Faculty Bibliography

The crucial importance of the earliest possible treatment of ischemic stroke has been stressed. This leads to the concept of prophylactic neuroprotection: long-term administration of neuroprotective agents to people at risk for stroke, so that the effects of focal ischemia are countered from the moment of onset of vascular occlusion. We at NYU (and researchers at several other centers) have been testing possible neuroprotective agents in the cardiopulmonary bypass setting. We believe that by such means we can rapidly and economically screen agents and dose schedules for efficacy. We believe that an agent demonstrably reducing mental impairment after cardiopulmonary bypass suggests that testing such an agent in a prospective manner in people at risk for stroke would be productive, and we propose a sequence for such trials: people during and in the first month after carotid endarterectomy, then postcarotid endarterectomy patients during long-term follow-up, and finally populations at risk for spontaneous stroke in the nonvascular surgery setting

Hemorrhage secondary to anticoagulant therapy is well documented. We report a patient who presented with acute vertigo and unilateral deafness while on warfarin and was found to have a probable hemorrhage in the labyrinth, identified on MRI

BACKGROUND: Treatments for acute ischemic stroke have evolved as knowledge about the pathophysiology of ischemic brain injury has advanced. Treatment strategies under development are aimed at offering neuroprotection acutely after focal cerebral ischemic injury, but delayed initiation of therapy may reduce efficacy. Pretreatment before ischemia begins could offer distinct advantages in patient groups at high risk for ischemic stroke. SUMMARY OF REVIEW: If a neuroprotective drug were available orally, safe, and relatively inexpensive, it could be considered for prophylactic use in high-risk populations. Prophylactic neuroprotection would include (1) short-term neuroprotection before and after high-stroke risk procedures, (2) long-term neuroprotection for primary and secondary intervention in populations at high risk for stroke, and (3) concomitant neuroprotection with agents that have multiple treatment effects. Patients undergoing procedures such as cardiac surgery, endarterectomy, or endovascular therapy, which have a risk of cerebral ischemic events during a defined period, might be considered for short-term, periprocedure prophylactic neuroprotection. Several populations at high long-term risk for initial ischemic stroke have been identified and include those with combinations of vascular risk factors, transient ischemic attacks, atrial fibrillation, and asymptomatic carotid stenosis. Such people, as well as those at risk for stroke recurrence after minor strokes, are readily identifiable and perhaps appropriate for long-term prophylactic neuroprotection. Patients with hypertension and cerebrovascular atherosclerosis have a high stroke risk, and therapies directed at these underlying disorders are available that also have concomitant neuroprotective effects. An ideal drug for trials in these patient groups has not yet been developed, and establishing its efficacy may prove to be an arduous and lengthy task. CONCLUSIONS: The possibility of ameliorating the consequences of an acute ischemic stroke by pretreating high-risk patients with appropriate neuroprotective agents needs to be explored. Several types of high-risk population for prophylactic neuroprotection can be envisioned and then studied in clinical trials

A meta-analysis was performed on the results of randomized placebo-controlled clinical trials of the effect of aspirin on occurrence of stroke or death in people who previously had suffered cerebral ischemia. The data from 8 such trials (a total of 5,287 subjects) shows a beneficial effect overall: the odds ratio is 0.82; 95% confidence interval (CI) 0.72-0.94; p < 0.01. When men are analyzed separately (n = 3,691) the benefit of aspirin is also statistically significant: odds ratio = 0.82; 95% CI = 0.70-0.96; p = 0.01. The analysis for women (n = 1,596) shows a similar odds ratio (0.82), but this result does not reach statistical significance in the smaller female cohort (95% CI = 0.63-1.05; p 0.12). On the basis of these data and in the absence of a valid biological hypothesis for an effect in women different from that in men, we consider justified the recommendation that aspirin be used to reduce the rate of occurrence of stroke or death in women as well as in men who have suffered cerebral ischemia

The effort to develop therapies that improve outcome after acute ischemic stroke should bear fruit in the near future. The availability of effective, safe and economical neuroprotectants as a spin-off from this effort will lead to the evaluation of prophylactic neuroprotection in selectively targeted populations. We propose three types of prophylactic neuroprotection and patient groups that might be evaluated in appropriate clinical trials. We anticipate the identification of other patient groups and more effective neuroprotectants, The medical community which directs its efforts at stroke prevention and acute therapy will have to consider and evaluate prophylactic neuroprotection along with the other two therapeutic approaches of prevention and acute therapy. This prophylactic-neuroprotection hypothesis should be testable in the near future. We welcome further debate and suggestions,

GM1 ganglioside, a normal constituent of plasma membranes, has demonstrated neuroprotective benefit when given prior to the induction of experimental cerebral ischaemia. GM1 has also shown beneficial effects in in vivo and in vitro studies on CNS tissue injured by prior ischaemia. Ischaemic mechanisms have been implicated in alteration of neuropsychological functioning reported after open-heart surgery. In this placebo-controlled double-blind study, 28 cognitively and neurologically normal adults undergoing nonemergency coronary artery bypass graft and/or heart valve replace- ment surgery were pre-operatively given two doses of GM1 or placebo (on the day before and the day of surgery). A neuropsychological test battery (13 tests yielding 22 scores) was administered prior to any study medication, approximately one week after surgery and after six months. Pre- operative and one-week testing have been completed; six-months testing continues (no treatment codes broken). As a measure of change in neuropsychological functioning, a 'net change' score was calculated for each patient for the one-week postoperative versus baseline comparison. The net change score equals the number of individual test scores improved by at least one SD minus the number of test scores worsened by at least one SD. The average net change score was -2.36. The average numbers of test scores improved and worsened by at least one SD were, respectively, 2.46 and 4.82 per patient. Seven patients (25%) had a positive net change score, 18 (64%) a negative net change score, and three ( 11 % ) a net change score of zero

Sixteen acceptably randomized studies of anticoagulant therapy after cerebral or retinal ischemia or infarction are reviewed and the results among 1,046 anticoagulated patients and 1,071 controls are analyzed. The following conclusions are derived. 1) Anticoagulant therapy has not been shown to be better than control management after transient ischemia or nonprogressing ischemic stroke; this is true whether the control management was deliberately ineffectual treatment (generally studies completed in 1974 or earlier) or platelet antiaggregant therapy (pooled results of three recent studies). 2) Although a study done 30 years ago demonstrated no benefit, a recent study showed benefit from anticoagulant therapy in patients who had had cerebral emboli of cardiac origin; additional controlled data are needed. 3) There is evidence that patients with thrombosis in evolution might benefit from anticoagulant therapy; additional controlled data are needed