Kr Lees

The Apolipoprotein E ε4 Allele and Outcome in Cerebrovascular Disease

Background and Purpose —Polymorphism of the apolipoprotein E gene ( APOE ) may influence outcome after traumatic brain injury and intracerebral hemorrhage, with the e4 allele being associated with poorer prognosis. We investigated APOE allele distribution in acute stroke and the effect of the e4 allele on outcome. Methods — APOE genotypes were determined in 714 stroke patients: 640 ischemic stroke and 74 intracerebral hemorrhage patients. The survival effect of the e4 allele was assessed with the use of a stratified log-rank test. A Cox proportional hazards regression model was used to estimate the independent effect of e4 dose (0, 1, or 2) on survival, and logistic regression was used to determine the effect on 3-month outcome (good if alive at home, poor if in care or dead). Results —Allele distribution matched the general population with no difference between the ischemic and hemorrhagic groups. Survival in the entire cohort was unaffected by e4 dose. Improved survival with increasing e4 dose was found in the ischemic group (relative hazard=0.76 per allele; P =0.04). If transient ischemic attacks were excluded, a trend for improved survival persisted ( P =0.06). With intracerebral hemorrhage, a trend was seen toward reduced survival with e4 ( P =0.07, log-rank test). Three-month outcome in the ischemic group was unaffected by e4 dose, and a trend toward poorer outcome with e4 was seen for intracerebral hemorrhage ( P =0.10). Conclusions —The APOE e4 allele had divergent effects on survival and outcome in ischemic and hemorrhagic strokes in this population. The reported adverse effect on patients with intracerebral hemorrhage was supported. The favorable survival effect on ischemic stroke patients requires further study.

Prevalence and characteristics of intracranial microemboli signals in patients with different types of prosthetic cardiac valves.

Background and Purpose Transcranial Doppler detection of microemboli is widely described, but there is no clear evidence of the clinical significance or nature of the embolic material in vivo. Thromboembolism is a major cause of morbidity in patients with prosthetic cardiac valves. We undertook this study to evaluate the prevalence and the acoustic characteristics of microembolic signals in three groups of patients with different prosthetic valves. Methods One hundred seventy-nine patients with prosthetic cardiac valves (85 Bjork-Shiley, 56 Medtronic-Hall, and 38 Carpentier-Edwards) and 25 normal subjects were examined using transcranial Doppler. Monitoring time was 30 minutes over the right middle cerebral artery. Results The prevalence and numbers of embolic signals were significantly higher in patients with Bjork-Shiley compared with those with Medtronic-Hall and Carpentier-Ed- wards valves (89% versus 50% and 53%, respectively; P<.001, χ2; 156 [112, 204] versus 2 [1, 4] and 2 [1, 4] signals/h, respectively; median [95% nonparametric confidence interval], both P<.001, multiple comparisons, Bonferroni correction). The signal intensity was significantly higher in patients with Bjork-Shiley and Medtronic-Hall valves than patients with Carpentier-Edwards valves (2435 [2345, 2527] and 2120 [1745, 2483] versus 225 [184, 287] power units, median [95% confidence interval], both P<.001). No correlation was found between embolic signal numbers and clinical parameters including history of neurological deficit, cardiac rhythm, duration of artificial valve, previous cardiac operations, or intensity of anticoagulation. Embolic signals were not detected in any of the control subjects. Conclusions Our data showed that the prevalence, quantity, and acoustic characteristics of Doppler embolic signals differ in patients having three different types of prosthetic heart valves. However, no correlation with clinical parameters was identified.

Anticardiolipin antibodies in an unselected stroke population

A pathogenetic role in thrombotic disease, particularly in young people, has been postulated for anticardiolipin antibody (ACA). We have carried out a prospective controlled study of 262 unselected patients with acute stroke and 226 controls to assess the prevalence and relation to age and vascular risk factors of ACA. Titres of IgG, IgA, or IgM ACA were above the upper normal limit in 38% of patients. The proportions of patients and controls with raised titres did not differ significantly (13 vs 8% IgG, 22 vs 29% IgA, 11 vs 7% IgM). IgG titres were higher among patients than among controls (mean 3.88 vs 2.86 u/mL [95% CI for difference 0.62-0.87], p = 0.0004), whereas IgA and IgM titres were lower in patients than in controls (IgA 4.82 vs 5.98 u/mL [1.12-1.60], p = 0.01; IgM 3.00 vs 3.64 u/mL [1.01-1.45], p = 0.04). However, within age tertiles the only significant difference between patients and controls for IgG ACA was in the oldest tertile. Analysis by number of risk factors for stroke showed a significant difference between the groups only for subjects with one risk factor. IgA and IgM ACA titres were higher among controls only in those with no vascular risk factors. We found no evidence to support the hypothesis that ACA is an independent risk factor for stroke in young people. The increase in IgG titre with age and number of vascular risk factors in stroke patients suggests that ACA may be a non-specific accompaniment of vascular disease. Routine testing for ACA in stroke patients is not justified.

Doppler emboli signals vary according to stroke subtype.

Background and Purpose Doppler ultrasound detection of emboli signals may assist in distinguishing erabolic from thrombotic stroke. Selected patient groups have a high incidence of such signals. We have examined consecutive stroke cases to identify the incidence of Doppler emboli in different etiologic subtypes of stroke. Methods Forty-five patients presenting with first-ever acute carotid territory cerebral ischemia were studied prospectively. Transcranial Doppler examination of both middle cerebral arteries, carotid color duplex ultrasound, and transthoracic or transesophageal echocardiography were completed within 48 hours of deficit onset. Clinical and imaging data were interpreted independent of emboli data, and stroke etiology was classified according to recent multicenter trial criteria. Results Middle cerebral artery signals were identified in at least one cerebral hemisphere in 41 of the 45 patients. Emboli signals were present in 29 of these 41 cases (71%). These signals were bilateral in 22, within the affected (symptomatic) cerebral hemisphere only in 5, and contralateral only in 2 cases. No emboli signals were detected in any of 8 patients with lacunar stroke. The overall difference in emboli signal counts between etiologic subgroups was significant (P=.001, Kruskal-Wallis). A significantly higher emboli signal count was found within affected cerebral hemispheres than contralaterally in the 8 patients with large artery atherosclerosis (11.3 versus 1 signals per hour, median [95% confidence interval, 3 to 40 and 0 to 3, respectively], P=.02), but this interhemisphere difference was not present for other etiologic subgroups. Conclusions Emboli signals are common in patients with acute stroke, with the notable exception of lacunar stroke. This is consistent with the small vessel etiology for the latter group and provides support for the relevance of Doppler emboli signal detection in thromboembolic cerebrovascular disease. (Stroke. 1994;25:382-384.)

Quantification of ultrasound emboli signals in patients with cardiac and carotid disease.

Background and Purpose The use of Doppler ultrasound to detect arterial emboli has major implications for the classification and treatment of stroke. Experimental studies indicate that embolic materials produce different ultrasound signals, depending on their acoustic properties. To examine the possibility of characterizing emboli of different sources in the clinical setting, we compared the emboli signals of patients with cardiac embolic sources with those of patients with signals of carotid embolic sources. Methods Transcranial Doppler monitoring (30 minutes per patient) of the middle cerebral arteries was performed in 80 patients with prosthetic cardiac valves and 20 patients with internal carotid artery stenosis. The signal power of emboli was calculated in relation to the background Doppler signal. Results In patients who were embolizing from prosthetic heart valves, the frequency of embolus signals was greater than in patients with carotid stenosis who were embolizing (mean ± SEM: 58.2 ± 11 versus 8.2 ± 3 signals per hour; P<.0001, two-sample t test), and total signal power and duration also were higher (power, 2231 ± 63 versus 455±109 power units; duration, 55.9±0.8 versus 29.9±1.4 milliseconds; both P<.001). The majority of emboli signals were seen during cardiac systole, especially in patients with carotid stenosis (89% in the first half of the cardiac cycle versus 72% in prosthetic valve patients). In 19 patients with prosthetic valves, embolus signals were also recorded from the anterior cerebral artery; the signal count was not significantly different from the middle cerebral artery (43.2 ± 12.5 versus 64.3 ± 16 per hour), but anterior cerebral artery signals were of higher power (3306 ± 148 versus 2441 ± 109 power units, P<.001). Conclusions There is promise of being able to distinguish emboli on the basis of power measurements. Emboli of different sources (eg, carotid and cardiac) appear to have different ultrasonic characteristics, which are likely to be based on composition and size.

Duration of Neuroprotective Treatment for Ischemic Stroke

BACKGROUND The therapeutic time window for thrombolysis appears to be extremely short, probably because of the hemorrhagic complications associated with late reperfusion of ischemic brain tissue. Other neuroprotective forms of treatment continue to be developed, although their efficacy has yet to be conclusively proved in patients. The duration of treatment in recent phase 3 trials ranges from a single bolus injection to 12 weeks of oral therapy. SUMMARY OF REVIEW In this article we discuss the factors that should influence the choice of route and duration of treatment. Excitotoxic injury following stroke evolves over at least 4 hours in rodents and possibly beyond 48 hours in humans. In addition, autoregulation and local cerebral perfusion are deranged for approximately 72 hours in patients with stroke. Neuroprotection should provide cover during this critical time. CONCLUSIONS Important considerations influencing drug administration should include the pharmacology of the compound (pharmacokinetics, mechanism of action, preclinical toxicity, and pharmaceutical properties), its safety and tolerability in patients, and the likelihood of continuing or recurrent cerebral ischemia, along with practical issues such as ease of administration and interactions with early rehabilitation and other therapies. Optimization of treatment will be possible only when neuroprotection is confirmed to be effective.

Safety and tolerability study of aptiganel hydrochloride in patients with an acute ischemic stroke.

BACKGROUND AND PURPOSE Aptiganel (CNS 1102) is a selective, noncompetitive antagonist that acts on the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor and is neuroprotective in experimental focal cerebral ischemia models at a plasma concentration of 10 ng/mL. In human volunteers, dose-limiting effects of aptiganel are blood pressure increases and central nervous system (CNS) excitation or depression. This study assessed the safety and tolerability of non-weight-adjusted doses of aptiganel in patients with acute ischemic stroke. METHODS This was a double-blind, randomized, placebo-controlled multicenter study in patients presenting within 24 hours of acute ischemic stroke. Ascending single intravenous bolus doses of aptiganel (3, 4.5, 6, and 7.5 mg) were assessed in 21 patients with a 3:1 active drug:placebo randomization schedule. In 15 subsequent patients, selected bolus doses were followed by constant intravenous infusion for 6 to 12 hours (6 mg plus 1 mg/h, n=10; then 4.5 mg plus 0.75 mg/h, n=15) in a 4:1 randomization schedule. Prospectively collected pharmacokinetic data guided selection of infusion rates. Neurological and functional status were recorded at entry and after 1 week, although the study was not designed to test efficacy. RESULTS Forty-six patients were randomized from 4 centers (3 in the United States and 1 in the United Kingdom): 36 received aptiganel HCl, and 10 were given placebo. Hypertension and CNS events were commonly reported after a bolus dose of 7.5 mg and after a 6-mg bolus followed by an infusion of 1 mg/h. The lower regimen of 4.5-mg bolus followed by infusion of 0.75 mg/h achieved plasma aptiganel concentrations of >10 ng/mL and was well tolerated by patients but still raised systolic blood pressure by approximately 30 mm Hg over baseline. CONCLUSIONS A 4.5-mg intravenous bolus of aptiganel HCl followed by infusion of 0.75 mg/h for 12 hours is a tolerable dose that can produce plasma drug concentrations shown to be neuroprotective in animal models. However, increases in systolic blood pressure and an excess of CNS effects were both observed at this dose.

Transhemispheric passage of microemboli in patients with unilateral internal carotid artery occlusion.

Background and Purpose Ischemic episodes distal to an internal carotid artery occlusion are common. We undertook this study to look for evidence of transhemispheric passage of embolic material in this patient category as a mechanism for embolic events. Methods Seven symptomatic patients with unilateral internal carotid artery occlusion and contralateral stenosis were examined by transcranial Doppler ultrasonography with 2-MHz probe (average monitoring time, 2.5 hours per patient). Both middle cerebral arteries and (if present) the reverse-flow anterior cerebral artery ipsilateral to the occluded internal carotid were monitored. Three patients were reexamined 1 month after carotid endarterectomy. Results Embolic signals were detected in the middle cerebral artery ipsilateral to the stenosed internal carotid artery in all seven patients and in the opposite middle cerebral artery in four patients. In these four patients, a reverse-flow anterior cerebral artery was observed in which embolic signals were detected. No embolic signals were detected after surgery in any of the three patients who underwent carotid endarterectomy. Conclusions Transhemispheric passage of embolic material occurs in patients with unilateral internal carotid artery occlusion and contralateral stenosis. Endarterectomy of the stenosed internal carotid artery may eliminate the detected embolic signals in both hemispheres. Transcranial Doppler ultrasonography could be used as a diagnostic tool to identify the embolic source in patients with unilateral carotid occlusion. (Stroke. 1993;24:1664-1666.)

Coagulation activity and emboli counts in patients with prosthetic cardiac valves.

Background and Purpose The underlying embolic material detected by transcranial Doppler ultrasound in patients with prosthetic heart valves remains unknown. We undertook this study to evaluate the relation between the number of Doppler emboli signals and the activity of the coagulation system. Methods Patients with various types of prosthetic valves (n=120) and patients in atrial fibrillation (n=20) were monitored for 30 minutes using transcranial Doppler with a 2-MHz probe. The plasma concentrations of cross-linked D-dimer, antithrombin-III, and thrombin-antithrombin III complex were measured. Results No correlation between the levels of any of the hematologic parameters and the number of emboli was demonstrated in the studied groups. The D-dimer levels were significantly higher in patients with mechanical prosthetic valves with an international normalized ratio under 2.0 compared with those with an international normalized ratio between 2 and 3.5 or above 3.5, and in patients with Medtronic-Hall versus Björk-Shiley or Carpentier-Edwards valve prostheses. Conclusions The lack of correlation between the activity of the coagulation system and the number of Doppler emboli in patients with prosthetic valves suggests that the underlying embolic material in these patients is not thrombotic. Our results also suggest that an increase of the anticoagulation intensity to an international normalized ratio above 3.5 does not result in a further decrease of the activity of the unstimulated coagulation system in patients with mechanical prosthetic valves.