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Home , Intracranial pressure

The pathophysiology of and elevated intracranial pressure

ANTHONY MARMAROU, PHD

he contribution of brain edema to brain ■ TRAUMATIC BRAIN EDEMA—VASOGENIC swelling in cases of traumatic injury, OR CELLULAR? , and tumor remains a critical By definition, edema is an abnormal accumulation Tproblem for which there is currently no of fluid within the brain parenchyma; it is subdivid- effective clinical treatment. It is well documented ed into vasogenic and cytotoxic types. Vasogenic that in , swelling leads to an elevation in edema is defined as fluid originating from blood ves- intracranial pressure (ICP), which is a frequent sels and accumulating around cells. Cytotoxic cause of death, and to very poor prognosis in sur- edema is defined as fluid accumulating within cells vivors. This swelling process has been classified into as a result of cell injury. The most common cytotox- four distinct degrees of severity based on studies of ic edema occurs in cerebral ischemia. Neurotoxic the Traumatic Coma Data Bank. Of great impor- edema is a subtype of cytotoxic edema caused by tance is the fact that the degree of swelling assessed high levels of excitatory amino acids. Heretofore, on the first CT scan, obtained soon after injury, is the edema specific to has gen- highly correlated with outcome (P < .0002). erally been considered to be of “vasogenic” origin, secondary to traumatic opening of the blood-brain ■ BRAIN SWELLING—EDEMA OR VASCULAR barrier. However, all three forms of edema can coex- ENGORGEMENT? ist, and their relative contributions to brain swelling Our experimental and clinical studies provide and elevated ICP have not been identified. This is a strong evidence that edema is primarily responsible critical problem, as effective treatment will clearly for the swelling process. For the past several decades, depend on the type of swelling. it has been generally accepted that the swelling Our own studies in this area are in sharp contrast process accompanying traumatic brain injury is to the general belief that traumatic brain injury mainly due to vascular engorgement, with blood results in a predominantly extracellular edema sec- volume providing the increase in brain bulk and ondary to blood-brain barrier opening. Although a subsequent rise in ICP. Edema was thought to play a vasogenic component may be present, we strongly minor role. However, our recent findings indicate suspect that the type of swelling in traumatic brain that edema, not vascular engorgement, is responsi- injury with or without associated mass lesion is pre- ble for brain swelling and that blood volume is actu- dominantly a cellular edema. A lack of barrier open- ally reduced following traumatic brain injury. Thus, ing in the presence of continued swelling has been it is important to shift our attention to brain edema noted in our clinical studies of head-injured patients and to understand the pathophysiologic mecha- in whom magnetic resonance “water maps” were nisms responsible for water movement into brain. obtained with gadolinium challenge. Experimentally, we have strong evidence that the type of swelling in diffuse injury is predominantly cellular. From the Department of Neurosurgery, Virginia Common- wealth University Medical Center, Richmond, Va. ■ IONIC DYSFUNCTION IN BRAIN INJURY Address: Anthony Marmarou, PhD, Department of Neuro- surgery, Virginia Commonwealth University Medical Center, It is well documented that ionic dysfunction occurs + 1001 East Broad Street, Suite 235, Richmond, VA 23219; e- with traumatic brain injury and that extracellular K mail: [email protected]. is transiently increased as a result of the depolariza-

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tion synchronous with mechanical insult. This loss lular swelling and cytotoxic edema, which we have of ionic homeostasis should be accompanied by a shown to be the primary contributor to raised ICP. concomitant movement of sodium. The seminal In traumatic brain injury, the initiating factors, studies by Betz et al and Gotoh et al measured uni- which result in the movement of ions, may differ directional movement of sodium into brain follow- from those primarily responsible in ischemia. For ing an ischemic injury, and work by other investiga- example, ATP reduction may not be due to tors has demonstrated a clear relationship between decreased cerebral blood flow since blood flow in tissue water content and sodium accumulation. As traumatic brain injury persists and delivery of sub- we have demonstrated a predominantly cellular strate is maintained. swelling, the extension of our work to the study of ionic movement is fundamental to a deeper under- ■ LABORATORY MODELS OF TRAUMATIC BRAIN standing of the formation of traumatic brain edema. INJURY WITH BRAIN SWELLING Traumatic brain injury triggers a cascade of events, including mechanical deformation, neuro- The study of traumatically induced swelling in the transmitter release, mitochondrial dysfunction, and laboratory has been difficult, in part because of a membrane depolarization, that leads to alterations lack of models that produce marked, rapid swelling in normal ionic gradients. Excitatory amino acids and, most important, a steady rise in ICP. Fluid per- released via mechanical deformation and mem- cussion, or direct dural impact, results in a sudden brane depolarization activate ligand-gated ion rise in that is sufficient to breach the channels, which allow ions to move down their blood-brain barrier and is not suitable for the study electrochemical gradients. In addition, membrane of edema produced by closed head injury. Moreover, depolarization resulting from ionic flux and trauma ICP increases only transiently and declines over triggers voltage-sensitive ion channels, providing time. Similarly, the classic model of subdural further routes for ionic movement. These ionic dis- , which has been used by many investiga- turbances are identified by an increase in extracel- tors, also produces only a transient rise in ICP fol- + lowed by a gradual recovery toward baseline. lular potassium ([K ]ecs) with a concomitant + For diffuse injury, we solved this problem with decrease in extracellular sodium ([Na ]ecs), calcium, and chloride. our development of a rat impact-acceleration model Restoration of ionic homeostasis is accomplished that develops marked swelling, a profound diffuse via cotransport and countertransport processes such axonal injury, and a steadily rising ICP when sec- as the Na+-K+ ATPase, Na+/K+/2Cl– cotransporter, ondary insults are superimposed upon the mechani- Na+-H+ transporter, and Na+-Ca2+ exchanger. cal trauma. For mass lesions, we found that super- However, if the injury is severe, or if secondary imposing a controlled subdural hemorrhage follow- insults occur, disruption of ionic homeostasis persists ing impact-acceleration injury resulted in similar as the cotransport and countertransport processes are effects. This combination, which mimics the clini- impaired and become incapable of returning ion cal scenario better than a subdural hemorrhage concentrations to their normal levels. Moreover, in alone, results in a remarkable, steady increase in the absence of adequate levels of ATP resulting from ICP to greater than 50 mm Hg . either an ischemic reduction in cerebral blood flow ■ MAGNETIC RESONANCE TECHNOLOGY: or insufficient production of ATP due to mitochon- DIFFUSION-WEIGHTED IMAGING TECHNIQUES drial dysfunction, energy-dependent ion pumps and AND PROTON SPECTROSCOPY cotransport and countertransport processes are inef- ficient in counteracting the normal dissipative flux It is not possible to differentiate between vasogenic of ions down their electrochemical gradients. (extracellular) and cytotoxic (cellular) edema by We hypothesize that the net balance of ionic conventional tissue water measurement. In vivo dif- movement that accompanies brain injury results in fusion-weighted imaging is a magnetic resonance the movement of cations out of the extracellular technique that, by employing strong magnetic field space into cells. The movement of sodium and cal- gradients, is sensitive to the random molecular cium is passively followed by chloride to maintain translation of water protons. Maps of the apparent electroneutrality, and is followed isosmotically by diffusion coefficient (ADC) can be derived from a water. If sustained, ionic disturbances result in cel- series of diffusion-weighted images obtained with

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different magnetic fields. Recent findings in experi- ment, such calcium loading leads to mitochondrial mental ischemia models suggest that ADC values permeability transition, which is linked to overt can provide earlier and more specific information mitochondrial failure. The accuracy of this assump- about tissue damage and characteristics of edema. tion is supported by several studies. More impor- Several studies have adopted this concept in distin- tantly, studies by Povlishock et al have shown that guishing the type of edema in ischemia and trau- cyclosporin A, which blocks mitochondrial perme- matic brain injury. The application of such new ability transition, translates into significant neuro- imaging techniques can quantify the temporal protection. changes and document the type of edema that is N-acetylaspartate (NAA) was discovered in 1956 occurring during both the acute and the late stages by Tallan, More, and Stain and is represented by the of edema development. largest peak in a proton spectrum (1H MRS). It is synthesized in mitochondria from L-aspartate and ■ N-ACETYLASPARTATE ASSESSED BY PROTON acetyl-CoA in a reaction catalyzed by an N-acetyl- SPECTROSCOPY AND MITOCHONDRIAL DYSFUNCTION transferase. NAA has been found histochemically to be a constituent of neurons and axons, with lesser We hypothesize that mitochondrial dysfunction amounts in glial cells. Large numbers of studies show prevents the restoration of ionic and cell volume NAA absent or reduced in (glioma), homeostasis. Hovda’s group has clearly implicated ischemia, degenerative disease, and inborn errors of ionic shifts as the major mechanisms for cellular and , and it is accepted fact that NAA levels organelle swelling. Moreover, Muizelaar has recent- correspond to tissue damage. Studies of NAA in ly demonstrated in rat brain suspensions that mito- severe brain injury are relatively few, and the tempo- chondrial function was profoundly reduced after ral course of NAA changes in trauma in association traumatic brain injury and that this was largely cal- with ADC values has not been studied. Because cium-dependent. Povlishock has posited that the NAA is synthesized by the mitochondria, it is rea- shear and tensile forces of injury induce mechanical sonable to posit that reduced tissue NAA will be poration of cell membranes that can cause an “exci- associated with regions of low ADC, low ATP, ionic tatory amino acid storm” that leads to intracellular dysfunction, and brain edema. This report describes calcium influx with subsequent mitochondrial load- the most recent information available on NAA ing. It is envisioned that in a permissive environ- reduction in human head injury.

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