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Neal F. Kassell

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Thomas W. Langfitt and Neal F. Kassell

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Introduction

Focused ultrasound surgery

W. Jeffrey Elias and Neal F. Kassell

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Transmission of Increased Intracranial Pressure

I. Within the Craniospinal Axis

Thomas W. Langfitt, James D. Weinstein, and Neal F. Kassell

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Satoshi Suzuki, Neal F. Kassell, and Kevin S. Lee

✓ Hemin is a prominent breakdown product of hemoglobin, and high levels of hemin are found in the cerebrospinal fluid during subarachnoid hemorrhage—induced vasospasm. The possible role of hemin in modifying vascular function was examined in the present study by testing its effects on nitric oxide synthase (NOS) activity in cultured rat aortic smooth-muscle cells. Nitric oxide synthase activity was estimated from the amounts of accumulated nitrite and nitrate, which are oxidative products of nitric oxide (NO). Hemin (1–100 µM) increased the levels of nitrite and nitrate in culture medium in a dose- and time-dependent manner. The hemin-induced elevation of nitrite and nitrate was inhibited significantly by the NOS inhibitor, Nω-nitro-l-arginine (300 µM), and by the protein synthesis inhibitor, cycloheximide (5 µg/ml). These results indicate that hemin is capable of stimulating the expression of an inducible isoform of NOS (iNOS) in vascular smooth muscle. Transcriptional expression of iNOS is known to cause injurious effects on the maintenance of cellular homeostasis by generating extremely high levels of NO. The generation of hemin from methemoglobin during hemolysis of a subarachnoid blood clot could therefore stimulate an excessive production of NO in vascular smooth-muscle cells. It is postulated that this series of events contributes to the development of vascular injury associated with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

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Marc N. Pilipuf, John C. Goble, and Neal F. Kassell

✓ The authors have developed a noninvasive head immobilization system for use in neuroimaging (magnetic resonance imaging, computerized tomography, single photon emission computerized tomography, and projection angiography), neurosurgical planning, and neurosurgery. These diagnostic and surgical procedures require patient immobilization, reproducible patient positioning, and anatomical localization. The thermoplastic system described in this technical note addresses each of these requirements with a high degree of accuracy and with no bone fixation. The reproducibility of positioning and effectiveness of immobilization were evaluated using nine healthy volunteers during repeated sessions of magnetic resonance imaging. The mean axial displacement for repeated positioning was 0.6 mm (variance 0.1 mm); the mean displacement during robust patient motion in the axial direction was 1.8 mm (variance 0.9 mm).

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Tomikatsu Toyoda, Neal F. Kassell, and Kevin S. Lee

Object. Inflammatory responses and oxygen free radicals have increasingly been implicated in the development of ischemic brain injury. In some cases, an attenuation of inflammation or free-radical injury can provide tissue protection. Diphosphoryl lipid A (DPL) is a detoxified derivative of a lipopolysaccharide (endotoxin) of Salmonella minnesota strain R595, which is capable of stimulating the immune system without eliciting direct toxic effects. In this study the authors examined the influence of preconditioning with DPL on ischemia/reperfusion injury in rats.

Methods. Sprague—Dawley rats were injected intravenously with either DPL or vehicle. Twenty-four hours later, some animals were tested for superoxide dismutase (SOD) activity. Others were subjected to a 3-hour period of focal cerebral ischemia and, after a reperfusion period of 24 hours, were killed. Infarction volume, SOD activity, and myeloperoxidase (MPO) activity were assayed in the postischemic animals.

Pretreatment with DPL produced significant reductions in cerebral infarction and MPO activity in the ischemic penumbra. A significant enhancement of basal SOD activity was observed 24 hours after DPL treatment (that is, before ischemia), and a further enhancement of SOD activity was seen in the ischemic penumbra 24 hours after reperfusion.

Conclusions. These data provide the first evidence of a neuroprotective effect of preconditioning with DPL in an in vivo model of cerebral ischemia. Although the precise mechanisms through which DPL exerts its neuroprotective influence remain to be established, an inhibition of the complex inflammatory response to ischemia and an enhancement of endogenous antioxidant activity are leading candidates.

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Antifibrinolytic therapy in the acute period following aneurysmal subarachnoid hemorrhage

Preliminary observations from the Cooperative Aneurysm Study

Neal F. Kassell, James C. Torner, and Harold P. Adams Jr.

✓ Antifibrinolytic therapy remains a controversial issue in the management of subarachnoid hemorrhage (SAH). The relationship of antifibrinolytic therapy with mortality, rebleeding, ischemia, hydrocephalus, and clotting abnormalities was studied in 672 patients in the International Cooperative Study on the Timing of Aneurysm Surgery. The patients with antifibrinolytic therapy had a significantly lower rebleeding rate, but higher rates of ischemic deficits and hydrocephalus. The net result was no difference in mortality in the 1st month following the initial SAH. Further clinical trials are needed to determine the overall effects of antifibrinolytic therapy.

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Giuseppe Lanzino, Neal F. Kassell, and the Participants

Object. To test the safety and efficacy of high-dose (15 mg/kg/day) tirilazad mesylate in women suffering from aneurysmal subarachnoid hemorrhage (SAH), a prospective randomized, double-blind, vehicle-controlled trial (parallel to the one conducted in Europe, Australia, New Zealand, and South Africa) was performed at 65 North American neurosurgical centers.

Methods. Of the 832 patients who were randomized, 823 received at least one dose of tirilazad (410 patients) or placebo vehicle containing citrate (413 patients). The two groups were similar with respect to their prognostic factors for overall outcome and delayed cerebral ischemia. There were no differences in medical and surgical interventions including hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution) between the two treatment groups.

In contrast to the accompanying study, the protocol for the North American study was formally amended, in that a sequential analysis of the primary efficacy end point, mortality rate at 91 days postdosing, was performed. This analysis revealed a statistically significant difference in mortality rates, favoring the study drug, among patients who were neurological Grade IV or V at admission (24.6% compared with 43.4% in the placebo-treated group, p = 0.016). No significant differences, however, were found when the entire patient population was considered (15.6% in the placebo-treated group and 13% in the tirilazad-treated group). Other major and secondary end points, which included rate of favorable outcome (74% in the placebo-treated group and 71% in the tirilazad-treated group); symptomatic vasospasm (38% in the placebo-treated group and 35% in the tirilazad-treated group); and vasospasm severity (severe symptomatic vasospasm in 14% of patients in both groups), were also not significantly different between the two groups. In patients with neurological Grades I through III, rates of favorable outcome advantageous to the vehicle-treated group were observed (83.3% compared with 76.7%, p = 0.04).

Conclusions. High-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Sequential analysis revealed a significant reduction in mortality rates among patients with neurological Grades IV and V, favoring the study drug and confirming the same effect observed in male patients in previous large studies. No beneficial effect was observed in patients who were in a good neurological grade at admission.

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David J. Boarini, Neal F. Kassell, and Hans C. Coester

✓ High-dose sodium thiopental is frequently used in neuroanesthesia. The authors performed a study to compare a shorter-acting barbiturate, methohexital, to sodium thiopental in producing high-dose barbiturate anesthesia. In two groups of five mongrel dogs each, regional cerebral blood flow (CBF) was determined using the radioactive-microsphere technique, and cardiovascular parameters were measured before, during, and 1 hour after a 1½hour period of deep barbiturate anesthesia with either sodium thiopental or methohexital. Doses of the barbiturates were adjusted to produce electroencephalogram burst suppression of greater than 30 seconds.

Both agents produced a similar degree of cardiac depression, reduction in CBF, and decrease in cerebral metabolic rate of oxygen (CMRO2). Changes in cerebral and peripheral vascular resistance indicated that methohexital caused less vasoconstriction than sodium thiopental. When the barbiturate infusions were discontinued, CMRO2 and CBF returned more rapidly toward control values in the methohexital group than in the thiopental group. The more rapid recovery time and decrease in cerebral vascular resistance with methohexital suggest that it may have some advantage over sodium thiopental during certain neurosurgical procedures.