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Anthony Marmarou

Object

Brain edema resulting from traumatic brain injury (TBI) or ischemia if uncontrolled exhausts volume reserve and leads to raised intracranial pressure and brain herniation. The basic types of edema—vasogenic and cytotoxic—were classified 50 years ago, and their definitions remain intact.

Methods

In this paper the author provides a review of progress over the past several decades in understanding the pathophysiology of the edematous process and the success and failures of treatment. Recent progress focused on those manuscripts that were published within the past 5 years.

Results

Perhaps the most exciting new findings that speak to both the control of production and resolution of edema in both trauma and ischemia are the recent studies that have focused on the newly described “water channels” or aquaporins. Other important findings relate to the predominance of cellular edema in TBI.

Conclusions

Significant new findings have been made in understanding the pathophysiology of brain edema; however, less progress has been made in treatment. Aquaporin water channels offer hope for modulating and abating the devastating effects of fulminating brain edema in trauma and stroke.

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Kenneth Shapiro and Anthony Marmarou

✓ The pressure-volume index (PVI) technique of assessing neural axis pressure-volume relationships was used as an adjunct to managing 22 children with severe head injuries and a Glasgow Coma Scale score of 8 or less. Ventricular cannulation was used to continuously monitor intracranial pressure (ICP). Actual PVI was measured by bolus injection of fluid and compared with predicted values determined from head circumference and spinal axis length in each patient. In 55% of the children, ICP was below 20 mm Hg at initial monitoring. During the course of monitoring, 86% of the children had ICP's exceeding 20 mm Hg. Reduced PVI (less than 80% of predicted normal) proved to be an accurate indicator of impending intracranial hypertension. The PVI proved to be a useful test for assessing the response to therapies for lowering ICP. This study demonstrates that reduced neural axis compliance accompanies intracranial hypertension following severe head injury in children, and that treatment of reduced neural axis compliance may prevent refractory intracranial hypertension.

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Panos P. Fatouros and Anthony Marmarou

Object. The authors present a quantitative in vivo magnetic resonance (MR) imaging method and propose its use for the accurate assessment of brain water in humans.

Methods. With this technique, a pure T1-weighted image of a selected brain slice in a patient is generated, and the image is subsequently converted to a pure water image by means of an equation derived from a tissue relaxation model. The image intensity in the resulting water map directly yields absolute measures of water expressed in grams of water per gram of tissue at a given anatomical location. The method has been validated previously in a series of phantom experiments and in an infusion model of brain edema in cats. In this report, the authors evaluate the method by using samples of tissue harvested from patients who underwent surgery for brain tumor removal and apply the technique to a series of normal volunteers, providing average regional brain water content (fw) values for a range of tissues. Application of the method in pathological conditions such as head trauma, tumor, and hydrocephalus allows quantification of regional or global increases in fw that result from edema.

Conclusions. It is now possible to obtain accurate brain water measurements with the anatomical resolution of MR imaging. This permits monitoring of the development and resolution of edema in a variety of clinical circumstances, thus enhancing understanding of the underlying pathophysiological processes.

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Kazuo Yoshida and Anthony Marmarou

✓ The metabolic brain acidosis after trauma has been thought to be harmful and to contribute to neurological deterioration. Amelioration of the brain acidosis either by systemic buffering agents or by hyperventilation has been proposed as a method of treatment. The objective of this study was to explore with magnetic resonance (MR) spectroscopy the metabolic changes in brain that occur with the use of hyperventilation, THAM (tromethamine; tris[hydroxymethyl]aminomethane), and a combination (THAM and hyperventilation) therapy in experimental fluid-percussion injury.

Brain lactate, brain pH, inorganic phosphate (Pi), and adenosine triphosphate levels were measured by 1H and 31P MR spectroscopy. Arterial and cerebrovenous lactate and water content in brain tissue was determined in 29 cats using the specific gravimetric technique. Following injury, the phosphocreatine (PCr)/Pi ratio, which is an index of cerebral energy depletion, decreased to 76% in four untreated animals, to 79% in 11 THAM-treated animals, to 68% in seven animals receiving hyperventilation, and to 66% in seven animals with combination THAM and hyperventilation therapy. The PCr/Pi ratio returned to a normal level in 8 hours in animals treated with THAM and THAM in combination with hyperventilation. The brain lactate index increased to 157% in the hyperventilation group after trauma. In cats receiving THAM plus hyperventilation, the brain lactate index was reduced to 142%, while the minimum rise of 126% was associated with treatment of THAM alone. In the THAM-treatment and combination-treatment groups, the water content of the white and gray matter was significantly decreased compared with that in untreated cat brains.

Prolonged hyperventilation provided relative ischemia in brain tissue and promoted more production of brain lactate, no recovery of the PCr/Pi ratio, and no decrease in brain edema. On the other hand, administration of THAM decreased production of brain lactate and brain edema and promoted the recovery of cerebral energy dysfunction. It was found that THAM ameliorates the deleterious effects of hyperventilation by minimizing energy disturbance and that it also decreases brain edema. The authors conclude that THAM may be effective in reducing brain tissue acidosis and helpful as a metabolic stabilizing agent following severe head injury.

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Kenji Ohata and Anthony Marmarou

✓ The transit routes of fluid and particulate matter through brain tissue remain unclear. The object of this study was to examine the movement of macromolecules through brain tissue to further clarify the clearance pathways of edema proteins as they migrate toward the cortex. For this purpose, albumin solution (20 µl rat albumin diluted to 65 mg/ml with mock cerebrospinal fluid (CSF)) was intracerebrally infused into the caudate putamen, and the migration through brain tissue as well as through the ultrastructure of the cortical surfaces was explored using an immunocytochemical technique. The authors observed immunoreactive product on the glial limitans and pial lining as well as in the extracellular space of the cortical neuropil at 24 hours postinfusion, confirming that the protein had reached the cortical surface.

To confirm the efflux of macromolecules into the subarachnoid CSF, 71,200 D fluorescein isothiocyanatedextran (FITC-dextran 71,200) was infused; cortical surfaces of brains removed en bloc as well as coronal sections were macroscopically observed under ultraviolet illumination at 15 minutes and 24 hours postinfusion. It was observed that infused FITC-dextran 71,200 mainly localized in the cortical white matter and caudate putamen of the infusion site at 15 minutes postinfusion and by 24 hours was distributed in the entire cortex of the infused hemisphere. However, the dynamics of lower-molecular-weight substances was completely different. The spatial distribution of FITC-dextran 4400 diverged upward toward the cortical surface and spread more extensively than FITC-dextran 71,200. These observations were consistent with a diffusion process as the spread of the tracer was dependent upon molecular size. These studies provide compelling evidence that a process other than bulk flow was involved in the spread of macromolecules through the extracellular space of the normal cortical neuropil to sink into the subarachnoid space. It was concluded that the CSF pathway via the extracellular space of the cortical neuropil is a primary route for clearance of extracellular edema proteins to the subarachnoid space and that diffusion is involved in this process.

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Hiroshi Takagi, Kenneth Shapiro, Anthony Marmarou and Hugh Wisoff

✓ Microgravimetric technique was used to measure the water content of tumors and adjacent brain. Multiple 1-cu mm samples were obtained from 17 patients with neurosurgical lesions. The site of each sample was located on the appropriate computerized tomography (CT) slice, and the water content correlated with the CT attenuation coefficient.

The water content of peritumor white matter in 11 patients with glioblastomas was 5% to 8% H2O/gm tissue greater than the water content of white matter measured in three normal control individuals. These areas corresponded to low CT attenuation coefficients (8 to 15 EMI units). There were no statistically significant differences between the water content of tumors and adjacent white matter, even though the CT attenuation coefficient of the tumor was often of higher value. Low CT attenuation coefficient areas surrounding meningioma, metastasis, and lymphoma always correlated with elevated water content. The greatest water content (84.7% H2O/gm tissue) was found in the white matter surrounding an arteriovenous malformation. There was no correlation between the CT attenuation coefficient of this tissue and the water content in the arteriovenous malformation.

This study shows that areas of low CT attenuation coefficient may correlate with measurements of the water content of tissue, but that increased water content may exist without demonstrable changes in the CT attenuation coefficient.

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A new model of diffuse brain injury in rats

Part II: Morphological characterization

Montasser A. Abd-Elfattah Foda and Anthony Marmarou

✓ A new model producing diffuse brain injury, without focal brain lesions, has been developed in rats. This has been achieved by allowing a weight of 450 gm to fall onto a metallic disc fixed to the intact skull of the animal which is supported by a foam bed. Two levels of injury were examined by adjusting the height of the falling weight to either 1 m or 2 m. Two groups of animals were studied. Group 1 animals were separated into three subgroups: 10 received a 1-m weight drop, 58 received a 2-m weight drop, and 13 served as controls; all were allowed to breathe spontaneously. Group 2 animals were separated into the same subgroups: four received a 1-m weight drop, six received a 2-m weight drop, and four served as controls; all of these were mechanically ventilated during the procedure. In Group 1, morphological studies using light and electron microscopy were performed at 1, 6, 24, or 72 hours, or 10 days after insult; all Group 2 rats were studied at 24 hours after injury.

Results from Group 1 animals showed that no mortality occurred with the 1-m level injury, while 59% mortality was seen with the 2-m level injury. On the other hand, no mortality occurred in Group 2 animals regardless of the level of trauma induced. However, the morphological changes observed in both groups were similar. Gross pathological examination did not reveal any supratentorial focal brain lesion regardless of the severity of the trauma. Petechial hemorrhages were noticed in the brain stem at the 2-m level injury. Microscopically, the model produced a graded widespread injury of the neurons, axons, and microvasculature. Neuronal injury was mainly observed bilaterally in the cerebral cortex. Brain edema, in the form of pericapillary astrocytic swelling, was also noted in these areas of the cerebral cortex and in the brain stem. Most importantly, the trauma resulted in a massive diffuse axonal injury that primarily involved the corpus callosum, internal capsule, optic tracts, cerebral and cerebellar peduncles, and the long tracts in the brain stem. It is concluded that this model would be suitable for studying neuronal, axonal, and vascular changes associated with diffuse brain injury.

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Anthony Marmarou, Harold F. Young and Gunes A. Aygok

Object

The primary objective of this study was to estimate the prevalence of idiopathic normal-pressure hydrocephalus (NPH), both diagnosed and undiagnosed, among residents of assisted-living and extended-care facilities, by using a practical screening tool. A secondary objective was to evaluate prospectively the diagnosis and outcome of surgical treatment in a subset of patients residing in healthcare facilities who were at risk for idiopathic NPH.

Methods

A retrospective chart analysis was performed using the medical records from four nursing homes. The final analysis included 147 patient records. Symptomatology and comorbidity were evaluated, as was the ability to perform activities of daily living. In a subset of 17 patients residing in healthcare facilities, the authors applied a standard idiopathic NPH diagnostic and management protocol and followed up the patients 1 year after treatment.

The estimated incidence of suspected idiopathic NPH among all patients in the retrospective survey ranged from 9 to 14%, depending on the diagnostic criteria used. Among the cohort of 17 patients available for an in-hospital study and 1-year follow up, 11 received shunts and seven of these showed either transient or sustained improvement.

Conclusions

A valid and practical diagnostic method is needed to identify idiopathic NPH accurately before admitting patients to a healthcare facility. Data from a prospective study of 17 patients residing in healthcare facilities indicated that supplementary tests remain predictive of a positive response to shunt insertion but cannot predict whether a favorable outcome will be sustained in a population of patients who have been confined to a wheelchair for a prolonged period of time. This finding supports the notion of a finite window of opportunity for successful treatment of idiopathic NPH and the imperativeness of an early diagnosis.

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Anthony Marmarou, Kenneth Shulman and James LaMorgese

✓ The distribution of compliance and outflow resistance between cerebral and spinal compartments was measured in anesthetized, ventilated cats by analysis of the cerebrospinal fluid (CSF) pressure response to changes in CSF volume. Cerebral and spinal compartments were isolated by inflating a balloon positioned epidurally at the level of C-6. The change of CSF volume per unit change in pressure (compliance) and change of CSF volume per unit of time (absorption) were evaluated by inserting pressure data from the experimental responses into a series of equations developed from a mathematical model. It was found that 68% of total compliance is contributed by the cerebral compartment while the remaining 32% is contained within the spinal axis. The cerebral compartment accounted for 84% of total CSF absorption. The mechanism for spinal absorption appears to be similar in that no differences were obvious on the basis of pressure dynamics.

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Anthony Marmarou, Kiyoaki Tanaka and Kenneth Shulman

✓ Significant errors are introduced into the measurement of brain tissue water by the specific gravity technique when the edema fluid contains protein. Protein adds to the tissue solids, increasing the density of the tissue, and masks the proportional increase of brain water. Existing equations relating measured specific gravity and tissue water are not applicable, and a new formula was developed that compensates for the protein component of edema and reduces the experimental error. The new method was applied to the measurement of tissue water in cat brain made edematous by direct infusion of fluids of known composition and volume to test the theory. This technique for improving the gravimetric assessment of brain edema is presented.