Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice.

Intravenous tissue plasminogen activator (tPA) is used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain. However, this protease also promotes neurodegeneration after intracerebral injection of excitotoxins such as glutamate, and neuronal damage after a cerebral infarct is thought to be mediated by excitotoxins. To investigate the effects of tPA on cerebral viability during ischemia/reperfusion, we occluded the middle cerebral artery in wild-type and tPA-deficient mice with an intravascular filament. This procedure allowed us to examine the role of tPA in ischemia, independent of its effect as a thrombolytic agent. tPA-deficient mice exhibited approximately 50% smaller cerebral infarcts than wild-type mice. Intravenous injection of tPA into tPA-/- or wild-type mice produced larger infarcts, indicating that tPA can increase stroke-induced injury. Since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke, future therapies should be aimed at countering the excitotoxic damage of tPA to afford even better neuroprotection after an acute cerebral infarct.

Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.

Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.

Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury.

Evidence indicates that both necrotic and apoptotic cell death contribute to tissue injury and neurological dysfunction following spinal cord injury. Caspases have been implicated as important mediators of apoptosis following acute central nervous system insults. We investigated whether caspase-1 and caspase-3 are involved in spinal cord injury-mediated cell death, and whether caspase inhibition may reduce tissue damage and improve outcome following spinal cord injury. We demonstrate a 17-fold increase in caspase-1 activity in traumatized spinal cord samples when compared with samples from sham-operated mice. Caspase-1 and caspase-3 activation were also detected by western blot following spinal cord injury, which was significantly inhibited by the broad caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. By immunofluorescence or in situ fluorogenic substrate assay, caspase-1 and caspase-3 expression were detected in neuronal and non-neuronal cells following spinal cord injury. N-Benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone treated mice, and transgenic mice expressing a caspase-1 dominant negative mutant, demonstrated a significant improvement of motor function and a reduction of lesion size compared with vehicle-treated mice. Our results demonstrate for the first time that both caspase-1 and caspase-3 are activated in neurons following spinal cord injury, and that caspase inhibition reduces post-traumatic lesion size and improves motor performance. Caspase inhibitors may be one of the agents to be used for the treatment of spinal cord injury.

Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.

Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatized brain tissue. Reduction of tissue injury and free radical production following brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also conferred by pharmacological inhibition of caspase-1 by intracerebroventricular administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone or the non-selective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces trauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1beta converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.

Transplantation of neural progenitor and stem cells: developmental insights may suggest new therapies for spinal cord and other CNS dysfunction.

Multipotent neural progenitors and stem cells may integrate appropriately into the developing and degenerating central nervous system. They may also be effective in the replacement of genes, cells, and nondiffusible factors in either a widespread or a more circumscribed manner, depending on the therapeutic demands of the clinical situation. In addition, they may be uniquely responsive to some types of neurodegenerative conditions. We believe that these various appealing capabilities are the normal expression of basic biologic properties and attributes of a stem cell. The therapeutic utility of some of those properties is illustrated in this review of ongoing work in our laboratory, particularly with regard to spinal dysfunction. In these examples, we believe we have tapped into a mechanism that underlies a remarkable degree of natural plasticity programmed into the nervous system at the cellular level, and we have now exploited those properties for therapeutic ends.

Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat.

Excessive accumulation of glutamate or other excitatory amino acids and the subsequent overactivity of NMDA receptors is currently thought to lead to neuronal injury in cerebral ischemia. Therefore, antagonists of the NMDA receptor may offer an approach for the treatment of ischemic brain injury. Dizocilpine (MK-801), an NMDA receptor-associated channel blocker, protects neurons in several rodent stroke models. However, this drug has numerous side effects and causes apoptosis of neonatal neurons. Recently, another NMDA receptor-associated channel blocker, memantine, has been shown to ameliorate NMDA-receptor mediated neurotoxicity in neuronal cell cultures and in focal cerebral ischemia models in adult rats without substantial side effects. Memantine has been used clinically in the treatment of Parkinson's disease and spasticity for a number of years. Here we tested the effects of memantine on focal stroke caused by photochemical thrombosis in neonatal rats and demonstrated a neuroprotective effect of memantine in this model. We also found excellent correlation between infarct size determined by magnetic resonance imaging (MRI) and histopathological analysis in the same animals. A single pre-ischemic dose of memantine (20 mg/kg) given 15 min prior to induction of stroke reduced the infarct size by 36.3% when compared to control animals treated with normal saline (P < 0.0001). At this dosage, memantine manifests few, if any, neurobehavioral side effects. Thus memantine appears to be both safe and effective in neonatal as well as adult animal models of stroke.

"Acquired" Chiari I malformation after multiple lumbar punctures: case report.

The authors present the history of a patient with a Chiari I malformation "acquired" after multiple traumatic lumbar punctures. The genesis of tonsillar descent is believed to be related to persistent leakage of cerebrospinal fluid secondary to the multiple traumatic lumbar punctures. The topic of acquired Chiari I malformations and complications of lumbar puncture is reviewed.

Hypertensive encephalopathy as a complication of hyperdynamic therapy for vasospasm: report of two cases.

OBJECTIVE AND IMPORTANCE: After developing subarachnoid hemorrhage, patients may deteriorate from a variety of well-known causes, including rebleeding, hydrocephalus, and vasospasm. Many patients now undergo empirical hyperdynamic vasospasm therapy with hypervolemia, induced hypertension, and nimodipine. CLINICAL PRESENTATION: We report two cases of iatrogenic hypertensive encephalopathy occurring during hyperdynamic therapy for cerebral vasospasm after subarachnoid hemorrhage. Hypertensive encephalopathy is a syndrome of rapidly evolving generalized or focal cerebral symptoms occurring in the setting of severe hypertension, which is reversible with antihypertensive therapy. INTERVENTION: The syndrome can be diagnosed in the appropriate clinical setting with computed tomographic or magnetic resonance imaging that demonstrates characteristic findings. In both cases, decreasing the blood pressure resulted in neurological improvement. CONCLUSION: In the setting of induced hypertensive/hypervolemic therapy for vasospasm, hypertensive encephalopathy should be considered as a potentially reversible cause of delayed neurological decline.

A case of acute vertigo with incidental aneurysms.

It is essential to decrease the risk to the patient to an absolute minimum when prophylactic procedures are offered against a relatively unpredictable (for the individual patient) natural history risk. Very careful preoperative planning and intraoperative execution are mandatory to maximize the chances of the patient for a successful outcome.

Computer-assisted surgical planning for cerebrovascular neurosurgery.

OBJECTIVE: We used three-dimensional reconstructed magnetic resonance images for planning the operations of 16 patients with various cerebrovascular diseases. We studied the cases of these patients to determine the advantages and current limitations of our computer-assisted surgical planning system as it applies to the treatment of vascular lesions. METHODS: Magnetic resonance angiograms or thin slice gradient echo magnetic resonance images were processed for three-dimensional reconstruction. The segmentation, based on the signal intensities and voxel connectivity, separated each anatomic structure of interest, such as the brain, vessels, and skin. A three-dimensional model was then reconstructed by surface rendering. This three-dimensional model could be colored, made translucent, and interactively rotated by a mouse-controlled cursor on a workstation display. In addition, a three-dimensional blood flow analysis was performed, if necessary. The three-dimensional model was used to assist in three stages of surgical planning, as follows: 1) to choose the best method of intervention, 2) to evaluate surgical risk, 3) to select a surgical approach, and 4) to localize lesions. RESULTS: The generation of three-dimensional models allows visualization of pathological anatomy and its relationship to adjacent normal structures, accurate lesion volume determination, and preoperative computer-assisted visualization of alternative surgical approaches. CONCLUSION: Computer-assisted surgical planning is useful for patients with cerebrovascular disease at various stages of treatment. Lesion identification, therapeutic and surgical option planning, and intraoperative localization are all enhanced with these techniques.

Results of linear accelerator-based radiosurgery for intracranial meningiomas.

OBJECTIVE: We report the outcomes of patients treated with linear accelerator-based radiosurgery for intracranial meningiomas at our institution. METHODS: We reviewed 127 patients with 155 meningiomas treated with stereotactic radiosurgery (SRS) at the study institutions between October 1988 and December 1995. RESULTS: There were 86 female and 41 male patients (median age, 61.5 yr; range, 19.9-87.9 yr). The median follow-up period was 31 months (range, 1.2-79.8 mo). The median tumor volume was 4.1 cc (range, 0.16-51.2 cc), and the median marginal dose was 15 Gy (range, 9-20 Gy). The tumor locations were as follows: convexity, 31 tumors; parasagittal/falcine, 39 tumors; cranial base, 82 tumors; and ventricular/pineal, 3 tumors. There were 106 benign, 26 atypical, and 18 malignant meningiomas and 5 cases of meningiomatosis. SRS was performed on 48 lesions as the initial treatment and on 107 lesions as adjunct therapy. Freedom from progression was observed in 107 patients (84.3%) at a median time of 22.9 months (range, 1.2-79.8 mo). Twenty patients (15.7%) had disease progression (16 marginal [12.6%] and 4 local [3.1%]) at a median time of 19.6 months (range, 4.1-69.3 mo); the median time for freedom from progression for the benign, atypical, and malignant meningiomas was 20.9, 24.4, and 13.9 months, respectively. Actuarial tumor control for the patients with benign meningiomas was 100, 92.9, 89.3, 89.3, and 89.3% at 1, 2, 3, 4, and 5 years, respectively. Six patients (4.7%) had permanent complications attributable to SRS (median time, 10.3 mo; range, 4.3-18.0 mo); 13 patients died as a result of causes related to the meningiomas (median, 17.5 mo; range, 4.3-37.3 mo). The 1-, 2-, 3-, 4-, and 5-year survival probability for the entire group of patients was 90.3, 82.6, 73.6, 70.5, and 68.2%, respectively; for patients with benign meningiomas, excluding death resulting from intercurrent disease, the survival probability was 97.6, 94.8, 91.0, 91.0, and 91.0%, respectively. The 1-, 2-, 3-, and 4-year survival probability for the patients with atypical and malignant meningiomas was 91.7, 83.3, 83.3, and 83.3% and 92.3, 64.6, 43.1, and 21.5%, respectively. CONCLUSION: Even though complications from SRS are expected more frequently with large tumors near critical structures, SRS is a safe and effective means of treating selected meningiomas.

Cerebral arteriovenous malformation feeding artery aneurysms: a theoretical model of intravascular pressure changes after treatment.

OBJECTIVE: A quantitative model may be used to estimate the magnitude of expected pressure changes along the vascular tree with shunt ablation and may provide information to assess the hemodynamic risk of arteriovenous malformation (AVM) treatment. METHODS: A computer model of the cerebral circulation was applied to estimate the changes in intravascular pressure, velocity, biomechanical stress, and shear stress that might be expected from either endovascular or surgical ablation of AVMs. Two AVM sizes and two feeding artery constellations were simulated. The effect of different shunt flows on vascular pressure was modeled. In each simulation, AVMs were occluded in a stepwise fashion. The effects of systemic hypertension and hypotension in various vascular zones were also simulated. RESULTS: As large (1000 ml/min) AVMs were occluded, the mean feeding arterial pressure increased from 18 to 68 mm Hg; the percent-occlusion at half-maximal pressure increase was 92%. For medium (500 ml/min) AVMs, feeding arterial pressure increased from 37 to 66 mm Hg; the percent-occlusion at half-maximal pressure increase was 71%. During manipulation of systemic pressure, hemodynamic changes in the circulation close to the nidus were proportionally less than changes in systemic pressure; the degree of proportionality depended on the magnitude of AVM shunt flow. CONCLUSION: In this simulation, shunt obliteration increased pressure in the nidus and feeding arteries with little effect on the proximal circulation. The shunt provided a "buffering" effect, i.e., higher flow fistulas were exposed to smaller variations in intravascular pressure in feeding artery and nidal pressures during manipulation of systemic pressure.

Computer-assisted interactive three-dimensional planning for neurosurgical procedures.

We have used three-dimensional reconstruction magnetic resonance imaging techniques to understand the anatomic complexity of operative brain lesions and to improve preoperative surgical planning. We report our experience with 14 cases, including intra- and extra-axial tumors and a vascular malformation. In each case, preoperative planning was performed using magnetic resonance imaging-based three-dimensional renderings of surgically critical structures, such as eloquent cortices, gray matter nuclei, white matter tracts, and blood vessels. Simulations, using the interactive manipulation of three-dimensional data, provided an efficient and comprehensive way to appreciate the anatomic relationships. Interactive three-dimensional computer-assisted preoperative simulations provided otherwise inaccessible information that was useful for the surgical removal of brain lesions.

Intracranial hemorrhage: diagnosis and emergency management.

Intracranial hemorrhages are an important cause of acute neurologic disease presenting in the emergency setting. To optimize outcome, it is important that the physician quickly recognize intracranial hemorrhages. To minimize mortality and neurologic morbidity, it is often necessary to initiate urgent therapy in the emergency rooms and to obtain neurosurgical consultation in order to pursue early surgical therapy. This article discusses the recognition and early treatment of the various types of intracranial hemorrhages.

Neurosurgical complications in craniofacial surgery.

A retrospective review of the neurosurgical complications that occurred between 1980 and 1989 at The Children's Hospital in Boston is described. The results are compared with reports from other craniofacial centers. A total of 355 cases are analyzed, with an overall complication rate of 8.6%. Infection and cerebrospinal fluid leaks are the most common problems. This article discusses techniques incorporated into personal methods to reduce the incidence of these complications.

Synostotic frontal plagiocephaly: anthropometric comparison of three techniques for surgical correction.

Surgical correction of synostotic frontal plagiocephaly ("unilateral coronal synostosis") focuses on distortions of the forehead and orbits. Technical variations include unilateral versus bilateral fronto-orbital positioning. Surgical alignment of the deviated nasal root was introduced in our unit. Anthropometry was used to assess anatomic outcome, and results were compared in 22 children with synostotic frontal plagiocephaly who had either (1) unilateral fronto-orbital advancement ("canthal advancement") (n = 8), (2) bilateral fronto-orbital advancement/ modeling without nasal straightening (n = 7), or (3) bilateral fronto-orbital advancement/modeling with closing wedge nasal osteotomy (n = 7). Postoperative fronto-orbital asymmetry was most marked in the group I patients wherein the ipsilateral supraorbital rim was retruded 3.9 mm and elevated 2.6 mm, on average relative to the corneal apex, compared with the normal side. Group II children averaged 2-mm orbital retrusion and 2.2-mm elevation. Group III patients averaged 1.4-mm orbital retrusion and 2.9-mm elevation. These differences in orbital rim measurements among the three groups were not statistically significant. Postoperative nasal root angulation of 4 degrees or more was found in more than 50 percent of children who had either a unilateral or a bilateral procedure, without nasal correction. In contrast, primary nasal osteotomy resulted in a nasal cant of 3 degrees or less in all children. This difference in nasal angulation among the three groups was statistically significant (p = 0.035). Group III had a straighter nasal angle than groups II and I (in that order). Measurement of the distances from nasion to inner and to outer canthi also reflected persistent deviation of the nasal root. Group III children had a more central radix than either group I or II (p = 0.05). The data in this study support an operative strategy of bilateral (parallelogrammic) positioning of the forehead/ superior orbits with primary correction of nasal root angulation.

Evaluating CT perfusion using outcome measures of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH and remains a leading cause of morbidity and mortality. Our aim was to evaluate CTP in aneurysmal SAH by using outcome measures of DCI. MATERIALS AND METHODS: This was a retrospective study of consecutive patients with SAH enrolled in a prospective institutional review board-approved clinical accuracy trial. Qualitative CTP deficits were determined by 2 neuroradiologists blinded to clinical and imaging data. Quantitative CTP was performed by using a standardized protocol with region-of-interest placement sampling of the cortex. Primary outcome measures were permanent neurologic deficits and infarction. The secondary outcome measure was DCI, defined as clinical deterioration. CTP test characteristics (95% CI) were determined for each outcome measure. Statistical significance was calculated by using the Fisher exact and Student t tests. ROC curves were generated to determine accuracy and threshold analysis. RESULTS: Ninety-six patients were included. Permanent neurologic deficits developed in 33% (32/96). CTP deficits were seen in 78% (25/32) of those who developed permanent neurologic deficits and 34% (22/64) of those without (P < .0001). CTP deficits had 78% (61%-89%) sensitivity, 66% (53%-76%) specificity, and 53% (39%-67%) positive and 86% (73%-93%) negative predictive values. Infarction occurred in 18% (17/96). CTP deficits were seen in 88% (15/17) of those who developed infarction and 41% (32/79) of those without (P = .0004). CTP deficits had an 88% (66%-97%) sensitivity, 59% (48%-70%) specificity, and 32% (20%-46%) positive and 96% (86%-99%) negative predictive values. DCI was diagnosed in 50% (48/96). CTP deficits were seen in 81% (39/48) of patients with DCI and in 17% (8/48) of those without (P < .0001). CTP deficits had 81% (68%-90%) sensitivity, 83% (70%-91%) specificity, and 83% (70%-91%) positive and 82% (69%-90%) negative predictive values. Quantitative CTP revealed significantly reduced CBF and prolonged MTT for DCI, permanent neurologic deficits, and infarction. ROC analysis showed that CBF and MTT had the highest accuracy. CONCLUSIONS: CTP may add prognostic information regarding DCI and poor outcomes in aneurysmal SAH.

Intraprocedural aneurysmal rupture during coil embolization of brain aneurysms: role of balloon-assisted coiling.

BACKGROUND AND PURPOSE: Intraprocedural aneurysmal rupture is a feared complication of coil embolization of intracranial aneurysms and is associated with high rates of morbidity and mortality. We report the incidence, endovascular management, and clinical outcome of patients with IAR, with emphasis on the role of the balloon-assisted technique. MATERIALS AND METHODS: We conducted a retrospective analysis of all intracranial aneurysms treated by coil embolization between September 2001 and June 2011. All patients with IAR were studied. Comparison of immediate clinical outcomes was performed by using univariate analysis (Fisher exact test). RESULTS: Of 652 intracranial aneurysms treated with coil embolization, an IAR occurred in 22 (3.4%). Rupture occurred during placement of coils in 18 cases, microcatheters in 2 cases, and a guidewire in 1 case, and during induction of anesthesia in 1 case. Before treatment, 15 of 22 (68%) patients were in good clinical condition (WFNS grade I). There were fewer patients with worsening of the WFNS grade following an IAR when the balloon-assisted technique was used (7.7%) compared with when it was not (55.5%) (P = .023). Death occurred in 2 (9.1%) patients. CONCLUSIONS: IAR is a potentially serious complication of coil embolization. If IAR occurs, balloon-assistance is helpful in obtaining rapid hemostasis resulting in better short-term outcomes.

Using quantitative CT perfusion for evaluation of delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH leading to permanent neurologic deficits, infarction, and death. Our aim was to prospectively evaluate the diagnostic accuracy of CTP and to determine a quantitative threshold for DCI in aneurysmal SAH. MATERIALS AND METHODS: Patients with SAH were prospectively enrolled in a protocol approved by the institutional review board. CTP was performed during the typical time period for DCI, between days 6 and 8 following SAH. Quantitative CBF, CBV, and MTT values were obtained by using standard region-of-interest placement sampling of gray matter. The reference standard for DCI is controversial and consisted of clinical and imaging criteria in this study. In a subanalysis of vasospasm, DSA was used as the reference standard. ROC curves determined the diagnostic accuracy by using AUC. Optimal threshold values were calculated by using the patient population utility method. RESULTS: Ninety-seven patients were included; 41% (40/97) had DCI. Overall diagnostic accuracy was 93% for CBF, 88% for MTT, and 72% for CBV. Optimal threshold values were 35 mL/100 g/min (90% sensitivity, 68% specificity) for CBF and 5.5 seconds (73% sensitivity, 79% specificity) for MTT. In the subanalysis (n = 57), 63% (36/57) had vasospasm. Overall diagnostic accuracy was 94% for CBF, 85% for MTT, and 72% for CBV. Optimal threshold values were 36.5 mL/100 g/min (95% sensitivity, 70% specificity) for CBF and 5.4 seconds (78% sensitivity, 70% specificity) for MTT. CONCLUSIONS: CBF and MTT have the highest overall diagnostic accuracy. Threshold values of 35 mL/100 g/min for CBF and 5.5-second MTT are suggested for DCI on the basis of the patient population utility method. Absolute threshold values may not be generalizable due to differences in scanner equipment and postprocessing methods.