks (e.g., chronic subduralhematoma) to gradually increasing headache, confu-sion, cognitive deterioration, and intermittent focalsymptoms (unconsciousness usually only after the finalherniation).

Similarly, tumors often lead to focal symptoms beforethe signs of increased ICP become evident. CSF disor-ders causing increased ICP are reviewed in Chapter 5.

IMAGING

Sustained intracranial hypertension, brain edema, andacute brain herniation signify catastrophic neurologicevents and require immediate recognition and treatmentto prevent irreversible injury and death. Computedtomography (CT) is the imaging modality of choice in

Fig. 4.6. (A) A 71-year oldman underwent stroke computed tomography (CT) within 2 hours of stroke ictus. Densemedia sign but

no hypodensity on CT. CT angiography shows M1 segment occlusion arrow (B) but good collateral circulation arrows (C). CT

perfusion and cerebral blood flowmap (D) showswide hypoperfusion,while the cerebral blood volumemap (E) shows only a small

defect in the basal ganglia area (arrows). The patient underwent thrombectomy with good clinical outcome.

30 V. LEINONEN ET AL.

critical patients as it is widely available, fast, andwell tol-erated. Acutely nonenhanced CT can diagnose orexclude intracranial hemorrhage, large mass, acutehydrocephalus, and brain herniation. It often indicatesthe cause of significantly increased ICP and brain edema.

However, interpretation of CT images in acute neu-rologic disease in the emergency department can bechallenging as the range of possible causes is wideand the imaging appearance of many of theseentities may overlap. Further imaging workup maynecessitate CT angiography (CTA), MR imaging(MRI, including MR angiography), or digital subtrac-tion angiography (DSA).

In SAH, CTA is usually routinely combined withnoncontrast-enhanced CT of the brain. It can diagnoseintracranial aneurysms and malformations. In intracere-bral hematomas the CTA spot sign is a common findingand is associated with higher risk of hematoma expan-sion and predicts active bleeding during surgery. In a

Fig. 4.8. Acute obstructive hydrocephalus (*) caused by bilat-

eral cerebellar infarction (arrows) in an elderly man.

Fig. 4.7. (A) Computed tomography (CT) of a right middle cerebral artery infarction approximately 10 hours after the onset of the

symptoms. CT on the first (B), fourth (C), and 12th (D) postoperative day after decompressive craniectomy indicating the pro-

gression of the edema frommainly cortical and deep gray-matter hypodensity, loss of gray- andwhite-matter distinction, and taper-

ing of the sulci to marked hypodensity of both the gray and white matter and finally hemorrhagic conversion and laminar necrosis.

RAISED INTRACRANIAL PRESSURE AND BRAIN EDEMA 31

setting of acute ischemic stroke, CTA is increasingly uti-lized and is associatedwith increased reperfusion therapyuse. It is often combined with CT perfusion. CTA candetect the occluded artery, characterize the length ofocclusion and the possible atherosclerotic lesions, andbe used to assess collateral circulation. DSA is usuallyperformed as an adjunct to neurointerventional proce-dures such as coiling of ruptured aneurysms orthrombectomy.

In MRI, cytotoxic and vasogenic edema after braininjury can be assessed by T2 imaging and diffusion-weighted imaging and measurement of ADC(Loubinoux et al., 1997; Badaut et al., 2007). TheT2-weighted image is the basic pulse sequence in clinicalMRI. Increased T2 signal intensity is related to increasedvascular permeability and water content. T2 value is atransverse relaxation time of excited protons andincreased T2 values reflect the development of vasogenicedema (Loubinoux et al., 1997; Rumpel et al., 1998;Badaut et al., 2007). Diffusion imaging provides infor-mation about cellular architecture such as cellular size,

membranes, and volume fraction (Rumpel et al.,1998). ADC is a prompt indicator for magnitude of dif-fusion of water molecules within tissue. In cytotoxicedema ADC value is reduced since cell swellingdecreases extracellular space and diffusion of the protonsin water molecules is restricted (Rumpel et al., 1998). Invasogenic edema the ADC values are elevated comparedto the normal brain. In tumors, ADC values may varyaccording to tissue cellularity, fluid viscosity, membranepermeability, macromolecular structures, microvascular-ity, and tumor blood flow.

NEUROPATHOLOGY

Macroscopy

In macroscopic evaluation the brain is often rounded.Flattened gyri against the skull and narrowed and com-pressed intervening sulci can be seen, as shown inFigures 4.13–4.15. On cross-section the ventricular cav-ities are narrowed and the boundary between gray andwhite matter may be blurred, and various lesions, such

Fig. 4.9. Acute thrombosis in right vertebral and basilar arteries. T2-weightedmagnetic resonance imaging 5 hours after the begin-

ning of symptoms shows high-signal intensity edema in right cerebellum, but the swelling is only mild. The area of edema is bright

in diffusion trace image indicating cytotoxic edema and death of neurons.

Fig. 4.10. (A) Fluid-attenutated inversion recovery and (B) contrast-enhanced T1-weightedmagnetic resonance image of a frontal

meningioma which has induced significant edema in the adjacent white matter.

32 V. LEINONEN ET AL.

as hemorrhage, tumor, or infarction, causing the edemacan be seen. The fresh weight is increased in proportionto the degree of edema. Lesions caused by herniation arefrequently seen as a consequence of edema.

Microscopy

The microscopic appearance of edema is usually spongyand the neuropil may appear loosened and edematous(Figs 4.16 and 4.17). After a longer period of time thevacuoles may be larger. Glial cells may be swollen. Incytotoxic edema, which is mainly confined within cells,the process is mostly diffuse. In vasogenic brain edemamyelin pallor and myelin disruption are common

histologic findings. Myelinated fibers may be swollenand astrocytes show elongated processes in contact withthe capillary walls. Hypertrophy and hyperplasia ofastrocytes as well as loss of oligodendrocytes and myelincan be seen.

PATHOGENESIS, EXPERIMENTALMODELS, AND BIOCHEMISTRY

All subtypes of brain edema seem to share commonmolecular precedents (Simard et al., 2007) but mecha-nisms driving the edema may vary according to the

Fig. 4.11. Left frontal abscess (Streptococcus constellatus) prior to surgical drainage in (A) T2-weighted, (B) diffusion apparentdiffusion coefficient (ADC)map, (C) diffusion trace, and (D) T1-weightedmagnetic resonance imagingwith gadolinium enhance-

ment. Vasogenic edema in thewhitematter around the abscess cavity has high signal intensity both in T2-weighted image andADC

map. Restricted diffusion of the pus inside the cavity appears dark on ADC map.

RAISED INTRACRANIAL PRESSURE AND BRAIN EDEMA 33

different etiologies (Norenberg, 1994). A number ofmolecules have been identified in connection withbrain edema formation. Some of the most importantseem to be vascular endothelial growth factor (VEGF),matrix metalloproteinases, aquaporins, Na+-K+-Cl–-co-transporter 1 (NKCC1), sulfonylurea receptor 1 reg-ulated nonselective cation channels (SUR1-regulated

NCCa-ATP), endothelin B receptor (ETB-R), and gluco-corticoid receptor (Michinaga and Koyama, 2015;Stokum et al., 2016).

Brain injury triggers expression of VEGF, whichdecreases expression of tight-junction proteins and thusleads to edema formation by weakening BBB (Weis andCheresh, 2005; Stokum et al., 2016).

Fig. 4.12. Herpes encephalitis and vasogenic edema in the right temporomesial and frontobasal areas.

Fig. 4.13. Massive edema in a car accident victim.

Fig. 4.14. Male aged 48 years. Glioblastoma. The patient died

of a tumor hemorrhage soon after a biopsy was taken.

34 V. LEINONEN ET AL.

Aquaporin-4 (AQP4) water transport seems to have asignificant role in the process of brain edema in variousCNS disorders (Saadoun and Papadopoulos, 2010; Papa-dopoulos and Verkman, 2013). Increased cytotoxicedema is seen in AQP4 overexpression mice (Yang

et al., 2008) and reduced cytotoxic edema in AQP4knockout mice (Thrane et al., 2011; Papadopoulos andVerkman, 2013). Compared with wild-type mice,AQP4 null mice develop more brain edema in tumor(Papadopoulos et al., 2004a), abscess (Bloch et al.,2005), SAH (Tait et al., 2010), and status epilepticus(Lee et al., 2012) models with BBB disruption probablydue to decreased elimination of vasogenic edema fluid(Papadopoulos and Verkman, 2013). AQP4 is expressedstrongly in astrocytomas, especially in glioblastoma(Saadoun et al., 2002). Furthermore, the level of AQPexpression in tumor cells correlates with the amount ofedema (Nico et al., 2009).

The theory on the glymphatic convection mechanismof CSF holds that cardiac pulsations in part pump CSFfrom the periarterial spaces through the extracellular tis-sue into the perivenous spaces facilitated by aquaporinwater channels. Ultra-fast MR encephalography indi-cates three types of physiologic mechanisms affectingcerebral CSF pulsations, including cardiac, respiratory,and very-low-frequency pulsations (Kiviniemi et al.,2016). The glymphatic system may have a major rolein the formation of ionic edema (Thrane et al., 2014).

Several animal models of brain edema have beenadopted. Animal models of TBI have been reviewedby Xiong et al. (2013). One of the most often used is con-trolled cortical impact brain injury (Yao et al., 2015). Anexperimental model of brain edema fluid percussioninjury, cerebral hemorrhage model, water intoxicationmodel, and liver failure model have been reviewed byMichinaga and Koyama (2015).

Brain function and structure in humans and animalsvary notably and the experimental studies are not alwaysfully representative of clinical settings. Histopathologicstudies on human brain edema are surprisingly scarceand should be encouraged. Although the potential forclinical diagnostics is notable, surgical brain samplesare seldom obtained during neurosurgical proceduresoutside of tumor surgery. Consecutive MRI imagestogether with brain biopsies, whenever possible, in com-bination with continuous monitoring of metabolites,inflammation, and nerve injury markers by means ofmicrodialysis, blood, and CSF samples would be neces-sary to confirm the experimental findings but also to clar-ify the edema process in human disorders.

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