[Cortical spreading depolarization phenomena in patients with traumatic and ischemic brain injuries. Results of a pilot study]. / Fenómenos de despolarización cortical propagada en los pacientes con lesiones cerebrales traumáticas e isquémicas. Resultados de un estudio piloto.

OBJECTIVES: To determine the frequency and duration of cortical spreading depolarization (CSD) and CSD-like episodes in patients with traumatic brain injury (TBI) and malignant middle cerebral artery infarction (MMCAI) requiring craniotomy. DESIGN: A descriptive observational study was carried out during 19 months. SETTING: Neurocritical patients. PATIENTS: Sixteen patients were included: 9 with MMCAI and 7 with moderate or severe TBI, requiring surgical treatment. INTERVENTIONS: A 6-electrode subdural electrocorticographic (ECoG) strip was placed onto the perilesional cortex. MAIN VARIABLES OF INTEREST: An analysis was made of the time profile and the number and duration of CSD and CSD-like episodes recorded from the ECoGs. RESULTS: Of the 16 patients enrolled, 9 presented episodes of CSD or CSD-like phenomena, of highly variable frequency and duration. CONCLUSIONS: Episodes of CSD and CSD-like phenomena are frequently detected in the ischemic penumbra and/or traumatic cortical regions of patients with MMCAI who require decompressive craniectomy or of patients with contusional TBI.

The gamut of blood flow responses coupled to spreading depolarization in rat and human brain: from hyperemia to prolonged ischemia.

Cortical spreading depolarizations (SD) have been shown to occur frequently in patients with aneurysmal subarachnoid hemorrhage (SAH) and are associated with delayed ischemic brain damage. In animal models the link between SD and cell damage is the microvascular spasm coupled to the passage of SDs, resulting in spreading ischemia. Here we compared the hemodynamic changes induced by SD between human and rat cerebral cortex. Specifically, we addressed the question, whether the full spectrum of regional cerebral blood flow (rCBF) responses to SD is found in the human brain in a similar fashion to animal models. SDs were identified by slow potential changes in electrocorticographic recordings and the rCBF response profiles and magnitudes were analyzed. We found a large variability of rCBF changes concomitant to SDs in rat and in human recordings. The spectrum ranged from normal hyperemic responses to prolonged cortical spreading ischemia with intermediate forms characterized by biphasic (hypoemic-hyperemic) responses. The bandwidths of rCBF responses were comparable and the relative response magnitudes of hypo- and hyperperfusion phases did not differ significantly between rats and humans. The correspondence of the rCBF response spectrum to SD between human and animal brain underscores the importance of animal models to learn more about the mechanisms underlying the early and delayed pathological sequelae of SAH.

Application of stereological estimates in patients with severe head injuries using CT and MR scanning images.

Severe brain damage is often followed by serious complications. Quantitative measurements, such as regional volume and surface area under various conditions, are essential for understanding functional changes in the brain and assessing prognosis. The affected brain tissue is variable, hence traditional imaging methods are not always applicable and automatic methods may not be able to match the individual observer. Stereological techniques are alternative tools in the quantitative description of biological structures, and have been increasingly applied to the human brain. In the present study, we applied stereological techniques to representative CT and MRI brain scans from five patients to describe how stereological methods, when applied to scans of trauma patients, can provide a useful supplement to the estimation of structural brain changes in head injuries. The reliability of the estimates was tested by obtaining repeated intra- and interobserver estimates of selected subdivisions of the brain in patients with acute head injury, as well as in an MR phantom. The estimates of different subdivisions showed a coefficient of variation (CV) below 12% in the patients and below 7% for phantom estimation. The validity of phantom estimates was tested by the average deviation from the true geometric values, and was below 10%. The stereological methods were compared with more traditional region-based methods performed on medical imaging, which showed a CV below 7% and bias below 14%. It is concluded that the stereological estimates may be useful tools in head injury quantification.

Aneurysmal subarachnoid haemorrhage in a patient with thyrotoxicosis.

A case of subarachnoid haemorrhage secondary to rupture of an intracranial aneurysm occurring in a patient with new-onset, frank thyrotoxicosis is described. This unusual case highlights the dilemma of whether to continue beta-blockers such as propanolol for frank thyrotoxicosis, or whether to assign higher priority to maintaining adequate cerebral perfusion pressure in established ischaemic deficit due to vasospasm. In a complicated case such as this, the Maudsley Mentation Test score and perfusion CT scanning are two useful adjuncts for the early detection and evaluation of the course of ischaemic deficit.

Depolarisation phenomena in traumatic and ischaemic brain injury.

1. Cortical spreading depression is a non-physiological global depolarisation of neurones and astrocytes that can be initiated with varying degrees of difficulty in the normally perfused cerebral cortex in the experimental laboratory. Induction is typically with electrical stimulation, needling of the cerebral cortex, or superfusion of isotonic or more concentrated potassium chloride solution. The phenomenon propagates across the cerebral cortex at a rate of 2-5 mm per minute, and is accompanied by marked but transient increases in cerebral blood flow, in local tissue oxygen tension, and most probably in metabolic rate. 2. Peri-infarct depolarisation is also a depolarisation event affecting neurones and glia, with an electrophysiological basis similar or identical to CSD, but occurring spontaneously in the ischaemic penumbra or boundary zone in focal cerebral cortical ischaemia. Most such events arise from the edge of the ischaemic core, and propagate throughout the penumbra, at a rate similar to that of cortical spreading depression. 3. Cortical spreading depression in the normally perfused cortex does not result in histological damage whereas peri-infarct depolarisations augment neuronal damage in the penumbra, and are believed by many authors to constitute an important, or the principal, mechanism by which electrophysiological penumbra progressively deteriorates, ultimately undergoing terminal depolarisation and thus recruitment into an expanded core lesion. 4. There is some experimental evidence to suggest that under some circumstances induction of episodes of cortical spreading depression can confer protection against subsequent ischaemic insults. 5. Although cortical spreading depression and peri-infarct depolarisations have been extensively studied in the experimental in vivo models, there is now clear evidence that depolarisations also occur and propagate in the human brain in areas surrounding a focus of traumatic contusion. 6. Whether such events in the injured human brain represent cortical spreading depression or peri-infarct depolarisation is unclear. However, invasive and probably non-invasive monitoring methods are available which may serve to distinguish which event has occurred. 7. Much further work will be needed to examine the relationship of depolarisation events in the injured brain with outcome from cerebral ischaemia or head injury, to examine the factors which influence the frequency of depolarisation events, and to determine which depolarisation events in the human brain augment the injury and should be prevented.

Glucose/insulin infusions in the treatment of subarachnoid haemorrhage: a feasibility study.

Hyperglycaemia following subarachnoid haemorrhage (SAH) is well recognized and has been shown to be associated with a worse prognosis. It is currently unclear whether this is a secondary phenomenon reflecting the magnitude of the stress response or whether it contributes directly to the pathophysiological disturbances within the brain. There is significant experimental work on ischaemic stroke to suggest that hyperglycaemia increases infarct volume. The authors propose that controlling blood glucose following SAH is safe and that it might improve outcome. All patients admitted with SAH were treated with insulin to control plasma glucose with a target range of 5.0-7.0 mmol/l. Episodes of hypoglycaemia were recorded. Outcome was assessed at 3 months using the Glasgow Outcome Scale. Fifty-five patients were recruited. 32/3389 (0.94%) of glucose readings fell below 3.5 mmol/l. All were treated with i.v. glucose without evidence of clinical deterioration. Insulin treatment for hyperglycaemia following SAH is feasible and safe. A randomised trial is required to assess any effect on outcome.

Oscillations in the near-infrared signal in patients with severe head injury.

OBJECTIVE: To use a non-invasive system, near infrared spectroscopy (NIRS) to detect oscillations in cerebral blood oxygenation in intensive care patients with severe traumatic brain injury. MATERIALS AND METHODS: 9 patients (7 male, 2 female) with a GCS < 8 were monitored in the intensive care units at King's College Hospital and the Royal London Hospital. A CCD-based spectrometer was coupled to the patient's forehead with one excitation and one detection optode. Spectra in the range of approximately 600-800 nm were collected at intervals of 2-4 seconds (subject to signal strength) and a curve-fitting algorithm applied, thus extracting time series data for oxyhaemoglobin (HbO), deoxyhaemoglobin (Hb) and cytochrome-c-oxidase (Cyt-c). The oxyhaemoglobin data was subjected to Fast Fourier Transform analysis. RESULTS: In all nine patients, unequivocal oscillations in the HbO signal were observed. The frequencies of these oscillations were at: 0.013-0.042 Hz (0.78-2.5 cycles min-1), 0.11 Hz (6.7 cycles min-1) and 0.19-0.28 Hz (12-16 cycles min-1). CONCLUSIONS: The presence of oscillations at 0.013-0.033 Hz, 0.11 Hz and 0.19-0.28 Hz are compatible with B-waves, vasomotion and respiratory cycles (respectively). However, due to the unknown contribution of the scalp to the NIR signal this data must be interpreted with care. Further work is required in order to investigate this.

Traumatic basilar pseudoaneurysm with a basilar-cavernous arteriovenous fistula.

A traumatic pseudoaneurysm of the basilar artery with a basilar-cavernous sinus arteriovenous fistula was diagnosed in a 12-year-old girl using CT, MRI and angiography. It was successfully treated by coil embolisation. We speculate on the mode of formation of this rare traumatic lesion.

Development of an index of biotic integrity for the Little Arkansas River Basin, Kansas.

An index of biotic integrity (IBI) was developed for the Little Arkansas River Basin (LARB) in south-central Kansas by establishing a reference condition for the watershed. Twelve metrics, in six categories, were chosen for use in the IBI. Fish assemblages from 30 sites were selected to represent the highest quality sites (reference sites) remaining in the LARB. In addition, 20 historical sites were used to show changes in the watershed over the last century. The modified IBI was then tested at 10 sites within the basin to assess the affects of urban and agricultural disturbances on fish community structure in the Wichita area. IBI scores were statistically lower for the urban versus the agricultural sites. Overall, IBI scores rated from poor to fair, supporting the contention that the fish communities within the LARB are impaired.

Cluster analysis of diffusion tensor magnetic resonance images in human head injury.

OBJECTIVE: Issues surrounding the nature of the edema associated with traumatic brain injury in humans, and its evolution in the acute phase, remain unresolved. This study aimed to characterize the topographical nature of the pathophysiological changes in human traumatic brain injury with diffusion tensor magnetic resonance imaging. METHODS: Multislice diffusion-weighted magnetic resonance imaging data were acquired from five patients undergoing elective ventilation for management of traumatic focal contusion or hematomas. The diffusion tensor and the T2-weighted intensity were then computed for every voxel in the image data set for each patient. The topographical distribution of abnormalities in the trace of the diffusion tensor and T2-weighted images were characterized by cluster analysis. RESULTS: In four patients with technically satisfactory data, a narrow band of tissue was observed in the periphery of focal lesions, which was characterized by selective reduction in the trace of the diffusion tensor, without any associated increase in the T2-weighted signal intensity. CONCLUSION: This change is interpreted as indicating either a partial redistribution of water from the extra- to intracellular compartment, or a reduction in the diffusivity of water in the intracellular or cytosolic environment. These diffusion and T2-weighted characteristics are also found in early ischemic change, hence, such regions may represent potentially salvageable tissue at risk of permanent damage. The study illustrates the advantage of using information contained within the diffusion tensor in addition to more conventional imaging sequences.

A fundamental role for the nitric oxide-G-kinase signaling pathway in mediating intercellular Ca(2+) waves in glia.

In this study, we highlight a role for the nitric oxide-cGMP-dependent protein kinase (NO-G-kinase) signaling pathway in glial intercellular Ca(2+) wave initiation and propagation. Addition of the NO donor molsidomine (100-500 microM) or puffing aqueous NO onto primary glial cell cultures evoked an increase in [Ca(2+)](i) in individual cells and also local intercellular Ca(2+) waves, which persisted after removal of extracellular Ca(2+). High concentrations of ryanodine (100-200 microM) and antagonists of the NO-G-kinase signaling pathway essentially abrogated the NO-induced increase in [Ca(2+)](i), indicating that NO mobilizes Ca(2+) from a ryanodine receptor-linked store, via the NO-G-kinase signaling pathway. Addition of 10 microM nicardipine to cells resulted in a slowing of the molsidomine-induced rise in [Ca(2+)](i), and inhibition of Mn(2+) quench of cytosolic fura-2 fluorescence mediated by a bolus application of 2 microM aqueous NO to cells, indicating that NO also induces Ca(2+) influx in glia. Mechanical stress of individual glial cells resulted in an increase in intracellular NO in target and neighboring cells and intercellular Ca(2+) waves, which were NO, cGMP, and G-kinase dependent, because incubating cells with nitric oxide synthase, guanylate cyclase, and G-kinase inhibitors, or NO scavengers, reduced Delta[Ca(2+)](i) and the rate of Ca(2+) wave propagation in these cultures. Results from this study suggest that NO-G-kinase signaling is coupled to Ca(2+) mobilization and influx in glial cells and that this pathway plays a fundamental role in the generation and propagation of intercellular Ca(2+) waves in glia.

Factors influencing the frequency of fluorescence transients as markers of peri-infarct depolarizations in focal cerebral ischemia.

BACKGROUND AND PURPOSE: Peri-infarct depolarizations (PIDs) that occur in ischemic boundary zones of the cerebral cortex of experimental animals have been shown to promote rather than simply to indicate the evolution of the lesion and are especially prominent in the rat. To study the influence of one factor, species, on PID incidence, we compared the frequency of PIDs in a primate species, the squirrel monkey, with that in the cat after middle cerebral artery occlusion. Plasma glucose was reviewed as a possible cause of interexperiment variability in the cat experiments. METHODS: In open-skull experiments under chloralose anesthesia, changes in cortical fluorescence believed to indicate NADH/NAD(+) redox state, as markers of PIDs, were recorded by serial imaging of the cortical surface in vivo for 4 hours after middle cerebral artery occlusion. RESULTS: Fluorescence transients occurred in squirrel monkeys at a frequency (mean+/-SD) of 0.7+/-0.8 hours(-1) (n=5), which was not significantly less than in that observed in cats (1.3+/-1.6 hours(-1), n=8). Data from the cat experiments indicated a relationship between number of transients (dependent) and plasma glucose, with a striking increase in PID frequency in association with values of mean postocclusion plasma glucose <4.1 mmol/L (Mann-Whitney U=15.0, P=0.034); this observation agrees well with other published findings. CONCLUSIONS: Transient changes in fluorescence strongly suggestive of peri-infarct depolarizations, either transient or terminal, occur and propagate in the ischemic cerebral cortex of a nonhuman primate. The results also suggest that the relationship of frequency of peri-infarct depolarizations with plasma glucose requires further examination, to confirm the finding and to determine a safe lower limit for a target range for control of plasma glucose if insulin is used in the management of patients with cerebral ischemia.

Design and evaluation of a system for microscope-assisted guided interventions (MAGI).

The problem of providing surgical navigation using image overlays on the operative scene can be split into four main tasks--calibration of the optical system; registration of preoperative images to the patient; system and patient tracking, and display using a suitable visualization scheme. To achieve a convincing result in the magnified microscope view a very high alignment accuracy is required. We have simulated an entire image overlay system to establish the most significant sources of error and improved each of the stages involved. The microscope calibration process has been automated. We have introduced bone-implanted markers for registration and incorporated a locking acrylic dental stent (LADS) for patient tracking. The LADS can also provide a less-invasive registration device with mean target error of 0.7 mm in volunteer experiments. These improvements have significantly increased the alignment accuracy of our overlays. Phantom accuracy is 0.3-0.5 mm and clinical overlay errors were 0.5-1.0 mm on the bone fiducials and 0.5-4 mm on target structures. We have improved the graphical representation of the stereo overlays. The resulting system provides three-dimensional surgical navigation for microscope-assisted guided interventions (MAGI).

Intercellular Ca(2+) waves in rat hippocampal slice and dissociated glial-neuron cultures mediated by nitric oxide.

Nitric oxide (NO) may participate in cell-cell communication in the brain by generating intercellular Ca(2+) waves. In hippocampal organotypic and dissociated glial-neuron (>80% glia) cultures local applications of aqueous NO induced slowly propagating intercellular Ca(2+) waves. In glial cultures, Ca(2+) waves and Mn(2+) quench of cytosolic fura-2 fluorescence mediated by NO were inhibited by nicardipine, indicating that NO induces Ca(2+) influx in glia which is dihydropyridine-sensitive. As NO treatments also depolarised the plasma membrane potential of glia, the nicardipine-sensitive Ca(2+) influx might be due to the activation of dihydropyridine-sensitive L-type Ca(2+) channels. Both nicardipine-sensitive intercellular Ca(2+) waves and propagating cell depolarisation induced by mechanical stress of individual glia were inhibited by pretreating cultures with either an NO scavenger or N(G)-methyl-L-arginine. Results demonstrate that NO can induce Ca(2+) waves in hippocampal slice cultures, and that Ca(2+) influx coupled to NO-mediated membrane depolarisation might assist in fashioning their spatio-temporal dynamics.

Stereo augmented reality in the surgical microscope.

We present an augmented reality system that allows surgeons to view features from preoperative radiological images accurately overlaid in stereo in the optical path of a surgical microscope. The purpose of the system is to show the surgeon structures beneath the viewed surface in the correct 3-D position. The technical challenges are registration, tracking, calibration and visualisation. For patient registration, or alignment to preoperative images, we use bone-implanted markers and a dental splint is used for patient tracking. Both microscope and patient are tracked by an optical localiser. Calibration uses an accurately manufactured object with high contrast circular markers which are identified automatically. All ten camera parameters are modelled as a bivariate polynomial function of zoom and focus. The overall system has a theoretical overlay accuracy of better than 1 mm. Implementations of the system have been tested on seven patients. Recent measurements in the operating room conformed to our accuracy predictions. For visualisation the system has been implemented on a graphics workstation to enable high frame rates with a variety of rendering schemes. Several issues of 3-D depth perception remain unsolved, but early results suggest that perception of structures in the correct 3-D position beneath the viewed surface is possible.

A system for microscope-assisted guided interventions.

We present a system for surgical navigation using stereo overlays in the operating microscope aligned to the operative scene. This augmented reality system provides 3D information about nearby structures and offers a significant advancement over pointer-based guidance, which provides only the location of one point and requires the surgeon to look away from the operative scene. With a previous version of this system, we demonstrated feasibility, but it became clear that to achieve convincing guidance through the magnified microscope view, a very high alignment accuracy was required. We have made progress with several aspects of the system, including automated calibration, error simulation, bone-implanted fiducials and a dental attachment for tracking. We have performed experiments to establish the visual display parameters required to perceive overlaid structures beneath the operative surface. Easy perception of real and virtual structures with the correct transparency has been demonstrated in a laboratory and through the microscope. The result is a system with a predicted accuracy of 0.9 mm and phantom errors of 0.5 mm. In clinical practice errors are 0.5-1.5 mm, rising to 2-4 mm when brain deformation occurs.

The relationship between pure tone thresholds and the radiological dimensions of acoustic neuromas.

A retrospective analysis of 109 consecutive patients presenting with acoustic neuromas between 1986 and 1997 were undertaken. Sufficient data were available in 104 cases for comparison. In 65 cases patients had undergone surgery and the radiological diagnosis of acoustic neuroma was confirmed histologically. In this group there were 25 large and 40 small tumors when a maximal radiological diameter of 2.5 cm was used to subdivide the groups. When pure tone thresholds were compared at specific frequencies, in those with hearing ears, there was no significant difference between the two groups. Our results are compared with recent series and the causes of hearing loss associated with acoustic neuroma are discussed.

The use of in vivo fluorescence image sequences to indicate the occurrence and propagation of transient focal depolarizations in cerebral ischemia.

A method for the detection and tracking of propagated fluorescence transients as indicators of depolarizations in focal cerebral ischemia is described, together with initial results indicating the potential of the method. The cortex of the right cerebral hemisphere was exposed for nonrecovery experiments in five cats anesthetized with chloralose and subjected to permanent middle cerebral artery (MCA) occlusion. Fluorescence with 370-nm excitation (attributed to the degree of reduction of the NAD/H couple) was imaged with an intensified charge-coupled device camera and digitized. Sequences of images representing changes in gray level from a baseline image were examined, together with the time courses of mean gray levels in specified regions of interest. Spontaneous increases in fluorescence occurred, starting most commonly at the edge of areas of core ischemia; they propagated usually throughout the periinfarct zone and resolved to varying degrees and at varying rates, depending on proximity of the locus to the MCA input. When a fluorescence transient reached the anterior cerebral artery territory, its initial polarity reversed from an increase to a decrease in fluorescence. An initial increase in fluorescence in response to the arrival of a transient may characterize cortex that will become infarcted, if pathophysiological changes in the periinfarct zone are allowed to evolve naturally.