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Context: Elucidation of the ischemic cascade has helped stimulate development of neuroprotective drugs aimed at limiting brain injury in the hours following an ischemic stroke. To date, none of these drugs has shown clinical efficacy.Objective: To examine the efficacy of gavestinel (GV150526), an antagonist of the glycine site of the N-methyl-D-aspartate receptor, as a neuroprotective therapy for acute ischemic stroke when administered within 6 hours of symptom onset.Design: The Glycine Antagonist in Neuroprotection (GAIN) Americas trial, a randomized, double-blind placebo-controlled trial with enrollment from April 1998 to October 1999.Setting: One hundred thirty-two hospital centers across the United States and Canada.Patients: The primary efficacy population consisted of 1367 ischemic stroke patients with a predefined level of limb weakness and functional independence prior to stroke, stratified at randomization by age (75 years) and initial stroke severity (National Institutes of Health [NIH] Stroke Scale scores of 2-5, 6-13, or >/=14).Intervention: Patients were randomly assigned to receive an intravenous loading dose (800 mg) plus 5 maintenance doses (200 mg every 12 hours) of gavestinel (n = 701) or placebo (n = 666) for 3 days.Main Outcome Measure: Functional capability at 3 months, measured by the Barthel Index (BI), with scores trichotomized as dead/0-55, 60-90, and 95-100, compared between the gavestinel and placebo groups.Results: Treatment groups were well matched for baseline characteristics. For each group, median NIH Stroke Scale was 12, median age was 72 years, and median time to treatment was 5.2 hours. No statistically significant improvement on the 3-month BI trichotomy was demonstrated for gavestinel (P =.79). The proportion who were functionally independent (BI score = 95-100) was 39% in the gavestinel group and 37% in the placebo group. No statistically significant difference in 3-month survival was observed using Kaplan-Meier curves (P =.11). No other secondary end point suggested an advantage for gavestinel. Among the 333 patients (24%) who received recombinant tissue-type plasminogen activator, there was also no benefit for gavestinel (P =.53). There were no serious safety issues.Conclusion: In this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months. [ABSTRACT FROM AUTHOR]

Context: The prevalence and clinical significance of early ischemic changes (EICs) on baseline computed tomography (CT) scan of the head obtained within 3 hours of ischemic stroke are not established., Objective: To determine the frequency and significance of EIC on baseline head CT scans in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (recombinant tissue plasminogen activator) Stroke Trial., Design and Setting: The original study, a randomized controlled trial, took place from January 1991 through October 1994 at 43 sites, during which CT images were obtained within 3 hours of symptom onset and prior to the initiation of rt-PA or placebo. For the current analysis, detailed reevaluation was undertaken after October 1994 of all baseline head CT scans with clinical data available pretreatment (blinded to treatment arm)., Patients: Of 624 patients enrolled in the trial, baseline CT scans were retrieved and reviewed for 616 (99%)., Main Outcome Measures: Frequency of EICs on baseline CT scans; association of EIC with other baseline variables; effect of EICs on deterioration at 24 hours (>/=4 points increase from the baseline National Institutes of Health Stroke Scale [NIHSS] score); clinical outcome (measured by 4 clinical scales) at 3 months, CT lesion volume at 3 months, death at 90 days; and symptomatic intracranial hemorrhage (ICH) within 36 hours of treatment., Results: The prevalence of EIC on baseline CT in the combined rt-PA and placebo groups was 31% (n = 194). The EIC was significantly associated with baseline NIHSS score (rho = 0.23; P<.001) and time from stroke onset to baseline CT scan (rho = 0.11; P =.007). After adjusting for baseline variables, there was no EIC x treatment interaction detected for any clinical outcome, including deterioration at 24 hours, 4 clinical scales, lesion volume, and death at 90 days (P>/=.25), implying that EIC is unlikely to affect response to rt-PA treatment. After adjusting for NIHSS score (an independent predictor of ICH), no EIC association with symptomatic ICH at 36 hours was detected in the group treated with rt-PA (P>/=.22)., Conclusions: Our analysis suggests that EICs are prevalent within 3 hours of stroke onset and correlate with stroke severity. However, EICs are not independently associated with increased risk of adverse outcome after rt-PA treatment. Patients treated with rt-PA did better whether or not they had EICs, suggesting that EICs on CT scan are not critical to the decision to treat otherwise eligible patients with rt-PA within 3 hours of stroke onset.

We used stored plasma samples from 409 patients in the National Institute of Neurological Diseases and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Trial to examine the relationship between an apolipoprotein (Apo) E2 or an Apo E4 phenotype and a favorable outcome 3 months after stroke, the risk of intracerebral hemorrhage, and the response to intravenous t-PA therapy. For the 27 patients with an Apo E2 phenotype who were treated with t-PA, the odds ratio (OR) of a favorable outcome at 3 months was 6.4 [95% confidence interval (CI) 2.7-15.3%] compared to the 161 patients without an Apo E2 phenotype who were treated with placebo. The 190 patients treated with t-PA who did not have an Apo E2 phenotype also had a greater, though less pronounced, likelihood of a favorable outcome (OR 2.0, 95% CI 1.2-3.2%) than patients without an Apo E2 phenotype treated with placebo. For the 31 patients with an Apo E2 phenotype treated with placebo, the OR of a favorable 3 month outcome was 0.8 (95% CI 0.4-1.7%) compared to the 161 patients without an Apo E2 phenotype treated with placebo. This interaction between treatment and Apo E2 status persisted after adjustment for baseline variables previously associated with 3 month outcome, for differences in the baseline variables in the two treatment groups and in the Apo E2-positive and -negative groups, and for a previously reported time-to-treatment x treatment interaction (p = 0.03). Apo E4 phenotype, present in 111 (27%) of the 409 patients, was not related to a favorable 3 month outcome, response to t-PA, 3 month mortality, or risk of intracerebral hemorrhage. We conclude that the efficacy of intravenous t-PA in patients with acute ischemic stroke may be enhanced in patients who have an Apo E2 phenotype, whereas the Apo E2 phenotype alone is not associated with a detectable benefit on stroke outcome at 3 months in patients not given t-PA. In contrast to prior studies of head injury and stroke, we could not detect a relationship between Apo E4 phenotype and clinical outcome.

Patients presenting with suspected acute stroke require rapid diagnosis and treatment. Neuroimaging is critical in determining acute-stroke type and thus appropriate management. A review of various neuroimaging techniques and their role in the evaluation of both acute ischemic stroke and acute hemorrhagic stroke is provided.

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.

Tirilazad mesylate, a nonglucocorticoid 21-aminosteroid, has been shown in experimental models to reduce vasospasm following subarachnoid hemorrhage (SAH) and to reduce infarct size from focal cerebral ischemia. To test whether treatment with tirilazad would reduce ischemic symptoms from vasospasm and improve overall outcome in patients with ruptured aneurysms, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 41 neurosurgical centers in Europe, Australia, and New Zealand. One thousand twenty-three patients were randomly assigned to receive 0.6, 2, or 6 mg/kg per day of intravenously administered tirilazad or a placebo containing the citrate vehicle. All patients were also treated with intravenously administered nimodipine. Patients receiving 6 mg/kg per day of tirilazad had reduced mortality (p = 0.01) and a greater frequency of good recovery on the Glasgow Outcome Scale 3 months after SAH (p = 0.01) than similar patients treated with vehicle. There was a reduction in symptomatic vasospasm in the group that received 6 mg/kg per day tirilazad; however, the difference was not statistically significant (p = 0.048). The benefits of treatment with tirilazad were predominantly shown in men rather than in women. There were no material differences between the outcomes in the groups treated with 0.6 and 2 mg/kg tirilazad per day and the group treated with vehicle. Tirilazad was well tolerated at all three dose levels. These observations suggest that tirilazad mesylate, at a dosage of 6 mg/kg per day, is safe and improves overall outcome in patients (especially in men) who have experienced an aneurysmal SAH.

A multicenter, randomized, blinded, placebo-controlled trial was conducted to study the possible role of intracisternally administered fibrinolytic agent recombinant tissue plasminogen activator (rt-PA) in preventing delayed onset cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). The target population was patients with ruptured saccular aneurysms causing severe SAH, placing them at high risk for vasospasm. Treatment consisted of a single 10 ml intraoperative injection of either vehicle buffer solution or rt-PA (1 mg/ml) into the opened basal subarachnoid cisterns immediately following aneurysm clipping. The major efficacy endpoint in this trial was angiographic vasospasm, and the major safety concern was intracranial hemorrhage. One hundred patients were randomized, 49 to placebo and 51 to rt-PA treatment. Baseline population characteristics were similar between the two groups. Severity of intracranial hemorrhage on computed tomographic scans was also similar between groups: 87.2% of both placebo and rt-PA treated patients had thick subarachnoid clots, and the rates for intracerebral and intraventricular hemorrhage were, respectively, 16.3% and 22.5% for placebo and 23.5% and 21.6% for rt-PA. Nine randomized patients did not receive treatment in the operating room, and in 8 this was due to conditions felt unsafe for the administration of a fibrinolytic agent. The overall incidence of angiographic vasospasm measured between the seventh and eleventh day following SAH was similar between the two groups, with arterial narrowing detected in 74.4% of dosed placebo patients and 64.6% of rt-PA treated patients. However, there was a trend toward lesser degrees of vasospasm in the rt-PA treated group. The rates for no or mild, moderate, and severe vasospasm were 69%, 16% and 15% in the rt-PA treated group, versus 42%, 35% and 23% in the placebo group (P = 0.07). When only those patients with thick subarachnoid clots were considered at the treating centers, there was a 56% relative risk reduction of severe vasospasm in the rt-PA treated group, which was significant (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: This report examines the frequency, type, and prognostic factors of medical (nonneurologic) complications after subarachnoid hemorrhage in a large, prospective study. The influences of contemporary neurosurgical, neurological, and critical care practice on mortality and morbidity rates after aneurysmal subarachnoid hemorrhage are evaluated., Design: A study of medical complications observed in the placebo limb of a large, randomized, controlled trial of the calcium antagonist, nicardipine, after subarachnoid hemorrhage., Setting: Patients were recruited from 50 hospitals in 41 neurosurgical centers in the United States and Canada., Patients: A total of 457 patients with subarachnoid hemorrhage, > or = 18 yrs of age, were randomly assigned to the placebo group. All patients arrived at the participating center within 7 days (mean 1.0 +/- 1.8 [SD] days) of rupture of an angiographically documented saccular aneurysm., Measurements and Main Results: The frequency rates of symptomatic vasospasm, rebleeding, and total mortality rate after subarachnoid hemorrhage at 3-month follow-up were 46%, 7%, and 19%, respectively. The frequency of having at least one severe (life-threatening) medical complication was 40%. The proportion of deaths from medical complications was 23%. This value was comparable with the proportion of deaths attributed to the direct effects of the initial hemorrhage (19%), rebleeding (22%), and vasospasm (23%) after aneurysmal rupture. The frequency of life-threatening cardiac arrhythmias was 5%; less ominous rhythm disturbances occurred in 30% of the patients. There was an increased frequency of cardiac arrhythmias on the day of, or day after, aneurysm surgery. Pulmonary edema occurred in 23% of the patients, with a 6% occurrence rate incidence of severe pulmonary edema. There was a wide variation from center to center, with the greatest frequency on days 3 through 7. There was a nonsignificant association of pulmonary edema with the use of hypertensive hypervolemic therapy (p = .10), and a significant association with the timing of surgery (p < .05). Some degree of hepatic dysfunction was noted in 24% of patients, the majority with only mild abnormalities of hepatic enzymes with no clinical accompaniment (4% frequency of severe hepatic dysfunction). Thrombocytopenia occurred in 4% of patients, usually in the setting of sepsis. Renal dysfunction was reported in 7% of the patients, with 15% of that figure deemed to be of life-threatening severity. There was an association (p = .001) with antibiotic therapy., Conclusions: Potentially preventable medical complications after ruptured cerebral aneurysm add to the total mortality rate of patients, and may increase length of hospital stay in the critical care setting. The proportion of deaths after subarachnoid hemorrhage from medical complications equals those deaths from either direct effects, rebleeding, or vasospasm individually. Pulmonary complications are the most common nonneurologic cause of death. Cardiac arrhythmia, although frequent, was not associated with significant mortality. The frequency of cardiac arrhythmia and pulmonary edema increased on the day of, or day after, aneurysm surgery. Renal and hepatic dysfunction, and blood dyscrasias, were also observed, underscoring the need for meticulous monitoring for metabolic and hematologic derangements.

Tirilazad mesylate, a 21-aminosteroid free-radical scavenger, has been shown to ameliorate cerebral vasospasm and reduce infarct size in animal models of subarachnoid hemorrhage (SAH) and focal cerebral ischemia. In preparation for performing large-scale clinical trials in humans with aneurysmal SAH, the safety of varying doses of tirilazad was tested in a randomized, double-blind, vehicle-controlled, sequential dose-escalation study at 12 Canadian neurosurgical centers. Two hundred forty-five patients with an aneurysmal SAH documented by angiography were enrolled in the study sequentially within 72 hours of hemorrhage. The patients were assigned to one of three dosage tiers: receiving 0.6 mg/kg, 2 mg/kg, or 6 mg/kg tirilazad or vehicle per day intravenously in divided doses through Day 10 following the SAH. All patients also received oral nimodipine. No serious side effects of tirilazad treatment were identified at any of the three doses, despite close monitoring of hepatic and cardiac toxicity. A trend toward improvement in overall 3-month patient outcome was seen in the 2 mg/kg per day tirilazad-treated group compared to the outcomes in the vehicle-treated groups. We conclude that tirilazad mesylate is safe in SAH patients at doses up to 6 mg/kg per day for up to 10 days and is a promising drug for the treatment of patients with aneurysmal SAH.

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.

Emergency treatment of acute thromboembolic stroke by lysis of the occlusive arterial clot has received increasing attention in recent years. Development of newer thrombolytic agents combined with an enhanced appreciation of the time course of reversible cerebral ischemia have led to further clinical and laboratory exploration of this approach to stroke treatment, which had previously been believed to be unsafe. Recent studies suggest that very early recanalization of cerebral arteries can be achieved with acceptable risks using either local arterial or intravenously administered thrombolytic agents. While most published reports have suggested clinical benefit, definitive proof of sustained clinical efficacy, as measured by overall functional outcome and compared to concurrent controls, remains to be established.

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.

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.

The International Cooperative Study on the Timing of Aneurysm Surgery evaluated the results of surgical and medical management in 3521 patients between December, 1980, and July, 1983. At admission, 75% of patients were in good neurological condition and surgery was performed in 83%. At the 6-month evaluation, 26% of the patients had died and 58% exhibited a complete recovery. Vasospasm and rebleeding were the leading causes of morbidity and mortality in addition to the initial bleed. Predictors for mortality included the patient's decreased level of consciousness and increased age, thickness of the subarachnoid hemorrhage clot on computerized tomography, elevated blood pressure, preexisting medical illnesses, and basilar aneurysms. The results presented here document the status of management in the 1980's.

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 2 1/2-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.

The relationship of time of surgery and vasospasm is influenced by three factors: (1) the time course of vasospasm, (2) the effectiveness of clot removal at surgery, and (3) the choice of medical management to prevent rebleeding and to treat vasospasm. Data to date demonstrate that angiographic vasospasm and vasospasm-related deficits occur in the period from 4 to 14 days after subarachnoid hemorrhage. Surgical intervention in the period of risk for vasospasm is associated with higher morbidity and mortality rates. Morbidity and mortality rates are lowest following surgery in patients who have delayed surgery; however, morbidity and mortality rates for overall management are equivalent for patients with early surgery because of vasospasm and rebleeding in patients waiting for delayed surgery. The surgical removal of the clot may be accomplished in only a limited number of patients, and most series do not reflect a large change in vasospasm occurrence following early surgery. Changes to more aggressive medical therapy in terms of prevention or reversal of ischemia from vasospasm rendered after the aneurysm is clipped and rebleeding is prevented have been initiated during the past decade. The effectiveness and safety of these treatments may play an important future role in the choice of time of surgery and the relationship of time of surgery to vasospasm-related deficits.

The role of antifibrinolytic drugs in the management of patients with aneurysmal subarachnoid hemorrhage continues to remain uncertain. Recent controlled studies suggest that although these agents may alter the course of the illness, they confer no benefit in terms of overall outcome. Confronted with these data, clinicians in North America have radically altered their management of patients with ruptured aneurysms in the last decade. In the Timing of Surgery Study (1980-1983), 54% of patients were treated with antifibrinolytic drugs and only 32% underwent surgical clipping of the aneurysm on days 0-3 from the subarachnoid hemorrhage. In contrast, only 13% of the patients in the Randomized Trial of Nicardipine in Subarachnoid Hemorrhage (1987-1989) received antifibrinolytics, whereas 53% had early surgery (unpublished observations). Further study will be required to determine if this strategy has resulted in an improvement in overall outcome. Some observers have suggested that as effective therapy for symptomatic vasospasm evolves (e.g., with hypertensive or hypervolemic therapy or calcium antagonists), the adverse effects of antifibrinolytic drugs on brain ischemia may be ameliorated. This idea must be confirmed by further evaluation of the combined use of these treatments. In the interim, antifibrinolytic drugs, if used at all, should be used with caution, and their use should be restricted to those patients judged not to be candidates for early surgery. If therapy cannot be started before day 7 after subarachnoid hemorrhage, it should not be started at all, as the reduced rate of rebleeding after the first 7 days does not justify the increased risk of brain ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

There are many special conditions which may predispose women to have a higher risk of stroke. These conditions include pregnancy and the puerperium, exogenous estrogen use, cerebral vasculitis, mitral valve prolapse and migraine. Recognition that certain stroke syndromes are more likely to affect women may aid the clinician in determining the optimal management of cerebrovascular disease and stroke in women.

Three elderly men being evaluated for cerebrovascular disease developed acute confusional states following arteriography with approximately 50 ml of meglumine iothalamate. Two patients became stuporous. All recovered in several days, and no specific cause was found for the disorder. In the absence of other demonstrated abnormalities, we suggest that in each patient the encephalopathy may have been a toxic reaction to the contrast agent.

Recent reports have indicated that antibiotic therapy alone may be successful in resolving brain abscesses. We utilized an animal model of brain abscess to evaluate the efficacy of penicillin with and without chloramphenicol in preventing the development of brain abscess. When penicillin therapy was initiated at the time of bacterial contamination and continued for four days, the bacteria were eliminated. When therapy was delayed for 24 hr, the number of bacteria in brain tissue samples was significantly reduced, but all samples still contained bacteria. When therapy was delayed for 48 hr, there was no therapeutic benefit. Addition of chloramphenicol to each of these regimens did not significantly alter the results. Extending the duration of therapy to eight days provided no improvement over the results obtained after four days.

Cerebral ischemia from vasospasm is a major cause of death and disability following aneurysmal subarachnoid hemorrhage (SAH). This study examines and compares the relative utility of the initial neurologic examination and early CT in predicting cerebral ischemia after SAH. The influence of antifibrinolytic drugs (AFD) in the development of cerebral ischemia was also studied. AFD increased the risk of cerebral ischemia regardless of the admitting neurologic condition or the findings of CT. Among patients given AFD, impaired orientation or alertness was associated with a higher risk of ischemia. Other neurologic signs were not predictive of ischemia. Clinical features were not predictive of ischemia among patients not given AFD. Focal, thick collections of blood on CT were highly predictive of ischemia, whether or not patients received AFD. Admitting CT is the best prognostic indicator for the development of cerebral ischemia after SAH. It should be used to supplement the clinical examination in selecting patients best suited for therapy to prevent vasospasm.

Although time has been recognized as a critical factor in the treatment of other arterial occlusive disorders, it has been an underemphasized variable in the treatment of acute stroke. Animal models of cerebral arterial occlusion have demonstrated that neurologic recovery is more likely the shorter the duration of occlusion. Complete recovery does not occur if the occlusion persists more than six hours. Prior trials have only rarely begun treatment within six hours of stroke onset. Over the past five years, we have participated in three stroke trials and have tried to identify factors that lead to delays in treatment. Factors that affect the time from stroke onset to arrival at the hospital include recognition of acute stroke by the patient, prehospital care personnel, and physicians. After arrival at the hospital, factors that can significantly delay treatment include the time to obtain computed tomography and the site of treatment (emergency department vs ICU). With proper attention, the time from patient arrival until treatment should be less than one hour. Future efforts should be directed toward reducing the time from stroke onset until arrival at the hospital. Education of the public, high-risk patients, prehospital care providers, and physicians may aid in these efforts.

Vasospasm is the leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (SAH). Transcranial Doppler ultrasonography (TCD) can detect the arterial narrowing noninvasively, but the sensitivity and specificity of this technique have not been reported in a population of patients with a high frequency of angiographic vasospasm. In this study, 34 consecutive patients with SAH undergoing angiography during the period of risk for vasospasm had technically adequate TCD examinations within 24 hours of the angiogram. Using a mean flow velocity of 120 cm/sec and above as indicative of vasospasm, TCD correctly detected angiographic vasospasm in 17 patients; there were no false positives. It correctly determined that 5 patients did not have vasospasm, whereas there were 12 false negatives. False negatives were frequently due to angiographic vasospasm involving vessels not assessable by TCD. The correlation between mean flow velocity and the angiographic residual lumen diameter of the middle cerebral artery was statistically significant. These data suggest that TCD is a highly specific (100%), but less sensitive (58.6%) test for the detection of angiographic vasospasm following SAH. Confirmatory angiography may be avoided if the TCD study is positive, but additional studies may be necessary if the clinical picture is suspicious and the TCD study is negative.

Thrombosis of the deep cerebral venous system is usually fatal, and patients are frequently stuporous or comatose at presentation. This report describes serial radiological and neuropsychological observations in an 18-year-old woman who remained alert and survived this disorder. In association with diencephalic edema seen on computed tomographic scan, she demonstrated disorientation, abulia, attentional deficits, memory loss, and dyscalculia and had impaired IQ scores: the performance scores were worse than the verbal scores. Significant aphasia or sensory loss was absent. She recovered full intellectual capacity in the course of follow-up examinations, and the diencephalic edema seen on the computed tomographic scan resolved despite persistent thrombosis of the straight sinus demonstrable on follow-up digital angiography.

Anticoagulation with heparin is frequently recommended for patients with progressing ischemic cerebral infarction, yet little data is available detailing the acute results of treatment with this agent. We report the results of continuous intravenous heparin treatment in 36 consecutive patients admitted with progressing ischemic infarction, all of whom had computed tomography scans to exclude the diagnosis of hemorrhage prior to treatment. Overall, 18 of 36 (50%) had continued neurologic worsening despite treatment. The incidence of further worsening was greater in carotid territory infarctions (14 of 19, 74%) than in either vertebrobasilar (2 of 8, 25%) or lacunar (2 of 9, 22%) infarctions (p less than 0.05, Fisher's exact test). These observations suggest that additional controlled studies of the efficacy of heparin in progressing ischemic infarction are warranted.