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The International Cooperative Study on the Timing of Aneurysm Surgery

Part 2: Surgical results

Neal F. Kassell, James C. Torner, John A. Jane, E. Clarke Haley Jr., Harold P. Adams, and participants

✓ A prospective, observational clinical trial was conducted by the International Cooperative Study on the Timing of Aneurysm Surgery to determine the best time in relation to the hemorrhage for surgical treatment of ruptured intracranial aneurysms. Sixty-eight centers contributed 3521 patients in a 2½-year period beginning in December, 1980. Analysis by a prespecified “planned” surgery interval demonstrated that there was no difference in early (0 to 3 days after the bleed) or late surgery (11 to 14 days). Outcome was worse if surgery was performed in the 7 to 10-day post-bleed interval. Surgical results were better for patients operated on after 10 days. Patients alert on admission fared best; however, alert patients had a mortality rate of 10% to 12% when undergoing surgery prior to Day 11 compared with 3% to 5% when surgery was performed after Day 10. Patients drowsy on admission had a 21% to 25% mortality rate when operated on up to Day 11 and 7% to 10% with surgery thereafter. Overall, early surgery was neither more hazardous nor beneficial than delayed surgery. The postoperative risk following early surgery is equivalent to the risk of rebleeding and vasospasm in patients waiting for delayed surgery.

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A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage

A report of the Cooperative Aneurysm Study

E. Clarke Haley Jr., Neal F. Kassell, James C. Torner, Laura L. Truskowski, Teresa P. Germanson, and the Participants

✓ High-dose intravenous nicardipine has been shown to reduce the incidence of angiographic and symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH), but treatment may be complicated by side effects, including hypotension or pulmonary edema/azotemia. From August, 1989, to January, 1991, 365 patients at 21 neurosurgical centers were entered into a randomized double-blind trial comparing high-dose (0.15 mg/kg/hr) nicardipine with a 50% lower dose (0.075 mg/kg/hr) administered by continuous intravenous infusion for up to 14 days following SAH. Patients in all neurological grades were eligible for the study.

During the study period, 184 patients were randomly assigned to receive high-dose nicardipine and 181 to receive the low dose. There were no significant differences in patient age, admission neurological condition, or amount and distribution of blood clot on initial computerized tomography scan. Patients in the high-dose group received a significantly smaller proportion of the planned dose than those in the low-dose group (80% ± 0.2% vs. 86% ± 0.2%, p < 0.05), largely because of premature treatment termination after adverse medical events. The incidence of symptomatic vasospasm was 31% in both groups, and the overall 3-month outcomes were nearly identical. These data suggest that, from a clinical standpoint, the results of high-dose and low-dose nicardipine treatment are virtually equivalent, but administration of low-dose nicardipine is attended by fewer side effects.

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The role of hemolysate in the facilitation of oxyhemoglobin-induced contraction in rabbit basilar arteries

Toshiki Aoki, Katsunobu Takenaka, Satoshi Suzuki, Neal F. Kassell, Oren Sagher, and Kevin S. Lee

✓ The importance of factors within hemolysate in modulating oxyhemoglobin (oxyHb)-induced contraction was examined in an in vitro model of rabbit basilar arteries. When the basilar arteries were exposed to purified oxyHb alone, the contractile response observed was significantly weaker than that seen in arteries exposed to hemolysate containing an equal concentration of oxyHb. In order to delineate the nature of the factors within hemolysate that facilitate contraction, hemolysate was fractionated, and various components were tested individually for their ability to elicit this effect. A low-molecular-weight fraction of hemolysate, ranging from 0.5 to 2.0 kD, elicited only a mild contraction. However, when this fraction was combined with purified oxyHb, the contractile response was comparable in magnitude to that of unfractionated hemolysate. These studies confirm that purified oxyHb is capable of inducing contraction in vitro. The data also demonstrate that oxyHb elicits a significantly weaker contraction than does hemolysate. In addition, the results suggest that low-molecular-weight components in hemolysate (in the 0.5- to 2.0-kD range), while incapable of inducing a potent contraction alone, may act in concert with oxyHb to elicit the vasoconstriction seen following subarachnoid hemorrhage.

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Treatment of cerebral vasospasm with intra-arterial papaverine

Neal F. Kassell, Gregory Helm, Nathan Simmons, C. Douglas Phillips, and Wayne S. Cail

✓ Cerebral vasospasm continues to be the leading treatable cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage. In this preliminary anecdotal series of 12 patients who were candidates for balloon angioplasty, vasospasm was treated instead with intra-arterial papaverine. Eight patients had marked angiographic reversal of the arterial narrowing following papaverine infusion, four of whom showed dramatic reversal of profound neurological deficits. Two patients deteriorated clinically 5 days after the initially successful papaverine infusions. In both, repeat angiography demonstrated severe recurrent vasospasm, which was partially reversed with a second intra-arterial papaverine treatment. Two patients developed focal neurological deficits during papaverine infusion, which resolved spontaneously over several hours after cessation of the intra-arterial infusion. Arterial narrowing in the posterior circulation and middle cerebral artery distribution appeared to be more responsive to papaverine infusion than was spasm in the anterior cerebral arteries. The infusion of 300 mg of papaverine over 1 hour seemed to be an adequate and safe dose to effect these angiographic and clinical improvements.

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A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America

E. Clarke Haley Jr., Neal F. Kassell, Carolyn Apperson-Hansen, Marie H. Maile, Wayne M. Alves, and Participants

✓ To test the safety and efficacy of tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, in improving the outcome of patients with aneurysmal subarachnoid hemorrhage (SAH), 902 patients were enrolled in a prospective randomized, double-blind, vehicle-controlled trial at 54 North American neurosurgical centers. Five patients were excluded prior to receiving any study drug. Of 897 patients who received at least one dose of study medication, 300 received a placebo containing a citrate vehicle, 298 received 2 mg/kg per day tirilazad, and 299 received 6 mg/kg per day tirilazad, all administered intravenously beginning within 48 hours of the SAH and continuing through 10 days posthemorrhage. All patients were also treated with orally administered nimodipine. At 3 months post-SAH, there were no significant differences (p < 0.025) among the groups with regard to mortality rate, favorable outcome on the Glasgow Outcome Scale, or employment status. During the first 14 days after the SAH, there were no significant differences among the groups in the incidence or severity of clinically symptomatic or angiographically identifiable cerebral vasospasm. Mortality data stratified by gender and neurological grade on admission (assessed according to a modified World Federation of Neurological Surgeons scale) demonstrated that the men with Grades IV to V had a 33% mortality rate in the vehicle group, 52% in the 2 mg/kg per day tirilazad group (p = 0.29), and 5% in the 6 mg/kg per day tirilazad group (p = 0.03). Tirilazad was well tolerated at both dose levels.

Tirilazad mesylate at dosage levels of up to 6 mg/kg per day for 8 to 10 days following SAH did not improve the overall outcome in patients with aneurysmal SAH in this trial. The differences in the efficacy of tirilazad in this trial and a previously reported trial in Europe, Australia, and New Zealand, in which dosage levels of tirilazad of 6 mg/kg per day reduced mortality rates and increased good recovery, may be a result of differences in admission characteristics of the patients and/or differences in management protocols, including the use of anticonvulsant medications.

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Nitric Oxide and Vasospasm

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Surgical management of unruptured basilar artery bifurcation aneurysms

Technical note

Aaron S. Dumont, Rod J. Oskouian Jr., Michael M. Chow, and Neal F. Kassell

The basilar artery (BA) bifurcation is the most common site for aneurysms arising from the posterior circulation. Their inhospitable location, nested within the narrow confines of the interpeduncular fossa anterior to the brainstem, coupled with the rich network of adjacent critical thalamoperforating arteries irrigating the midbrain and thalamus, pose difficult anatomical obstacles for the surgeon.

The age old adage that the only cure for intracranial aneurysms remains exclusion from circulation before rupture still holds true. Although management of unruptured aneurysms in general is still controversial, unruptured aneurysms of the BA bifurcation can be treated surgically with acceptable rates of morbidity. The clinician must gather and weigh all clinical, pathological, and radiological data when formulating recommendations for the individual patient.

In the present report the authors describe their current technique for the surgical management of unruptured BA bifurcation aneurysms; this represents the culmination of the senior author's (N.K.) experience in the management of both ruptured and unruptured BA bifurcation aneurysms. A modified, right-sided subtemporal transtentorial approach has been adopted in all cases of isolated unruptured BA bifurcation aneurysms. Technical nuances are described.

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Transcranial magnetic resonance–guided focused ultrasound for temporal lobe epilepsy: a laboratory feasibility study

Stephen Monteith, John Snell, Mathew Eames, Neal F. Kassell, Edward Kelly, and Ryder Gwinn


In appropriate candidates, the treatment of medication-refractory mesial temporal lobe epilepsy (MTLE) is primarily surgical. Traditional anterior temporal lobectomy yields seizure-free rates of 60%–70% and possibly higher. The field of magnetic resonance–guided focused ultrasound (MRgFUS) is an evolving field in neurosurgery. There is potential to treat MTLE with MRgFUS; however, it has appeared that the temporal lobe structures were beyond the existing treatment envelope of currently available clinical systems. The purpose of this study was to determine whether lesional temperatures can be achieved in the target tissue and to assess potential safety concerns.


Cadaveric skulls with tissue-mimicking gels were used as phantom targets. An ablative volume was then mapped out for a “virtual temporal lobectomy.” These data were then used to create a target volume on the InSightec ExAblate Neuro system. The target was the amygdala, uncus, anterior 20 mm of hippocampus, and adjacent parahippocampal gyrus. This volume was approximately 5cm3. Thermocouples were placed on critical skull base structures to monitor skull base heating.


Adequate focusing of the ultrasound energy was possible in the temporal lobe structures. Using clinically relevant ultrasound parameters (power 900 W, duration 10 sec, frequency 650 kHz), ablative temperatures were not achieved (maximum temperature 46.1°C). Increasing sonication duration to 30 sec demonstrated lesional temperatures in the mesial temporal lobe structures of interest (up to 60.5°C). Heating of the skull base of up to 24.7°C occurred with 30-sec sonications.


MRgFUS thermal ablation of the mesial temporal lobe structures relevant in temporal lobe epilepsy is feasible in a laboratory model. Longer sonications were required to achieve temperatures that would create permanent lesions in brain tissue. Heating of the skull base occurred with longer sonications. Blocking algorithms would be required to restrict ultrasound beams causing skull base heating. In the future, MRgFUS may present a minimally invasive, non-ionizing treatment of MTLE.

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Subarachnoid hemorrhage and diffuse vasculopathy in an adult infected with HIV

Case report

D. Kojo Hamilton, Neal F. Kassell, Mary E. Jensen, and Aaron S. Dumont

✓This 34-year-old man with a 10-year history of HIV infection presented with an acute onset of severe headache, fever, nausea, vomiting, and left-sided weakness. Computed tomography (CT) scanning demonstrated diffuse subarachnoid hemorrhage (SAH), and subsequent CT angiography revealed multiple large and giant intracranial aneurysms with diffuse vasculopathy. The patient's CD4-positive cell count was low, although he had been receiving combination antiret-roviral therapy and his viral load was undetectable.

The preponderance of the literature on HIV-infected patients with intracranial vascular involvement has concerned children in whom there is a high viral load. In such children, appropriate antiretroviral therapy may result in the complete resolution of these vascular abnormalities. In the present study, the authors report on the unique case of an HIV-infected adult patient who presented with SAH, diffuse intracranial vasculopathy, and multiple giant and fusiform aneurysms, despite having received adequate antiretroviral treatment and demonstrating an undetectable viral load. Intracranial vascular involvement in these patients may become increasingly common as the management of HIV infection continues to improve and afflicted patients survive for longer periods.

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Aaron S. Dumont and Neal F. Kassell