Brain tissue water content in patients with idiopathic normal pressure hydrocephalus.

Relatively little is known regarding the water content of brain tissue in idiopathic normal-pressure hydrocephalus (NPH) patients. The objective of our study was to determine absolute water content non-invasively in hydrocephalic patients, particularly in the anterior and posterior ventricular horns and in the periventricular white matter. Ten patients who were diagnosed and treated for idiopathic NPH in our clinic were selected for study. Magnetic resonance imaging (MRI) techniques were used to obtain anatomical image slices for quantitative brain water measurements. Apparent diffusion coefficient measures were also extracted from regions of interest. To our knowledge, this is the first study to confirm that periventricular lucency seen on MRI represents increased water content in the extracellular space that is markedly elevated prior to shunting.

Traumatic brain edema in diffuse and focal injury: cellular or vasogenic?

The objective of this study was to confirm the nature of the edema, cellular or vasogenic, in traumatic brain injury in head-injured patients using magnetic resonance imaging techniques. Diffusion-weighted imaging methods were quantified by calculating the apparent diffusion coefficients (ADC). Brain water and cerebral blood flow (CBF) were also measured using magnetic resonance and stable Xenon CT techniques. After obtaining informed consent, 45 severely injured patients rated 8 or less on Glasgow Coma Scale (32 diffuse injury, 13 focal injury) and 8 normal volunteers were entered into the study. We observed that in regions of edema, the ADC was reduced, signifying a predominantly cellular edema. The ADC values in diffuse injured patients without swelling were close to normal and averaged 0.89 +/- 0.08. This was not surprising, as ICP values for these patients were low. In contrast, in patients with significant brain swelling ADC values were reduced and averaged 0.74 +/- 0.05 (p < 0.0001), consistent with a predominantly cellular edema. We also found that the CBF in these regions was well above ischemic threshold at time of study. Taking these findings in concert, it is concluded that the predominant form of edema responsible for brain swelling and raised ICP is cellular in nature.

Bolus tracer delivery measured by MRI confirms edema without blood-brain barrier permeability in diffuse traumatic brain injury.

INTRODUCTION: Previous studies have shown that edema formation after diffuse traumatic brain injury (TBI) with secondary insult is cytotoxic and not vasogenic. This assumption is based on observations of reduced apparent diffusion coefficient (ADC) and lack of significant accumulation of intravascular tracer in brain tissue. However, ADC reduction does not exclude vasogenic edema, and intravascular tracer can only accumulate when it reaches the tissue and is not perfusion limited. This study aims to confirm tissue delivery of intravascular tracer and lack of BBB opening during a phase of rapid brain swelling after diffuse TBI. METHODS: Rats were exposed to either TBI using the impact acceleration model combined with 30 minutes of hypoxia and hypotension, or sham injury. At 2 or 4 hours after injury, ADC and tissue water content were assessed using MRI. Gd-DTPA was given followed by a combination of rapid T2 imaging (60 seconds) and T1 imaging (30 minutes). Signal intensity changes were analyzed to determine a bolus effect (dynamic susceptibility contrast) and longer-term tissue accumulation of Gd-DTPA. RESULTS: Mean increase in cortical water content on the left was 0.8% at 2 hours, 2.1% at 4 hours; on the right it was 0.5% at 2 hours and 1.7% at 4 hours (p < 0.05). Mean ADC reduction over 4 hours was 0.04 x 10(-3) mm2/s on the left and 0.06 x 10(-3) mm2/s on the right. Kinetic analysis of signal intensity changes after Gd-DTPA showed no significant difference in inward transfer coefficient (BBB permeability) between sham injury and 2 or 4 hours post-injury. T2 imaging showed consistent tissue delivery of a bolus of Gd-DTPA to the tissue at 2 and 4 hours post-injury, comparable to sham animals. CONCLUSIONS: Progressive cerebral edema formation after diffuse TBI occurred during ADC reduction and without continued BBB permeability. Tissue delivery of Gd-DTPA was confirmed, verifying that lack of tracer accumulation is due to an intact BBB and not to limited perfusion.

Effect of dimethyl sulfoxide on blood-brain barrier integrity following middle cerebral artery occlusion in the rat.

Dimethyl sulfoxide (DMSO) is widely used as a solvent for other drugs, i.e., for the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) and the V1a receptor-antagonist SR49059, to reduce brain edema. We studied the effect of DMSO on blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO) and the consequences on brain edema development. Male Sprague-Dawley rats were randomly assigned to sham procedure or infusion of 1% DMSO, PMA (230 microg/kg in 1% DMSO), or SR49059 (1 mg/kg in 1% DMSO) followed by MCAO (each group n = 10). After a 2-hour period of ischemia and 2 hours reperfusion, the animals were sacrificed for assessment of brain water content, sodium, and potassium concentration. BBB integrity was assessed by Evans blue extravasation. Statistical analysis was performed by ANOVA followed by a Tukey post hoc test. Low-dose DMSO treatment following MCAO significantly opened the BBB on the ischemic side (p < 0.037). PMA and SR49059 did not have any additional effect on BBB compromise compared to DMSO (p = 1.000, p < 0.957, respectively). We conclude that DMSO as a vehicle for drug administration may increase the drug concentration into the extracellular space, but since BBB permeability is increased, it may also provide an avenue for development of vasogenic edema.

Protective effect of the V1a receptor antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat.

There exists no pharmacological treatment for fulminating brain edema. Since evidence indicates that brain aquaporin-4 (AQP4) water channels are modulated by vasopressin V1a receptors, we examined the edema-reducing properties of the selective V1a receptor antagonist, SR49059, following middle cerebral artery occlusion (MCAO). Male Sprague-Dawley rats were randomly assigned to sham procedure, vehicle, or SR49059 infusion at different dosages (each n = 6,480 microL/hr, 640 microL/hr, 720 microL/hr) and starting 60 minutes before or after MCAO. After a 2-hour period of ischemia and 2 hours of reperfusion, the animals were sacrificed for assessment of brain water content, sodium, and potassium concentration. Statistics were performed using an ANOVA followed by a Tukey post hoc analysis. SR049059 treatment reduced brain water content in the infarcted area given at 640 microL/hr (p = 0.036), 720 microL/hr 60 minutes before (p = 0.002) or 60 minutes after (p = 0.005) MCAO. The consecutive sodium shift into the brain was prevented (p = 0.001), while the potassium loss was inhibited only by pre-treatment (p = 0.003). These findings imply that in ischemia-induced brain edema, the selective V1a receptor-antagonist SR49059 inhibits brain edema and the subsequent sodium shift into brain. This substance offers a new avenue in brain edema treatment and prompts further study into AQP4 modulation.

Modulation of AQP4 expression by the protein kinase C activator, phorbol myristate acetate, decreases ischemia-induced brain edema.

The protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), is known to interact with aquaporin-4 (AQP4), a water-selective transporting protein abundant in astrocytes and ependymal cells, that has been found to decrease osmotically-induced swelling. The purpose of this study was to examine whether PMA given at different time points following focal ischemia induced by middle cerebral artery occlusion (MCAO) reduces brain edema by AQP4 modulation. Male Sprague-Dawley rats were randomly assigned to sham procedure, vehicle, or PMA infusion (230 microg/kg), starting either 60 minutes before, or 30 or 60 minutes after MCAO (each group n = 12). After a 2-hour period of ischemia and 2 hours of reperfusion, the animals were sacrificed for assessment of brain water content, sodium, and potassium concentrations. AQP4 expression was assessed by immunoblotting. Statistical analysis was performed by ANOVA followed by Tukey's post hoc test. PMA treatment significantly reduced brain water content concentration in the infarcted area when started before or 30 minutes post-occlusion (p < 0.001, p = 0.022) and prevented the subsequent sodium shift (p < 0.05). Furthermore, PMA reduced ischemia-induced AQP4 up-regulation (p < 0.05). Attenuation of the ischemia-induced AQP4 up-regulation by PMA suggests that the reduction in brain edema formation following PMA treatment was at least in part mediated by AQP4 modulation.

The importance of translational research in brain injury.

Progress in the understanding of the pathophysiologic process and management of brain injury provides a unique challenge to the young investigator. Currently, there are teams both in the laboratory and clinical settings which may or may not interact as a result of the depth and breadth of the problems before them. For example, laboratory teams may be focused on cellular or molecular mechanisms of injury while the clinical investigator is attempting to deal with refractory ICP and it's treatment. It is clear that many aspects of biological research must indeed be approached using molecular techniques of neuroscience and much has been learned. However, the translational aspect of this effort may be elusive as it is unclear at present how these molecular techniques translate into the intensive care unit and the patient. For many, the research paths taken in the laboratory and ICU will always remain independent. For those who desire a more direct pathway to treatment, the "bench to bedside" approach is one which is more likely to yield results. Several examples will be given to strengthen the notion that we must not abandon the translational aspect of research but to embrace the process if we are to further improve outcome from brain injury.

Three-year outcome of shunted idiopathic NPH patients.

The incidence of idiopathic normal pressure hydrocephalus (iNPH) has increased as a result of improved longevity. This report describes the 3-year outcome of shunted iNPH patients compared to three-month outcome after shunting. Patients (n = 50) (Age 70.4 +/- 8.9) admitted to our service were diagnosed and treated according to a fixed protocol for management of iNPH and after shunting were followed at least three times per year in clinic. The outcome of 50 patients was graded according to the level of improvement in symptoms as Excellent/Good, Partial or None in each category of Gait, Incontinence and Dementia. If we lump favorable (excellent, good, partial recovery) vs poor recovery (none), we found from 3 months to 3 years, a moderate decline in gait performance (91% to 75%), a retention of memory improvement (80%-80%) and an improvement in incontinence occurred over time (70%-82.5%). With proper diagnosis and management of iNPH, shunting of patients is associated with a favorable risk/benefit ratio that is reasonably long lasting.

Contribution of raised ICP and hypotension to CPP reduction in severe brain injury: correlation to outcome.

The aim of this study was to determine to what degree hypotension and ICP contribute to the reduction of cerebral perfusion pressure (CPP), particularly in light of the shift in emphasis to CPP management by the use of pressors. The study population consisted of severely head injured patients extracted retrospectively from the Traumatic Coma Data Bank and compared with 139 patients from the Smith Kline component of the American Brain Injury Consortium database where outcome was available. The percentage time that ICP exceeded 20 mm Hg and CPP less than 60 mm Hg was computed for 5 days post injury. At each hour when CPP was less than 60 mm Hg the contribution of raised ICP and low arterial pressure or both was determined. In the first cohort, hypotension was the predominant factor leading to CPP reduction. With use of the CPP concept of treatment, the major contribution to CPP shifted to ICP and arterial hypotension played less of a role. Overall, CPP management has been associated with improved outcome.

Mitochondrial injury measured by proton magnetic resonance spectroscopy in severe head trauma patients.

The aim of this study was to evaluate the extent of mitochondrial injury by assessing N-Acetyl-Aspartate by MR spectroscopy in head injured patients and relating the extent of mitochondrial injury to outcome. The study population (n = 15) consisted of head injured patients (GCS < 8) in whom legal consent was obtained for MRS studies. Studies were performed on a 1.5 Tesla Vision/Siemens system. Size of Voxel equaled 8 cm3 with location determined from T1 images. Voxels were positioned adjacent to the lesion and in the contralateral hemisphere for focal and bilateral for diffuse. Mitochondrial impairment was considered as percent reduction in NAA/ Cr ratio compared to matched controls. Mitochondrial impairment gradually increases soon after injury reaching a nadir at 10 days. Subsequently, mitochondria recover in patients with favorable outcome, but remains impaired in patients with poor outcome. The prognostic value of NAA/Cr to assist in management and also to serve as a surrogate endpoint for clinical trials appears promising.

Guidelines for management of idiopathic normal pressure hydrocephalus: progress to date.

The aim of this project was to develop evidenced based guidelines for the diagnosis and management of idiopathic normal pressure hydrocephalus (iNPH). An advisory panel consisting of the authors assisted by international experts met on several occasions and formulated preliminary guidelines for iNPH managemen. The authors developed evidentiary tables based on available literature from 1966 to the present. Additional meetings to refine the evidentiary tables and incorporate expert opinion when necessary resulted in the development the iNPH guidelines. Evidence based guidelines identifying the value of clinical examination, brain imaging, Tap Test, CSF drainage, ICP monitoring and Surgical Management in diagnosing and treating the iNPH patient were developed. These are the first international evidence based guidelines focused on iNPH. Class I data were scant and guidelines relied mostly on class II and III evidence. It became clear that more prospective randomized studies are needed to resolve some of the controversial issues such as iNPH classification and sensitivity of diagnostic tests for identifying shunt responsive iNPH.

Mortality from traumatic brain injury.

It is the general sense that mortality has been decreasing in recent years compared to earlier studies described by the NIH traumatic coma data bank. We studied mortality during the period of 1984 to 1996 to determine if indeed mortality from severe traumatic brain injury was decreasing and to identify factors which might account for the reduction. The study population (N = 1839) consisted of severely head injured patients extracted retrospectively from the TCDB (635), MCV (382), and 822 patients from clinical trial databases conducted in the United States. Mortality was obtained from each of the databases for the age range form 16 to 65. Penetrating injury and treatment groups in the clinical trial databases were excluded. Mortality in the year 1984 equaled 39% and gradually decreased to a level of 27% in 1996. When adjusting for age, motor score and pupil reaction, the mortality of the period from 1984 to 1987 was significantly higher (p < 0.05) than that of the period 1988 to 1996. During the period 1984 through 1996, mortality from severe brain injury steadily declined. Factors other than age, motor score and pupil reactivity over time are responsible for this reduction. This reduction over time is an important factor for prognostic modeling of TBI.

Impact acceleration injury in the rat: evidence for focal axolemmal change and related neurofilament sidearm alteration.

Recently we reported that traumatic brain injury evokes local changes in the axolemma's permeability, in concert with local cytoskeletal changes involving neurofilament (NF) compaction and sidearm loss, all of which contribute to the genesis of reactive axonal change. Since it was of concern that these events may be either injury model- or species-specific, we sought to address these phenomena in a different but well-characterized animal model and species. Further, to provide more compelling insight into the potential for NF compaction and sidearm alteration, we also employed antibodies specific for the NF rod domains, which are readily visualized only when the NF sidearms are disturbed. Rats were subjected to impact acceleration injury. To assess the potential for altered axolemmal permeability, 5 animals received intrathecal horseradish peroxidase (HRP), normally excluded by the intact axolemma. To assess the potential for NF sidearm alteration, another 14 animals were processed for the visualization of antibodies targeting the NF rod domain at 5 minutes (min) to 24 hours (h) postinjury. All animals were evaluated at the LM and EM levels. Those animals receiving intrathecal HRP showed immediate focal alterations in the axolemma's permeability to the normally excluded tracer. Over a 2 h period, these axons demonstrated NF compaction. Antibodies targeted to the rod domains revealed focal intra-axonal immunoreactivity in sites closely correlated with those showing altered axolemmal permeability. These same sites also demonstrated evidence of NF compaction and sidearm loss/perturbation. Collectively, these findings suggest that occurrence of altered axolemmal permeability and concomitant cytoskeletal change are features common to traumatic brain injury in various animal models and species. Further, these studies underscore the utility of antibodies targeting the rod domain for the early detection of traumatically induced reactive change.

Mechanism of pseudotumor in Guillain-Barré syndrome.

A patient with pseudotumor cerebri and Guillain-Barré syndrome was studied with serial measurements of pressure-volume index, CSF outflow resistance (Ro), and CSF production rate. The results were comparable to findings in previous cases of idiopathic pseudotumor. Although Ro was elevated and progressively diminished as the pseudotumor syndrome improved, the extent of elevation in Ro was inadequate to account for raised CSF pressure. These results suggest an alternative explanation for pseudotumor based on raised effective venous pressures at points of CSF outflow that are passively reflected in raised CSF pressure. A parallel rise in vascular and CSF pressure may also explain why patients with pseudotumor tolerate such high intracranial pressures.

Vegetative state after closed-head injury. A Traumatic Coma Data Bank Report.

To elucidate the clinical course of the vegetative state after severe closed-head injury, the Traumatic Coma Data Bank was analyzed for outcome at the time of discharge from the hospital and after follow-up intervals ranging up to 3 years after injury. Of 650 patients with closed-head injury available for analysis, 93 (14%) were discharged in a vegetative state. In comparison with conscious survivors, patients in a vegetative state sustained more severe closed-head injury as reflected by the Glasgow Coma Scale scores and pupillary findings and more frequently had diffuse injury complicated by swelling or shift in midline structures. Of 84 patients in a vegetative state who provided follow-up data, 41% became conscious by 6 months, 52% regained consciousness by 1 year, and 58% recovered consciousness within the 3-year follow-up interval. A logistic regression failed to identify predictors of recovery from the vegetative state.

Xenon/computed tomography cerebral blood flow measurements. Methods and accuracy.

We performed a series of five baboon experiments to compare cerebral blood flow measured with an improved stable xenon/CT method and the radiolabelled microsphere technique at a PaCO2 of 40 mm Hg. The xenon/CT method was implemented by fitting the arterial xenon uptake with a double exponential function, by measuring the oxygen and carbon dioxide concentrations continuously during each breath and by taking into account the lung-to-brain transit time of xenon. The time of xenon inhalation was extended to 30 minutes to obtain more reliable estimates of CBF in white matter regions. The results indicate an overall correlation coefficient of 0.92 between the two methods and good numeric agreement.

Intracellular acidosis in human and experimental brain injury.

Brain tissue acidosis is considered to play a role in the complex sequence of events following traumatic brain injury. This report reviews the experimental and clinical research conducted at the Medical College of Virginia to help clarify the extent of metabolic derangement that occurs and to evaluate the effect of treatment. Experimental injury models in ventilated animals showed that trauma produces a mild brain tissue acidosis that recovers within hours of injury. Hypoxia combined with trauma produces a relative ischemia and exacerbates the acidosis, which eventually resolves with resuscitation. Other studies revealed that CSF lactate measurements should be interpreted with caution, particularly in patients with subarachnoid hemorrhage. The results of two randomized clinical trials testing therapeutic effects of sustained hyperventilation and treatment with tromethamine (THAM) are discussed.

Increased intracranial pressure in head injury and influence of blood volume.

This article reviews the progress made by the Traumatic Coma Data (TCD) bank participants in studying the influence of raised intracranial pressure (ICP) on outcome in head-injured patients and summarizes new concepts of the pathophysiologic mechanisms involved n ICP rise.

Biomechanical aspects of a fluid percussion model of brain injury.

The fluid percussion model is in widespread use for the study of brain injury. However, the tissue deformation characteristics of the model have not been determined. Studies have suggested that at high levels of fluid percussion, the fluid percussion model is primarily a model of brainstem injury. It was proposed that this occurs as a direct result of the volume influx to the cranial vault at the moment of impact. This study examines the biomechanical deformation produced by the fluid percussion model. The purpose of this investigation was to describe the regional strain distribution in brain tissue at the moment of impact and to determine the effect of volume efflux produced by the percussion device. A cat skull was sectioned parasagittally and filled with an optically transparent gel. A grid pattern was painted in the midsagittal plane and was used to record the surrogate brain tissue deformation in response to fluid percussion loading. Motion of the grid pattern at low and high levels of fluid percussion loading was recorded using a high-speed camera, and a series of photographs developed from the high-speed film were analyzed to determine the intracranial strain distribution at these loading levels. The results of these studies indicated that the maximum site of strain was located in the region of the lower brainstem and that deformations were negligible in other regions of the brain. These studies provide an explanation for the pathophysiologic results obtained in a parallel series of experiments from which it was concluded that high-level fluid percussion is predominantly a model of lower brainstem injury.

Contrasting effects of dopamine therapy in experimental brain injury.

Management of cerebral perfusion pressure (CPP) is thought to be important for the treatment of traumatic brain injury (TBI). Vasopressors have been advocated as a method of increasing mean arterial blood pressure (mABP) and cerebral perfusion pressure (CPP) in the face of rising intracranial pressure (ICP). There are unresolved issues and theoretical risks about this therapy. This study therefore examined the effects of dopamine on physiological and MRI/MRS parameters in (1) a rodent model of rapidly rising intracranial pressure, caused by diffuse injury with secondary insult and (2) a model of cortical contusion. Dopamine was capable of restoring CPP in the model of rapidly rising ICP. This CPP restoration was associated with a partial restoration of CBF. Two profiles of change in the Apparent Diffusion Coefficient of water (ADCw) were seen; one in which ADCw recovered to baseline, and one in which ADCw remained persistently low. Dopamine did not alter these profiles. MRI assessed tissue water content was increased four hours after injury and dopamine increased cerebral water content in both subgroups of injury; significantly in the group with a persistently low ADCw (p < 0.01). In contusional injury, dopamine significantly worsened edema in both the ipsi- and contralateral hippocampus and temporal cortex. This occurred in the absence of ADCw changes, except in the contralateral hippocampus, where both water content and ADCw values rose with treatment, suggesting extracellular accumulation of water. In conclusion, although dopamine is capable of partially restoring CBF after injury, situations exist in which dopamine therapy worsens the swelling process. It is possible therefore that subgroups of patients exist who experience adverse effects of vasopressor treatment, and consequently the effects of vasopressor therapy in the clinical setting need to be more carefully evaluated.