Aaron S. Dumont, Giuseppe Lanzino, and Neal F. Kassell
Giuseppe Lanzino, Neal F. Kassell, Nicholas W. C. Dorsch, Alberto Pasqualin, Lennart Brandt, Peter Schmiedek, Laura L. Truskowski, Wayne M. Alves, and the Participants
Object. Findings from previous multicenter clinical trials have suggested that tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tirilazad in women with SAH.
Methods. To test the efficacy of a higher tirilazad mesylate dose in female patients, a prospective randomized, doubleblind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of tirilazad mesylate or a placebo containing the citrate vehicle. The two groups were similar in prognostic factors for delayed cerebral ischemia and overall outcome. High-dose tirilazad appeared to be well tolerated because no differences in the incidence of untoward medical events were noted between the two groups. Medical and surgical interventions were no different in the two treatment groups except for hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution), which was more often used in the placebo-treated group to counteract symptomatic vasospasm (24% of patients given placebo compared with 18% of patients given tirilazad, p = 0.02).
Mortality rates and overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, were not different between the two groups, despite a significantly lower incidence of delayed cerebral ischemia in patients given tirilazad. Post hoc subgroup analysis by neurological grade also did not reveal significant differences in outcome, although a trend toward a lower mortality rate favoring the study drug was present in patients with neurological Grade IV and V at admission (32% compared with 37%). Symptomatic vasospasm occurred in 33.7% of the placebo-treated patients as opposed to 24.8% of the patients who were given tirilazad (p = 0.005). The severity of symptomatic vasospasm was also attenuated by administration of the study drug (severe symptomatic vasospasm was reported in 11% of the placebo-treated patients compared with 6% of patients in the tirilazad-treated group (p = 0.008). Clinical cerebral infarction from vasospasm was also reduced from 13% in the vehicle-treated group to 8% in the tirilazad-treated group (p < 0.04).
Conclusions. The authors conclude that high-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, the primary end point (mortality rate at 3 months post-SAH) was not affected by the study drug. The use of other potentially effective rescue therapies (that is, hypervolemia, hemodilution, and induced hypertension) to counteract vasospasm may have been responsible for these contrasting observations between the two groups.
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.
Report of two cases
Mark E. Shaffrey, Giuseppe Lanzino, M. Beatriz S. Lopes, Richard B. Hessler, Neal F. Kassell, and Scott R. Vandenberg
✓ Immature teratomas arising within the central neuraxis are rare neoplasms. These tumors contain diverse cell lineages that retain an embryonal character and display phenotypic differentiation attributed to the three classic germ layers. The clinical management of these lesions is unclear, due in part to their low incidence and to an incomplete understanding of their natural history. Although the potential for phenotypic differentiation and cellular maturation within immature teratomas arising in the gonads is well documented, this has not been described in the intracranial tumors. In the present report, the authors describe two cases of intracranial immature teratomas, one involving the pineal region and the other involving the left frontotemporal lobes, which underwent cellular differentiation and maturation. At initial resection, the tumors from both cases were composed predominantly of primitive neuroepithelial tissue that was admixed with immature and differentiating mesenchymal and epithelial structures. No foci of germinoma, endodermal sinus, choriocarcinoma, or embryonal carcinoma tissue were present. Subsequent resections in both cases revealed an absence of immature tissue. The tumor in Case 1 contained only differentiated epithelial and mesenchymal tissue with no neuroepithelial component, whereas the tumor in Case 2 demonstrated abundant mature neuronal and glial tissue. These two cases from different intracranial sites suggest that spontaneous maturation may be a significant aspect of the natural history of intracranial immature teratomas.
Giuseppe Lanzino, Neal F. Kassell, Teresa P. Germanson, Gail L. Kongable, Laura L. Truskowski, James C. Torner, John A. Jane, and Participants
✓ Advanced age is a recognized prognostic indicator of poor outcome after subarachnoid hemorrhage (SAH). The relationship of age to other prognostic factors and outcome was evaluated using data from the multicenter randomized trial of nicardipine in SAH conducted in 21 neurosurgical centers in North America. Among the 906 patients who were studied, five different age groups were considered: 40 years or less, 41 to 50, 51 to 60, 61 to 70, and more than 71 years. Twenty-three percent of the individuals enrolled were older than 60 years of age. Women outnumbered men in all age groups.
Level of consciousness (p = 0.0002) and World Federation of Neurological Surgeons grade (p = 0.0001) at admission worsened with advancing age. Age was also related to the presence of a thick subarachnoid clot (p = 0.0001), intraventricular hemorrhage (p = 0.0003), and hydrocephalus (p = 0.0001) on an admission computerized tomography scan. The rebleeding rate increased from 4.5% in the youngest age group to 16.4% in patients more than 70 years of age (p = 0.002). As expected, preexisting medical conditions, such as diabetes (p = 0.028), hypertension (p = 0.0001), and pulmonary (p = 0.0084), myocardial (p = 0.0001), and cerebrovascular diseases (p = 0.0001), were positively associated with age. There were no age-related differences in the day of admission following SAH, timing of the surgery and/or location, and size (small vs. large) of the ruptured aneurysm.
During the treatment period, the incidence of severe complications (that is, those complications considered life threatening by the reporting investigator) increased with advancing age, occurring in 28%, 33%, 36%, 40%, and 46% of the patients in each advancing age group, respectively (p = 0.0002). No differences were observed in the reported frequency of surgical complications. No age-related differences were found in the overall incidence of angiographic vasospasm; however, symptomatic vasospasm was more frequently reported in the older age groups (p = 0.01). Overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, was poorer with advancing age (p < 0.001). Multivariate analysis of overall outcome, adjusting for the different prognostic factors, did not remove the age effect, which suggests that the aging brain has a less optimal response to the initial bleeding. Age as a risk factor is a continuum; however, there seems to be a significant increased risk of poor outcome after the age of 60 years.
Gail L. Kongable, Giuseppe Lanzino, Teresa P. Germanson, Laura L. Truskowski, Wayne M. Alves, James C. Torner, Neal F. Kassell, and the Participants
✓ Female gender is a recognized risk factor for the occurrence of aneurysmal subarachnoid hemorrhage. In the present study the authors analyzed differences in admission characteristics and outcome between 578 women (64%) and 328 men (36%) who were enrolled in a recently completed clinical trial. The female-to-male ratio was nearly 2:1. The women in the study were older than the men (mean age 51.4 years vs. 47.3 years, respectively, p < 0.001). Female patients harbored aneurysms of the internal carotid artery more frequently than male patients (36.8% vs. 18.0%, p < 0.001) and more often had multiple aneurysms (32.4% vs. 17.6%, p < 0.001). On the other hand, anterior cerebral artery aneurysms were more commonly encountered in men (46.1% in men vs. 26.6% in women, p < 0.001). Other baseline prognostic factors were balanced between the gender groups. Surgery was performed equally in both sexes (98%), although the time to operation was shorter for women (mean 3.6 days for women vs. 5.3 days for men, p = 0.0002). In the placebo group, the occurrence of vasospasm was not statistically different between the two groups. Primary causes of death and disability were the same, and favorable outcome rates at 3 months were not statistically different between the genders (69.7% for women vs. 73.4% for men, p = 0.243). The odds of a favorable outcome in women versus one in men were not statistically significant either before or after adjustment for age. These observations lead the authors to suggest that although women are older and harbor more aneurysms, the 3-month outcome for women and men who experience aneurysmal subarachnoid hemorrhage is the same.
Giuseppe Lanzino, Neal F. Kassell, Teresa Germanson, Laura Truskowski, and Wayne Alves
✓ Plasma glucose levels were studied in 616 patients admitted within 72 hours after subarachnoid hemorrhage (SAH). Glucose levels measured at admission showed a statistically significant association with Glasgow Coma Scale scores, Botterell grade, deposition of blood on computerized tomography (CT) scans, and level of consciousness at admission. Elevated glucose levels at admission predicted poor outcome. A good recovery, as assessed by the Glasgow Outcome Scale at 3 months, occurred in 70.2% of patients with normal glucose levels (≤ 120 mg/dl) and in 53.7% of patients with hyperglycemia (> 120 mg/dl) (p = 0.002). The death rates for these two groups were 6.7% and 19.9%, respectively (p = 0.001). The association was still maintained after adjusting for age (> or ≤ 50 years) and thickness of clot on CT scans (thin or thick) in the subset of patients who were alert/drowsy at admission. Increased mean glucose levels between Days 3 and 7 also predicted a worse outcome; good recovery was observed in 132 (73.7%) of 179 patients who had normal mean glucose levels (≤ 120 mg/dl) and 160 (49.7%) of 322 who had elevated mean glucose levels (> 120 mg/dl) (p < 0.0001). Death occurred in 6.7% and 20.8% of the two groups, respectively (p < 0.0001). It is concluded that admission plasma glucose levels can serve as an objective prognostic indicator after SAH. Elevated glucose levels during the 1st week after SAH also predict a poor outcome. However, a causal link between hyperglycemia and outcome after delayed cerebral ischemia, although suggested by experimental data, cannot be established on the basis of this study.