✓ 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.
Preliminary observations from the Cooperative Aneurysm Study
Neal F. Kassell, James C. Torner and Harold P. Adams Jr.
Raheel Ahmed, Arnold H. Menezes and James C. Torner
Surgical excision is the mainstay treatment for resectable low-grade intramedullary spinal cord tumors (IMSCTs) in the pediatric age group. Chemotherapy and radiation treatments are generally reserved for progressive or recurrent disease. Given the indolent nature of low-grade tumors and the potential side effects of these approaches, their long-term treatment benefits are unclear. The aim of the study was to determine long-term disease outcomes and the therapeutic roles of surgery and adjuvant therapies in pediatric patients with low-grade IMSCTs over an extended follow-up period.
Case records for all pediatric patients (< 21 years of age) with a histopathological diagnosis of low-grade IMSCT were selected over a period from January 1975 to January 2010. Outcome variables including McCormick functional grade, overall survival (OS), and progression-free survival (PFS) were analyzed with respect to demographic and treatment variables.
Case records of 37 patients with low-grade IMSCTs were identified, with a mean follow-up duration of 12.3 ± 1.4 years (range 0.5–37.2 years). Low-grade astrocytomas were the most prevalent histological subtype (n = 22, 59%). Gross-total resection (GTR) was achieved in 38% of patients (n = 14). Fusion surgery was required in 62% of patients with pre- or postoperative deformity (10 of 16). On presentation, functional improvement was observed in 87% and 46% of patients in McCormick Grades I and II, respectively, and in 100%, 100%, and 75% in Grades III, IV, and V, respectively. Kaplan-Meier PFS rates were 63% at 5 years, 57% at 10 years, and 44% at 20 years. OS rates were 92% at 5 years, 80% at 10 years, and 65% at 20 years. On multivariate analysis, shunt placement (hazard ratio [HR] 0.33, p = 0.01) correlated with disease progression. There was a trend toward improved 5-year PFS in patients who received adjuvant chemotherapy and radiation therapy (RT; 55%) compared with those who did not (36%). Patients who underwent subtotal resection (STR) were most likely to undergo adjuvant therapy (HR 7.86, p = 0.02).
This extended follow-up duration in patients with low-grade IMSCTs beyond the first decade indicates favorable long-term OS up to 65% at 20 years. GTR improved PFS and was well tolerated with sustained functional improvement in the majority of patients. Adjuvant chemotherapy and RT improved PFS in patients who underwent STR. These results emphasize the role of resection as the primary treatment approach, with adjuvant therapy reserved for patients at risk for disease progression and those with residual tumor burden.
Kelly B. Mahaney, Michael M. Todd, Emine O. Bayman and James C. Torner
Subarachnoid hemorrhage (SAH) results in significant morbidity and mortality, even among patients who reach medical attention in good neurological condition. Many patients have neurological decline in the perioperative period, which contributes to long-term outcomes. The focus of this study is to characterize the incidence of, characteristics predictive of, and outcomes associated with acute postoperative neurological deterioration in patients undergoing surgery for ruptured intracranial aneurysm.
The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) was a multicenter randomized clinical trial that enrolled 1001 patients and assesssed the efficacy of hypothermia as neuroprotection during surgery to secure a ruptured intracranial aneurysm. All patients had a radiographically confirmed SAH, were classified as World Federation of Neurosurgical Societies (WFNS) Grade I–III immediately prior to surgery, and underwent surgery to secure the ruptured aneurysm within 14 days of SAH. Neurological assessment with the National Institutes of Health Stroke Scale (NIHSS) was performed preoperatively, at 24 and 72 hours postoperatively, and at time of discharge. The primary outcome variable was a dichotomized scoring based on an IHAST version of the Glasgow Outcome Scale (GOS) in which a score of 1 represents a good outcome and a score > 1 a poor outcome, as assessed at 90-days' follow-up. Data from IHAST were analyzed for occurrence of a postoperative neurological deterioration. Preoperative and intraoperative variables were assessed for associations with occurrence of postoperative neurological deterioration. Differences in baseline, intraoperative, and postoperative variables and in outcomes between patients with and without postoperative neurological deterioration were compared with Fisher exact tests. The Wilcoxon rank-sum test was used to compare variables reported as means. Multiple logistic regression was used to adjust for covariates associated with occurrence of postoperative deficit.
Acute postoperative neurological deterioration was observed in 42.6% of the patients. New focal motor deficit accounted for 65% of postoperative neurological deterioration, while 60% was accounted for using the NIHSS total score change and 51% by Glasgow Coma Scale score change. Factors significantly associated with occurrence of postoperative neurological deterioration included: age, Fisher grade on admission, occurrence of a procedure prior to aneurysm surgery (ventriculostomy), timing of surgery, systolic blood pressure during surgery, ST segment depression during surgery, history of abnormality in cardiac valve function, use of intentional hypotension during surgery, duration of anterior cerebral artery occlusion, intraoperative blood loss, and difficulty of aneurysm exposure. Of the 426 patients with postoperative neurological deterioration at 24 hours after surgery, only 46.2% had a good outcome (GOS score of 1) at 3 months, while 77.7% of those without postoperative neurological deterioration at 24 hours had a good outcome (p < 0.05)
Neurological injury incurred perioperatively or in the acute postoperative period accounts for a large percentage of poor outcomes in patients with good admission WFNS grades undergoing surgery for aneurysmal SAH. Avoiding surgical factors associated with postoperative neurological deterioration and directing investigative efforts at developing improved neuroprotection for use in aneurysm surgery may significantly improve long-term neurological outcomes in patients with SAH.
A randomized trial of nicardipine in subarachnoid hemorrhage: angiographic and transcranial Doppler ultrasound results
A report of the Cooperative Aneurysm Study
E. Clarke Haley Jr., Neal F. Kassell, James C. Torner and Participants
✓ Calcium antagonist drugs were proposed for use in patients with recent aneurysmal subarachnoid hemorrhage (SAH) because of their ability to block the effects of a wide variety of vasoconstrictor substances on cerebral arteries in vitro. It was suggested that these agents might, therefore, be useful in ameliorating cerebral vasospasm and its ischemic consequences which frequently complicate SAH. This hypothesis was tested in an arm of a randomized double-blind placebo-controlled trial of high-dose intravenous nicardipine in patients with recently ruptured aneurysms. Participating investigators were required to send selected copies of all admission and follow-up angiograms obtained between Days 7 and 11 following hemorrhage (the peak period of risk for vasospasm) to the Central Registry of the Cooperative Aneurysm Study for blinded interpretation and review for the presence and severity of angiographic vasospasm. In centers with transcranial Doppler ultrasound (TCD) capabilities, middle cerebral artery (MCA) mean flow velocities were measured and recorded.
Angiograms obtained between Days 7 and 11 were available for 103 (23%) of 449 patients receiving nicardipine and 121 (26%) of 457 receiving placebo. There was a balance of prognostic factors for vasospasm between the groups. Fifty-one percent of placebo-treated patients had moderate or severe vasospasm on “Day 7–11 angiograms” compared to 33% of nicardipine-treated patients. This difference is statistically significant (p < 0.01). Sixty-seven (49%) of 137 placebo-treated patients examined with TCD between Days 7 and 11 had mean MCA flow velocities exceeding 120 cm/sec compared to 26 (23%) of 112 nicardipine-treated patients (significant difference, p < 0.001). These data suggest that high-dose intravenous nicardipine reduces the incidence and severity of delayed cerebral arterial narrowing in patients following aneurysmal SAH.
A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage
A report of the Cooperative Aneurysm Study
E. Clarke Haley Jr., Neal F. Kassell, James C. Torner and Participants
✓ Because of their action as cerebral vasodilators, dihydropyridine calcium antagonists have received intense scrutiny for their potential benefit in ameliorating the devastating consequences of delayed cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). From October, 1987, to September, 1989, 41 North American neurosurgical centers in the Cooperative Aneurysm Study accrued 906 patients with recent (Days 0 to 7) aneurysmal SAH into a prospective randomized double-blind placebo-controlled trial of high-dose intravenous nicardipine to test whether treatment with this agent improved overall outcome. Eligible patients received 0.15 mg/kg/hr of either nicardipine or placebo by continuous infusion for up to 14 days following hemorrhage. The 449 patients randomly assigned to the nicardipine-treated group and the 457 patients assigned to the placebo-treated group were balanced with regard to prognostic factors for ischemic deficits from vasospasm and for overall outcome. Other medical and surgical interventions were used with similar frequency in both groups, except that antihypertensive agents were used less frequently in the nicardipine-treated patients (26% of the nicardipine-treated group vs. 43% of the placebo-treated group, p < 0.001), and more patients in the placebo-treated group had intentional hypervolemia, induced hypertension, and/or hemodilution administered therapeutically for symptomatic vasospasm (38% of the placebo-treated group vs. 25% of the nicardipine-treated group, p < 0.001). The incidence of symptomatic vasospasm during the treatment period was higher in the placebo-treated group (46%) than in the nicardipine-treated group (32%) (p < 0.001). Despite the reduction in symptomatic vasospasm in the nicardipine-treated group, overall outcome at 3 months was similar between the two groups. Fifty-five percent of nicardipine-treated patients were rated as having a good recovery according to the Glasgow Outcome Scale at follow-up review and 17% were dead, compared to 56% and 18%, respectively, in the placebo-treated group (not statistically significant).
These data suggest that high-dose intravenous nicardipine treatment is associated with a reduced incidence of symptomatic vasospasm in patients with recent aneurysmal SAH, but not with an improvement in overall outcome at 3 months when compared to standard management in North America. It is postulated that, while nicardipine prevents vasospasm, hypertensive/hypervolemic therapy may be effective in reversing ischemic deficits from vasospasm once they occur.
Carl J. Graf, George E. Perret and James C. Torner
✓ The case records of 191 patients with a cerebral arteriovenous malformation (AVM) were reviewed to determine bleeding characteristics of these lesions. Possible influences of age, sex, the location and size of the AVM, type of initial hemorrhage, and condition of the patients were analyzed. Of these 191 patients, 102 had a single hemorrhage, 32 had a recurrent hemorrhage, and 57 never bled. The follow-up period for patients with an unruptured AVM was a mean of 4.8 years and a maximum of 31 years; for those with a ruptured AVM, the mean was 2 years, and the maximum 37 years.
Size of the AVM was significantly related to the risk of first hemorrhage. The average yearly risk for first hemorrhage was between 2% and 3%. Bleeding occurred most frequently in the 11- to 35-year-old age group. The risk of rebleeding increased with advancing age. Among 93 patients followed after their AVM had ruptured, the risk of rebleeding was 6% in 1 year. After the first year, the average rebleeding rate was about 2% per year up to 20 years.
Patrick W. Hitchon, Jeffrey M. Lobosky, Thoru Yamada and James C. Torner
✓ Spinal cord blood flow (SCBF) in 10 sheep subjected to laminectomy at L6–7, T6–7, and C7–T1 was compared to that of 10 control sheep subjected to anesthesia alone. Blood flow was measured using the radioactive microsphere technique, with the PaCO2 maintained at 40 ± 2 mm Hg. Both laminectomy and control animals showed a decrease in SCBF at a rate of 7% to 16%/hr for the 3 hours following the first blood flow determination. When prelaminectomy and postlaminectomy SCBF values were compared to their counterparts in the control animals, there were no significant differences. Laminectomy does not appear to alter SCBF from control values. Spinal evoked potentials (SEP's) were elicited in the laminectomy group by direct cord stimulation at C-7 and L-7. No changes were noted in amplitude or latency of SEP's over time in either caudal or rostral conduction.
Kelly B. Mahaney, Michael M. Todd and James C. Torner
The past 30 years have seen a shift in the timing of surgery for aneurysmal subarachnoid hemorrhage (SAH). Earlier practices of delayed surgery that were intended to avoid less favorable surgical conditions have been replaced by a trend toward early surgery to minimize the risks associated with rebleeding and vasospasm. Yet, a consensus as to the optimal timing of surgery has not been reached. The authors hypothesized that earlier surgery, performed using contemporary neurosurgical and neuroanesthesia techniques, would be associated with better outcomes when using contemporary management practices, and sought to define the optimal time interval between SAH and surgery.
Data collected as part of the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) were analyzed to investigate the relationship between timing of surgery and outcome at 3 months post-SAH. The IHAST enrolled 1001 patients in 30 neurosurgical centers between February 2000 and April 2003. All patients had a radiographically confirmed SAH, were World Federation of Neurosurgical Societies Grades I–III at the time of surgery, and underwent surgical clipping of the presumed culprit aneurysm within 14 days of the date of hemorrhage. Patients were seen at 90-day follow-up visits. The primary outcome variable was a Glasgow Outcome Scale score of 1 (good outcome). Intergroup differences in baseline, intraoperative, and postoperative variables were compared using the Fisher exact tests. Variables reported as means were compared with ANOVA. Multiple logistic regression was used for multivariate analysis, adjusting for covariates. A p value of less than 0.05 was considered to be significant.
Patients who underwent surgery on Days 1 or 2 (early) or Days 7–14 (late) (Day 0 = date of SAH) fared better than patients who underwent surgery on Days 3–6 (intermediate). Specifically, the worst outcomes were observed in patients who underwent surgery on Days 3 and 4. Patients who had hydrocephalus or Fisher Grade 3 or 4 on admission head CT scans had better outcomes with early surgery than with intermediate or late surgery.
Early surgery, in good-grade patients within 48 hours of SAH, is associated with better outcomes than surgery performed in the 3- to 6-day posthemorrhage interval. Surgical treatment for aneurysmal SAH may be more hazardous during the 3- to 6-day interval, but this should be weighed against the risk of rebleeding.
John A. Jane, Neal F. Kassell, James C. Torner and H. Richard Winn
✓ The authors summarize the findings of previous studies relating to the natural history of aneurysms and arteriovenous malformations (AVM's). Ruptured aneurysms have their highest rate of rebleeding on Day 1, and at least 50% will rebleed during the 6 months after the first hemorrhage. Thereafter, the rate drops to at least 3% a year. This is the same rate as seen in anterior and posterior communicating artery aneurysms treated by anterior cerebral artery clipping and carotid ligation; these operations provide immediate protection but do not result in long-term diminution of the risk of rebleeding. Patients with unruptured incidental and unruptured multiple aneurysms rebleed at a rate of 1% per year, as do patients with subarachnoid hemorrhage of unknown etiology. The risk of rebleeding for AVM's is 3% a year.
Brian J. Dlouhy, Ana W. Capuano, Karthik Madhavan, James C. Torner and Jeremy D. W. Greenlee
Patients with hydrocephalus often present with both intraventricular obstructive and communicating components, and determination of the predominant component is difficult. Other investigators have observed that third ventricular floor deformation, or “bowing” of the third ventricular floor, is a good indicator of intraventricular obstructive hydrocephalus, resulting in higher success rates with endoscopic third ventriculostomy (ETV). However, additional third ventricular bowing assessment and statistical evidence demonstrating a difference in ETV outcome with third ventricular bowing is needed. The authors hypothesized that patients with preoperative bowing of the third ventricle would exhibit greater long-term success rates after ETV and that lack of bowing would result in increased failure rates after ETV.
The authors determined success and failure for 59 ETVs performed in 56 patients, and recorded patient age, time to failure, and preoperative third ventricular anatomy, as well as history of infection, intraventricular hemorrhage, and previous shunt. Third ventricular anatomy was assessed on MR imaging for bowing, which was classified as any of the following: depression of the third ventricular floor, enlargement of the supraoptic recess, anterior curvature of the lamina terminalis, dilation of the proximal aqueduct to a greater extent than the distal aqueduct, and blunting or posterior bowing of the suprapineal recess. Univariate and multivariate analyses of ETV failure and the time to failure were performed using logistic regression and the Cox proportional hazards model, respectively.
After adjusting for patient age and history of infection, there was a significant association between lack of anterior third ventricular preoperative bowing (either lamina terminalis, supraoptic recess, or third ventricular floor) and ETV failure (adjusted HR 2.79, 95% CI 1.08–7.20). Of the patients with bowing, 70.5% experienced success with ETV, as did 33.3% of the patients without bowing. Among the individual structures, absence of bowing in the anterior aspect of the third ventricular floor was significantly associated with censored time to ETV failure (multivariate HR 2.59, 95% CI 1.01–6.66; final model including age and history of infection).
The presence of preoperative third ventricular bowing is predictive of ETV success, with nearly a 3-fold likelihood of success compared with patients treated with ETV in the absence of such bowing. Although bowing is predictive, 33% of patients without bowing were also treated successfully with ETV.