Takenori Yamaguchi

The Cognitive Abilities Screening Instrument (CASI): A Practical Test for Cross-Cultural Epidemiological Studies of Dementia

The Cognitive Abilities Screening Instrument (CASI) has a score range of 0 to 100 and provides quantitative assessment on attention, concentration, orientation, short-term memory, long-term memory, language abilities, visual construction, list-generating fluency, abstraction, and judgment. Scores of the Mini-Mental State Examination, the Modified Mini-Mental State Test, and the Hasegawa Dementia Screening Scale can also be estimated from subsets of the CASI items. Pilot testing conducted in Japan and in the United States has demonstrated its cross-cultural applicability and its usefulness in screening for dementia, in monitoring disease progression, and in providing profiles of cognitive impairment. Typical administration time is 15 to 20 minutes. Record form, manual, videotape of test administration, and quizzes to qualify potential users on the administration and scoring of the CASI are available upon request.

Ebselen in Acute Ischemic Stroke A Placebo-Controlled, Double-blind Clinical Trial

BACKGROUND AND PURPOSE The effect of ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action, on the outcome of acute ischemic stroke was evaluated in a multicenter, placebo-controlled, double-blind clinical trial. METHODS Patients diagnosed as having acute ischemic stroke who could receive drug treatment within 48 hours of stroke onset were enrolled. Oral administration of ebselen granules suspended in water (150 mg BID) or placebo was started immediately after admission and was continued for 2 weeks. The major end points were the Glasgow Outcome Scale scores at 1 month and 3 months after the start of treatment. The modified Mathew Scale and modified Barthel Index scores at 1 month and 3 months were also studied as secondary outcome measures. RESULTS Three hundred two patients were enrolled in the trial. Intent-to-treat analysis of 300 patients (151 given ebselen and 149 given placebo) revealed that ebselen treatment achieved a significantly better outcome than placebo at 1 month (P = .023, Wilcoxon rank sum test) but not at 3 months (P = .056, Wilcoxon rank sum test). The improvement was significant in patients who started ebselen within 24 hours of stroke onset but not in those who started treatment after 24 hours. There was a corresponding improvement in the modified Mathew Scale and modified Barthel Index scores. CONCLUSIONS Early treatment with ebselen improved the outcome of acute ischemic stroke. Ebselen may be a promising neuroprotective agent.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial

BACKGROUND The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING Otsuka Pharmaceutical.

Optimal Intensity of Warfarin Therapy for Secondary Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation A Multicenter, Prospective, Randomized Trial

BACKGROUND AND PURPOSE The optimal intensity of warfarin therapy for secondary prevention of stroke in nonvalvular atrial fibrillation (NVAF) remains unclear. We studied the efficacy and safety of conventional- and low-intensity warfarin therapy in a prospective, randomized, multicenter trial. METHODS The study population consisted of patients with NVAF (<80 years old) who had a stroke or transient ischemic attack. The patients were randomly allocated into a conventional-intensity group (international normalized ratio [INR] 2.2 to 3.5) and a low-intensity group (INR 1.5 to 2.1). They were carefully monitored, and the annual rate of recurrent ischemic stroke and major hemorrhagic complications were compared between the groups. RESULTS We enrolled 115 patients (mean age 66.7+/-6.5 years) into the study. Fifty-five and 60 patients were allocated into the conventional- and low-intensity groups, respectively. The trial was stopped after a follow-up of 658+/-423 days, when major hemorrhagic complications occurred in 6 patients of the conventional-intensity group and the frequency (6.6% per year) was significantly higher than that in the low-intensity group (0% per year, P=0.01, Fishers exact test). All of the 6 patients with major bleeding were elderly (mean age 74 years), and their mean INR before the major hemorrhage was 2.8. The annual rate of ischemic stroke was low in both groups (1.1% per year in the conventional-intensity group and 1.7% per year in the low-intensity groups) and did not differ significantly. CONCLUSIONS For secondary prevention of stroke in persons with NVAF, especially in old patients, the low-intensity warfarin (INR 1.5 to 2. 1) treatment seems to be safer than the conventional-intensity (INR 2.2 to 3.5) treatment.

Predisposing Factors to Enlargement of Spontaneous Intracerebral Hematoma

BACKGROUND AND PURPOSE Enlargement of intracerebral hemorrhage is a major cause of clinical deterioration. Identification of factors that predispose to hematoma enlargement is important in managing patients. METHODS We selected 186 patients (71 women and 115 men; mean age, 64.8 +/- 12.5 years) with spontaneous intracerebral hemorrhage who had undergone an initial CT within 24 hours and a second scan within 120 hours of symptom onset. We compared patients with (n = 41) and without (n = 145) hematoma enlargement according to clinical characteristics and laboratory data. RESULTS By multiple logistic regression analysis (n = 139), interaction of long interval (> 6 hours) from onset to first CT and small hematoma (< 25 cm3) strongly reduced risk of enlargement. The analysis also demonstrated that the following factors independently predisposed to enlargement: history of brain infarction; liver disease; interaction of fasting plasma glucose > or = 141 mg/dL and systolic blood pressure on admission > or = 200 mm Hg; and interaction of glycosylated hemoglobin A1c > or = 5.1% and systolic blood pressure on admission > or = 200 mm Hg. CONCLUSIONS A patient examined > 6 hours after ictus who has a hematoma volume < 25 cm3 is unlikely to experience further hematoma growth. Prevention of brain infarction and premorbid management of liver disease may serve to lower the risk of hematoma enlargement. Although it remains controversial whether antihypertensive drugs should be used in the acute phase of intracerebral hemorrhage, poorly controlled diabetics with high systolic blood pressure (> or = 200 mm Hg) on admission also were at high risk of hematoma enlargement.

Hemorrhagic transformation in cerebral embolism

We studied the mechanism of hemorrhagic infarction after acute cerebral embolism in 160 patients by brain computed tomography and angiography. Hemorrhagic infarction during the month after the embolic event was evident in 65 patients (40.6%). Initial angiography a median of 1.5 (range 1-60) days after the event revealed occlusion of the cerebral arteries in 117 of 142 patients (82.4%), and reopening of the vessels was observed in 56 (94.9%) of 59 patients who had follow-up angiography a median of 20 (range 3-47) days after the event. The incidence of hemorrhagic infarction was higher in patients greater than or equal to 70 years old (31 of 61, 50.8%) than in those aged 50-69 years (27 of 72, 37.5%) or less than 50 years (seven of 27, 25.9%) (greater than or equal to 70 vs. less than 50, p less than 0.05). In patients with moderate or large infarcts, hemorrhagic infarction developed in 50.0% or 51.5%, respectively, while in those with small infarcts it developed in only 2.9% (p less than 0.05). No correlation was found between hemorrhagic infarction and history of hypertension or blood pressure during the acute stage of stroke. Thrombolytic and/or anticoagulant therapy did not affect the incidence of hemorrhagic infarction (40.0% with vs. 40.7% without therapy) but tended to cause massive hematoma. Our results indicate that hemorrhagic transformation in cerebral embolism is caused not only by reopening of the occluded vessels but also by other factors such as age and size of the infarct. Hypertension per se seems to be less important for hemorrhagic infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Cilostazol Stroke Prevention Study: A Placebo-Controlled Double-Blind Trial for Secondary Prevention of Cerebral Infarction

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction.

Alteplase at 0.6 mg/kg for Acute Ischemic Stroke Within 3 Hours of Onset: Japan Alteplase Clinical Trial (J-ACT)

Background and Purpose— Based on previous studies comparing different recombinant tissue plasminogen activator (rt-PA) doses, we performed a clinical trial with 0.6 mg/kg, which is lower than the internationally approved dosage of 0.9 mg/kg, aiming to assess the efficacy and safety of alteplase in acute ischemic stroke for the Japanese. Methods— Our prospective, multicenter, single-arm, open-label trial was designed with a target sample size of 100 patients. The primary end points were the proportion of patients with a modified Rankin Scale (mRS) score of 0 to 1 at 3 months and the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from published reports. The protocol was defined according to the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study with slight modifications. Results— Among the 103 patients enrolled, 38 had an mRS of 0 to 1 at 3 months; this proportion (36.9%) exceeded the predetermined threshold of 33.9%. sICH within 36 hours occurred in 6 patients; this incidence (5.8%) was lower than the threshold of 9.6%. Conclusions— In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.

Alteplase at 0.6 mg/kg for Acute Ischemic Stroke Within 3 Hours of Onset

Background and Purpose— Based on previous studies comparing different recombinant tissue plasminogen activator (rt-PA) doses, we performed a clinical trial with 0.6 mg/kg, which is lower than the internationally approved dosage of 0.9 mg/kg, aiming to assess the efficacy and safety of alteplase in acute ischemic stroke for the Japanese. Methods— Our prospective, multicenter, single-arm, open-label trial was designed with a target sample size of 100 patients. The primary end points were the proportion of patients with a modified Rankin Scale (mRS) score of 0 to 1 at 3 months and the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from published reports. The protocol was defined according to the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study with slight modifications. Results— Among the 103 patients enrolled, 38 had an mRS of 0 to 1 at 3 months; this proportion (36.9%) exceeded the predetermined threshold of 33.9%. sICH within 36 hours occurred in 6 patients; this incidence (5.8%) was lower than the threshold of 9.6%. Conclusions— In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.

'Spectacular shrinking deficit' Rapid recovery from a major hemispheric syndrome by migration of an embolus

We studied the clinical features of a major hemispheric stroke syndrome with rapid recovery (“spectacular shrinking deficit” [SSD]) compared with stroke patients with the same major initial manifestations but without rapid recovery (non-SSD). There were 118 patients with an initial major hemispheric syndrome; 14 patients (12%) had SSD. All but one SSD patient met criteria for cardiogenic brain embolism. Angiographic examination within 24 hours after stroke onset demonstrated that the occlusion sites in SSD differed from those in non-SSD and suggested that rapid embolus migration had occurred in all SSD patients but in only five of 39 non-SSD. Infarcts in SSD were smaller and often scattered over the cortices and deeper structures. Hemorrhagic transformation was less frequent in SSD. In patients with a potential cardiac source of emboli, SSD was more likely to occur in nondiabetic men less than 60 years of age.