M. Limburg

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Mortality and Morbidity of Surgery for Unruptured Intracranial Aneurysms A Meta-Analysis

BACKGROUND AND PURPOSE Greater availability and improvement of neuroradiological techniques have resulted in more frequent detection of unruptured aneurysms. Because prognosis of subarachnoid hemorrhage is still poor, preventive surgery is increasingly considered as a therapeutic option. Elective surgery requires reliable data on its risks. Therefore, we performed a meta-analysis on the mortality and morbidity of surgery for unruptured intracranial aneurysms. METHODS Through Medline and additional searches by hand, we retrieved studies on clipping of unruptured (additional, symptomatic, or incidental) aneurysms published from 1966 through June 1996. Two authors independently extracted data. We used weighted linear regression for data analysis. RESULTS We included 61 studies that involved 2460 patients (57% female; mean age, 50 years) and at least 2568 unruptured aneurysms (27% >25 mm, 30% located in the posterior circulation). Mortality was 2.6% (95% confidence interval [CI], 2.0% to 3.3%). Permanent morbidity occurred in 10.9% (95% CI, 9.6% to 12.2%) of patients. Postoperative mortality was significantly lower in more recent years for nongiant aneurysms and aneurysms with an anterior location; the last 2 characteristics were also associated with a significantly lower morbidity. CONCLUSIONS In studies published between 1966 and 1996 on clipping of unruptured aneurysms, mortality was 2.6% and morbidity was 10.9%. In calculating the pros and cons of preventive surgery, these proportions should be taken into account.

Risk Factors for Falls of Hospitalized Stroke Patients

BACKGROUND AND PURPOSE Patients with stroke are at a high risk for falling. We assessed the fall incidence and risk factors for patients hospitalized as the result of an acute stroke. METHODS We studied a cohort of 720 stroke patients from 23 hospitals in The Netherlands. The data were abstracted from the medical and nursing records. RESULTS We studied 346 women and 374 men with a median age of 75 years; 77% of the patients had had a cerebral infarct, 17% had had a hemorrhage, and 6% had had an undefined stroke. We recorded 104 patients (14%) who fell at least once; there were a total of 173 falls. The incidence of falls was 8.9/1000 patients per day. The daily incidence was 6.2/1000 patients for first falls and 17.9/1000 patients for second falls. Heart disease (relative risk [RR], 1.6; 95% confidence interval [CI], 1.0 to 2.4), mental decline (RR, 1.6; 95% CI, 1.0 to 2.4), and urinary incontinence (RR, 2.3; 95% CI, 1.3 to 4.1) were incremental risk factors for first falls, whereas the use of major psychotropic drugs lowered the fall risk (RR, 0.5; 95% CI, 0.3 to 0.8). The fall RR for patients with one previous fall was 2.2 (95% CI, 1.5 to 3.2), adjusted for the other risk factors. Most falls occurred during the day. Approximately 25% of the falls caused slight-to-severe injury, whereas three falls (2%) led to hip fractures. CONCLUSIONS Stroke patients have at risk of falling. The identification of patients at risk may be a first step toward the implementation of fall-prevention measures for these patients.

Costs of Medical Care After First-Ever Stroke in the Netherlands

BACKGROUND AND PURPOSE Stroke causes high morbidity and mortality. The aging of the population further increases the demands on healthcare costs. METHODS We estimated the lifetime direct costs of care of first-ever stroke patients in the Netherlands in 1991 using epidemiological data from national and international studies. In addition, we examined the effect of an aging population on future healthcare costs. RESULTS The lifetime costs for 24,007 first-ever stroke patients are estimated to be 1870 million Dutch guilders (Dfl) (1 Dfl = 0.53 US dollar, 1991). Per-person costs are higher for women (83,000 Dfl) than for men (71,000 Dfl). The major cost component of first-year costs is hospital costs (45%), while nursing home costs dominate lifetime costs (50%). An increase of the elderly population older than 65 years of 27% between 1991 and 2010 might lead to a parallel increase of total costs of 30%, or 1.5% per year. CONCLUSIONS Long-term care rather than acute care dominates the lifetime costs for stroke patients now and in the future.

Calcium Antagonists for Ischemic Stroke A Systematic Review

Background and Purpose — Stroke is a common disease, and many trials with calcium antagonists as possible neuroprotective agents have been conducted. The aim of this review is to determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. Methods — Acute stroke trials were identified with help of the Cochrane Collaboration Stroke Group and personal contacts. All randomized trials (published and unpublished) investigating a calcium antagonist (acting on voltage-sensitive calcium channels) were included. Poor outcome, defined as death or dependency in activities of daily living, was used as main outcome. Analyses were, if possible, “intention-to-treat”; pooled relative risks with 95% CIs were calculated. Results — Forty-seven trials were identified, of which 29 were included (7665 patients). No effect of calcium antagonists on poor outcome at the end of follow-up (relative risk, 1.04; 95% CI, 0.98 to 1.09) or on death at end of follow-up (relative risk, 1.07; 95% CI, 0.98 to 1.17) was found. Sensitivity analyses on route of administration and time interval between stroke and start of treatment showed no effect on outcome. In subgroups of unpublished and methodologically sound trials, a statistically significant negative effect for calcium antagonists was found. This contrasts with results of published trials and trials of moderate or poor methodological quality. Conclusions — The presented evidence rules out a clinically important effect of calcium antagonists after ischemic stroke. The large amount of data leads to narrow CIs with no significant heterogeneity, and the overall results are therefore likely to be statistically robust.

Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial.

Backgound and Purpose — The Very Early Nimodipine Use in Stroke (VENUS) trial was designed to test the hypothesis that early treatment with nimodipine has a positive effect on survival and functional outcome after stroke. This was suggested in a previous meta-analysis on the use of nimodipine in stroke. However, in a recent Cochrane review we were unable to reproduce these positive results. This led to the early termination of VENUS after an interim analysis. Methods — In this randomized, double-blind, placebo-controlled trial, treatment was started by general practitioners or neurologists within 6 hours after stroke onset (oral nimodipine 30 mg QID or identical placebo, for 10 days). Main analyses included comparisons of the primary end point (poor outcome, defined as death or dependency after 3 months) and secondary end points (neurological status and blood pressure 24 hours after inclusion, mortality after 10 days, and adverse events) between treatment groups. Subgroup analyses (on final diagnosis and based on the per-protocol data set) were performed. Results — At trial termination, after inclusion of 454 patients (225 nimodipine, 229 placebo), no effect of nimodipine was found. After 3 months of follow-up, 32% (n=71) of patients in the nimodipine group had a poor outcome compared with 27% (n=62) in the placebo group (relative risk, 1.2; 95% CI, 0.9 to 1.6). A treatment effect was not found for secondary outcomes and in the subgroup analyses. Conclusions — The results of VENUS do not support the hypothesis of a beneficial effect of early nimodipine in stroke patients.

A Stroke-Adapted 30-Item Version of the Sickness Impact Profile to Assess Quality of Life (SA-SIP30)

BACKGROUND AND PURPOSE In view of the growing therapeutic options in stroke, measurement of quality of life has become increasingly relevant as an outcome parameters. The Sickness Impact Profile (SIP) is one of the most widely used measures to assess quality of life. To overcome the major disadvantage of the SIP, its length, we constructed a short stroke adapted 30-item SIP version (SA-SIP30). METHODS Data on the original SIP version were collected for 319 communicative patients at 6 months after stroke. The 12 subscales and the 136 items of the original SIP were reduced to 8 subscales with 30 items in a three step procedure, on the basis of relevancy and homogeneity. Reliability of the SA-SIP30 was evaluated by means of an analysis of homogeneity (Cronbachs alpha coefficient). Different types of validity were assessed: construct, clinical, and external validities. RESULTS Homogeneity of the SA-SIP30 was demonstrated by a high Cronbachs alpha (0.85). Principal component analyses revealed the same two dimensions as in the original SIP (a physical and a psychosocial dimension). The SA-SIP30 could explain 91% of the variation in scores of the original SIP in the same cohort of patients, and 89% in a different cohort. Furthermore, the SA-SIP30 was related to other functional health measures similar to how the original SIP was. We could demonstrate that the SA-SIP30 was able to distinguish patients with lacunar infarctions from patients with cortical or subcortical lesions. CONCLUSIONS We conclude that the SA-SIP30 is a feasible and clinimetrically sound measure to assess quality of life after stroke.

Cerebrovascular disease in Ehlers-Danlos syndrome type IV.

We describe two patients with cerebrovascular complications of Ehlers-Danlos syndrome type IV. A 16-year-old girl with spontaneous internal carotid artery dissection and a 46-year-old woman with aneurysmal subarachnoid hemorrhage and multiple aortic dissections were both deficient in collagen type III, analyzed in cultured skin fibroblasts. To our knowledge, spontaneous carotid artery dissection associated with collagen type III deficiency has not been reported previously. Early clinical recognition of this syndrome is of great importance in view of the hazards of angiography and surgery. Collagen type III deficiency plays a role in the pathogenesis of intracranial saccular aneurysms and may also be involved in the pathogenesis of carotid cavernous fistulas and dissections of the cervical arteries.

Impairment of cerebrovascular reactivity in long-term type 1 diabetes

The early preclinical detection of cerebrovascular complications in individuals with diabetes is one of the goals of care described in the St. Vincent Declaration. In accordance with this goal, the aim of the present work was to investigate whether altered cerebral microvascular function in patients suffering from type 1 diabetes can be detected with a transcranial Doppler probe after the administration of acetazolamide. A total of 72 type 1 diabetic patients and 40 healthy control subjects entered the study. Patients were divided into two groups: those with long-term diabetes (disease duration of >10 years, n = 37) and those with short-term diabetes (disease duration of ≤10 years, n = 35). Mean blood-flow velocity in the middle cerebral artery (MCAV) was measured at rest and at 5, 10, 15, and 20 min after intravenous administration of 1 g acetazolamide with a transcranial Doppler probe and expressed as the percentage change from the pretest measurement. The percentage increase in MCAV (cerebrovascular reactivity) was calculated at each time point and compared between the groups. Cerebrovascular reserve capacity (CRC), expressed as the maximal percentage increase of the MCAV, was compared between the groups. Additionally, a reproducibility study of CRC was performed in 10 patients, using intra-class correlations. Cerebrovascular reactivity in the long-term diabetes group was lower (means ± SD: 5 min, 23.4 ± 15.4%; 10 min, 28.8 ± 17.0%; 15 min, 30.0 ± 15.6%; 20 min, 24.2 ± 17.8%) than that of the control subjects (5 min, 43.5 ± 23.9%; 10 min, 55.3 ± 24.0%; 15 min, 56.7 ± 23.8%; 20 min, 54.8 ± 25.9%) and the short-term diabetic patients (5 min, 43.6 ± 25.9%; 10 min, 52.2 ± 27.7%; 15 min, 55.3 ± 32.2%; 20 min, 45.8 ± 35.8%). CRC was lower in the long-term diabetes group than in the control group or the short-term diabetes group. Impairment of cerebrovascular reactivity was associated with retino- and nephropathy and increased levels of fibrinogen. In contrast, CRC was independent from actual glucose, insulin, glycosylated hemoglobin, von Willebrand factor antigen, and α-2 macroglobulin levels. Transcranial Doppler measurements of the changes in MCAV after stimulation with acetazolamide can detect altered cerebral microvascular function in patients with diabetes. Cerebrovascular reactivity and reserve capacity are reduced in patients with long-term diabetes. Further prospective studies should delineate the clinical significance of our results.

Prevalence of Symptomatic Intracranial Aneurysm and Ischaemic Stroke in Pseudoxanthoma Elasticum

Background: Pseudoxanthoma elasticum (PXE) is an heritable connective tissue disorder with clinical manifestations of the ocular, dermal, and cardiovascular system. The purpose of this study was to investigate the prevalence of symptomatic intracranial aneurysms (IAs) and ischaemic stroke (IS) in PXE. Methods: The records of 100 patients with PXE were retrieved. All patients were contacted and data on complications were collected. The literature was reviewed regarding PXE, ISs, and IAs. Results: No patient with PXE had a symptomatic IA as presenting symptom. One patient presented with an IS. During follow-up of 94 of the 100 patients (mean follow-up 17.1 years, range 1–49 years), none presented a symptomatic IA (3,168 retrospective patient observation years and 1,602 prospective patient observation years). Upper gastrointestinal haemorrhage during follow-up occurred in 17 patients, in 1 patient during aspirin use. One patient has IS as presenting symptom and a recurrence during follow-up, and 7 patients had IS during follow-up. All were caused by small-vessel disease. The relative risk of IS in PXE under 65 years compared with the general population was 3.6 (95% confidence interval 3.3–4.0). Conclusions: On the basis of the currently available data, an association between symptomatic IAs and PXE is unlikely. However, the incidence of IS, due to small-vessel disease, was increased. Antiplatelet therapy in patients with PXE may lead to a high incidence of upper gastrointestinal haemorrhages.