Glioma cells have a remarkable capacity to infiltrate the brain and migrate long distances from the tumor, making complete surgical resection impossible. Yet, little is known about how glioma cells interact with the complex microenvironment of the brain. To investigate the patterns and dynamics of glioma cell infiltration and migration, we stereotactically injected eGFP and DsRed-2 labeled rat C6 glioma cells into neonatal rat forebrains and used time-lapse microscopy to observe glioma cell migration and proliferation in slice cultures generated from these brains. In this model, glioma cells extensively infiltrated the brain by migrating along the abluminal surface of blood vessels. Glioma cells intercalated their processes between the endothelial cells and the perivascular astrocyte end feet, but did not invade into the blood vessel lumen. Dynamic analysis revealed notable similarities between the migratory behavior of glioma cells and that previously observed for glial progenitor cells. Glioma cells had a characteristic leading process and migrated in a saltatory fashion, with bursts of migration separated by periods of immobility, and maximum speeds of over 100 microm/h. Migrating glioma cells proliferated en route, pausing for as short as an hour to divide before the daughter cells resumed migrating. Remarkably, the majority of glioma cell divisions took place at or near vascular branch points, suggesting that mitosis is triggered by local environmental cues. This study provides the first dynamic analysis of glioma cell infiltration in living brain tissue and reveals that the migration and proliferation of transplanted glioma cells is directed by interactions with host brain vasculature.

The authors prospectively used a new hand-held point-and-shoot pupillometer to assess pupillary function quantitatively. Repetitive measurements were initially made in more than 300 healthy volunteers ranging in age from 1 to 87 years, providing a total of 2,432 paired (alternative right eye, left eye) measurements under varying light conditions. The authors studied 17 patients undergoing a variety of nonintracranial, nonophthalmological, endoscopic, or surgical procedures and 20 seniors in a cardiology clinic to learn more about the effects of a variety of drugs. Additionally, the authors carried out detailed studies in 26 adults with acute severe head injury in whom intracranial pressure (ICP) was continuously monitored. Finally, five patients suffering from subarachnoid hemorrhage were also studied. Quantitative pupillary measurements could be reliably replicated in the study participants. In healthy volunteers the resting pupillary aperture averaged 4.1 mm and the minimal aperture after stimulation was 2.7 mm, resulting in a 34% change in pupil size. Constriction velocity averaged 1.48 +/- 0.33 mm/second. Pupillary symmetry was striking in both healthy volunteers and patients without intracranial or uncorrected visual acuity disorders. In the 2,432 paired measurements in healthy volunteers, constriction velocity was noted to fall below 0.85 mm/second on only 33 occasions and below 0.6 mm/second on eight occasions (< one in 310 observations). In outpatients, the reduction in constriction velocity was observed when either oral or intravenous narcotic agents and diazepam analogs were administered. These effects were transient and always symmetrical. Among the 26 patients with head injuries, eight were found to have elevations of ICP above 20 mm Hg and pupillary dynamics in each of these patients remained normal. In 13 patients with a midline shift greater than 3 mm, elevations of ICP above 20 mm Hg, when present for 15 minutes, were frequently associated with a reduction in constriction velocity on the side of the mass effect to below 0.6 mm/second (51% of 156 paired observations). In five patients with diffuse brain swelling but no midline shift, a reduction in constriction velocities did not generally occur until the ICP exceeded 30 mm Hg. Changes in the percentage of reduction from the resting state following stimulation were always greater than 10%, even in patients receiving large doses of morphine and propofol in whom the ICP was lower than 20 mm Hg. Asymmetry of pupillary size greater than 0.5 mm was observed infrequently (< 1%) in healthy volunteers and was rarely seen in head-injured patients unless the ICP exceeded 20 mm Hg. Pupillometry is a reliable technology capable of providing repetitive data on quantitative pupillary function in states of health and disease.

Overall significantly greater frequencies of brain swelling and intracranial hypertension were found in female compared with male patients (35% compared with 24% [p < 0.0008] and 39 compared with 31% [p < 0.03], respectively). The highest rates were found in female patients younger than 51 years old (38% compared with 24% [p < 0.002] and 40% compared with 30% [p < 0.02], respectively, in male patients younger than 51 years of age). This effect was independent of injury severity (GCS) scores, which were not different in male and female patients. Female patients younger than 50 years tended to have worse outcomes, but the difference was not statistically significant. Thus, female patients who sustain severe head injury, especially (presumably) premenopausal ones aged 50 years and younger, are significantly more likely to experience brain swelling and intracranial hypertension than male patients with a comparable injury severity, suggesting that younger women may benefit from more aggressive monitoring and treatment of intracranial hypertension.

STEM CELL THERAPY has emerged as a promising novel therapeutic endeavor for traumatic brain injury, spinal cord injury, stroke, and epilepsy in experimental studies. A few preliminary clinical trials have further supported its safety and early efficacy after transplantation into humans. Although not yet clinically available for central nervous system disorders, stem cell technology is expected to evolve into one of the most powerful tools in the biological management of complex central nervous system disorders, many of which currently have limited treatment modalities. The identification of stem cells, discovery of neurogenesis, and application of stem cells to treat central nervous system disorders represent a dramatic evolution and expansion of the neurosurgeon's capabilities into the neurorestoration and neuroregeneration realms. In Part 3 of a 5-part series on stem cells, we discuss the theory, experimental evidence, and clinical data pertaining to the use of stem cells for the treatment of traumatic, vascular, and epileptic disorders.