Garnette R. Sutherland

Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas.

SummaryMatrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis.

POSTISCHEMIC HYPOTHERMIA: A CRITICAL APPRAISAL WITH IMPLICATIONS FOR CLINICAL TREATMENT

The use of hypothermia to mitigate cerebral ischemic injury is not new. From early studies, it has been clear that cooling is remarkably neuroprotective when applied during global or focal ischemia. In contrast, the value of postischemic cooling is typically viewed with skepticism because of early clinical difficulties and conflicting animal data. However, more recent rodent experiments have shown that a protracted reduction in temperature of only a few degrees Celsius can provide sustained behavioral and histological neuroprotection. Conversely, brief or very mild hypothermia may only delay neuronal damage. Accordingly, protracted hypothermia of 32–34°C may be beneficial following acute clinical stroke.A thorough mechanistic understanding of postischemic hypothermia would lead to a more selective and effective therapy. Unfortunately, few studies have investigated the mechanisms by which postischemic cooling conveys its beneficial effect. The purpose of this article is to evaluate critically the effects of postischemic temperature changes with a comparison to some current drug therapies. This article will stimulate new research into the mechanisms of lengthy postischemic hypothermia and its potential as a therapy for stroke patients.

Hyperperfusion Syndrome: Toward a Stricter Definition

OBJECTIVEHyperperfusion syndrome is a rare and potentially devastating complication of carotid endarterectomy or carotid artery angioplasty and stenting. With the advent of new imaging techniques, we reviewed our experience with this phenomenon. METHODSThis report is a retrospective review of 129 consecutive cases of carotid endarterectomy performed between June 1, 2000, and May 31, 2002, and 44 consecutive cases of carotid artery angioplasty and stenting performed between January 1, 1997, and May 31, 2002. We specifically searched for examples of patients who developed postprocedural nonthrombotic neurological deficits that typified the hyperperfusion syndrome. RESULTSSeven cases of hyperperfusion syndrome occurred, four after endarterectomy (3.1% of carotid endarterectomy cases) and three after stenting (6.8% of stenting cases). The cases of hyperperfusion were classified as presenting with 1) acute focal edema (two cases with stroke-like presentation, attributable to edema immediately after revascularization), 2) acute hemorrhage (two cases of intracerebral hemorrhage immediately after stenting and one case immediately after endarterectomy), or 3) delayed classic presentation (two cases with seizures, focal motor weakness, and/or late intracerebral hemorrhage at least 24 hours after endarterectomy). CONCLUSIONHyperperfusion syndrome may be more common and more variable in clinical presentation than previously appreciated.

Effect of Age in Rodent Models of Focal and Forebrain Ischemia

BACKGROUND AND PURPOSE The majority of animal experiments examining the nature and treatment of stroke have used relatively young animals ranging in age from 2 to 6 months. However, significant morphological, neurochemical, and behavioral changes occur with aging in rodents particularly during the first 24 months of age. This study examines the effect of age in two models of transient ischemia a forebrain and a focal model in male Wistar rats. METHODS We induced forebrain ischemia of 12 minutes duration by bilateral carotid artery occlusion with controlled hypotension at a mean blood pressure of 45 mm Hg and using an intraluminal filament technique, induced focal middle cerebral artery occlusion of 100 minutes duration at a mean blood pressure of 60 mm Hg. Physiological parameters were monitored and maintained within normal limits. On day 7 after ischemia, the rats were perfusion-fixed and the brains removed for quantitative histopathology. RESULTS After forebrain ischemia, older rats showed significantly less CA1 neuronal necrosis than the younger group (P < .003), whereas both striatal and neocortical injury were significantly greater in the older group (P < .05). Among animals subjected to focal ischemia, the volume of infarcted tissue and the number of necrotic neurons in the area adjacent to the infarction were both greater in older rats (P < .05). CONCLUSIONS This study emphasizes the importance of age in models of forebrain and focal ischemia. The interaction between age-related changes in morphology, neurochemistry, and behavior on the ischemic cascade complicates the interpretation of mechanistic data, and pharmacological effects observed in younger animals may not necessarily translate to an older population.

The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study

Energy metabolism in the human brain is not fully understood. Classically, glucose is regarded as the major energy substrate. However, lactate (conventionally a product of anaerobic metabolism) has been proposed to act as an energy source, yet whether this occurs in man is not known. Here we show that the human brain can indeed utilize lactate as an energy source via the tricarboxylic acid cycle. We used a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C substrates into the brain and recover (13)C metabolites from the brain, and high-resolution (13)C nuclear magnetic resonance. Microdialysis catheters were placed in the vicinity of focal lesions and in relatively less injured regions of brain, in patients with traumatic brain injury. Infusion with 2-(13)C-acetate or 3-(13)C-lactate produced (13)C signals for glutamine C4, C3 and C2, indicating tricarboxylic acid cycle operation followed by conversion of glutamate to glutamine. This is the first direct demonstration of brain utilization of lactate as an energy source in humans.

Prophylactic anticonvulsants in patients with brain tumour.

OBJECTIVE We conducted a clinical trial to determine if prophylactic anticonvulsants in brain tumour patients (without prior seizures) reduced seizure frequency. We stopped accrual at 100 patients on the basis of the interim analysis. METHODS One hundred newly diagnosed brain tumour patients received anticonvulsants (AC Group) or not (No AC Group) in this prospective randomized unblinded study. Sixty patients had metastatic, and 40 had primary brain tumours. Forty-six (46%) patients were randomized to the AC Group and 54 (54%) to the No AC Group. Median follow-up was 5.44 months (range 0.13-30.1 months). RESULTS Seizures occurred in 26 (26%) patients, eleven in the AC Group and 15 in the No AC Group. Seizure-free survivals were not different; at three months 87% of the AC Group and 90% of the No AC Group were seizure-free (log rank test, p = 0.98). Seventy patients died (unrelated to seizures) and survival rates were equivalent in both groups (median survival = 6.8 months versus 5.6 months, respectively; log rank test, p = 0.50). We then terminated accrual at 100 patients because seizure and survival rates were much lower than expected; we would need > or = 900 patients to have a suitably powered study. CONCLUSIONS These data should be used by individuals contemplating a clinical trial to determine if prophylactic anticonvulsants are effective in subsets of brain tumour patients (e.g. only anaplastic astrocytomas). When taken together with the results of a similar randomized trial, prophylactic anticonvulsants are unlikely to be effective or useful in brain tumour patients who have not had a seizure.

Long-term Glioblastoma Multiforme Survivors: a Population-based Study

BACKGROUND Long-term glioblastoma multiforme survivors (LTGBMS) are uncommon. The frequency which these occur in an unselected population and factors which produce these unusually long survivors are unknown. OBJECTIVES To determine in a population-based study 1) the frequency of LTGBMS in a population and 2) identify which patient, treatment or tumor characteristics would predict which glioblastoma (GBM) patient would become a LTGBMS. METHODS The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in southern Alberta between 1/1/75-12/31/91. Patient charts were reviewed and histology re-examined by a blinded neuropathologist. LTGBMS were defined as GBM patients surviving > or = 3 years after diagnosis. Each LTGBMS was compared to three age-, gender-, and year of diagnosis-matched controls to compare patient, treatment, and tumor factors to GBM patients without long-term survival. RESULTS There were 279 GBMs diagnosed in the study period. Five (1.8%) survived > or = three years (range, 3.2-15.8 years). Seven additional long-term survivors, who carried a diagnosis of GBM, were excluded after neuropathologic review; the most common revised diagnosis was malignant oligodendroglioma. LTGBMS (avg. age = 45 years) were significantly younger when compared to all GBM patients (avg. age = 59 years, p = 0.0001) diagnosed in the study period. LTGBMS had a higher KPS at diagnosis (p = 0.001) compared to controls. Tumors from LTGBMS tended to have fewer mitoses and a lower Ki-67 cellular proliferative index compared to controls. Radiation-induced dementia was common and disabling in LTGBMS. CONCLUSIONS These data highlight the dismal prognosis for GBM patients who have both a short median survival and very small chance (1.8%) of long-term survival. The LTGBMS were younger, had a higher performance status, and their tumors tended to proliferate less rapidly than control GBM patients. When long-term survival does occur it is often accompanied by severe treatment-induced dementia.

Primary intracerebral hemorrhage.

This article reviews the epidemiology, pathophysiology and management of primary intracerebral hemorrhage. In North American and European populations, 15% of strokes are due to intracerebral hemorrhage. Pathologically in hypertension, early arteriolar proliferation of smooth muscle is followed later by smooth muscle cell death and collagen deposition. This eventually leads to occlusion or ectasia of arterioles. The latter leads to Charcôt-Bouchard aneurysm formation and possible intracerebral hemorrhage. Amyloid deposition in the tunica media causes similar brittle arterioles. Fibrin globes in concentric spheres attempt to seal off the site of bleeding. But vasculopathy (either amyloid or hypertensive) inhibits the contractile capability of arterioles. The size of the final sphere of blood at cessation of bleeding determines the clinical spectrum, from asymptomatic to fatal. Since arteriolar bleeding is slower than arterial bleeding, several hours exist where intervention may be useful. While medical intervention is controversial, guidelines for blood pressure, intracranial pressure, glucose and seizure management exist. Surgical trials have tended to show no benefit. Recombinant factor VIIa is undergoing investigation as hemostatic therapy for intracerebral hemorrhage, to limit clot expansion and possibly also as a hemostatic adjunct to surgery.

Advances in mobile intraoperative magnetic resonance imaging.

OBJECTIVE The goal was to enhance a mobile magnetic resonance imaging system developed for neurosurgery. Components of the system included an actively shielded, 1.5-T superconducting magnet, a titanium operating room table, a radiofrequency (RF) head coil that could be disassembled, and local RF shielding. METHODS The system was designed and implemented by the Division of Neurosurgery, University of Calgary (Calgary, Alberta, Canada), in collaboration with the National Research Council of Canada Institute for Biodiagnostics (Winnipeg, Manitoba, Canada). The ceiling-mounted, 1.5-T magnet was moved into and out of the surgical field as required. After initial success in monitoring the resection of various intracranial and cranial base lesions, significant modifications to the system were made by Innovative Magnetic Resonance Imaging Systems, Inc. (Winnipeg, Manitoba, Canada), and BrainLAB (Heimstetten, Germany). These modifications included the design and construction of a shorter magnet with a larger bore and stronger gradients, widening of the titanium operating room table, modification of the RF coil housing to allow vertical movement and incorporation of a three-pin head-clamp, construction of a transparent, copper-impregnated RF shield, and integration with a surgical navigation system. RESULTS The movable intraoperative imaging system has now been used for 101 neurosurgical procedures, including the previously reported cases. CONCLUSION The modifications to the system have enhanced its integration with established neurosurgical techniques and have improved patient safety. The larger magnet bore size, together with the ability to move the RF coil vertically, allows placement of patients in prone or lateral positions. Surgical navigation has been successfully integrated with the intraoperatively acquired high-resolution images. The ability to identify and resect residual lesions before wound closure remains a tremendous immediate advantage of this technology.

Surgical robotics: a review and neurosurgical prototype development.

PURPOSEThe purpose of this article is to update the neurosurgical community on the expanding field of surgical robotics and to present the design of a novel neurosurgical prototype. It is intended to mimic standard technique and deploy conventional microsurgical tools. The intention is to ease its integration into the “nervous system” of both the traditional operating room and surgeon. CONCEPTTo permit benefit from updated intraoperative imaging, magnetic resonance imaging-compatible materials were incorporated into the design. Advanced haptics, optics, and auditory communication with the surgical site recreate the sight, sound, and feel of neurosurgery. RATIONALEMagnification and advanced imaging have pushed surgeons to the limit of their dexterity and stamina. Robots, in contrast, are indefatigable and have superior spatial resolution and geometric accuracy. The use of tremor filters and motion scalers permits procedures requiring superior dexterity. DISCUSSIONBreadboard testing of the prototype components has shown spatial resolution of 30 &mgr;m, greatly exceeding our expectations. Neurosurgeons will not only be able to perform current procedures with a higher margin of safety but also must speculate on techniques that have hitherto not even been contemplated. This includes coupling the robot to intelligent tools that interrogate tissue before its manipulation and the potential of molecular imaging to transform neurosurgical research into surgical exploration of the cell, not the organ.