Transient ischemic attack without self-awareness of symptoms witnessed by bystanders: analysis of the PROMISE-TIA registry.

BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) can occur without self-awareness of symptoms. We aimed to investigate characteristics of patients with a tissue-based diagnosis of TIA but having no self-awareness of their symptoms and whose symptoms were witnessed by bystanders. METHODS: We used data from the multicenter registry of 1414 patients with a clinical diagnosis of TIA. For patients without evidence of ischemic lesions on imaging, clinical characteristics were compared between patients with and without self-awareness of their TIA symptoms. RESULTS: Among 896 patients (559 men, median age of 70 years), 59 (6.6%) were unaware of their TIA symptoms, but had those symptoms witnessed by bystanders. Patients without self-awareness of symptoms were older and more frequently female, and more likely to have previous history of stroke, premorbid disability, and atrial fibrillation, but less likely to have dyslipidemia than those with self-awareness. Patients without self-awareness of symptoms arrive at hospitals earlier than those with self-awareness (P < 0.001). ABCD2 score was higher in patients without self-awareness of symptoms than those with self-awareness (median 5 vs. 4, P = 0.002). Having no self-awareness of symptoms was a significant predictor of ischemic stroke within 1 year after adjustment for sex, ABCD2 score, and onset to arrival time (hazard ratio = 2.44, 95% confidential interval: 1.10-4.83), but was not significant after further adjustment for arterial stenosis or occlusion. CONCLUSIONS: Patients with a TIA but having no self-awareness of their symptoms might have higher risk of subsequent ischemic stroke rather than those with self-awareness, suggesting urgent management is needed even if patients have no self-awareness of symptoms.

Impact of B-type natriuretic peptide (BNP) on development of atrial fibrillation in people with Type 2 diabetes.

AIMS: To examine if a simple biomarker can identify people with diabetes who are at high risk of atrial fibrillation. METHODS: A retrospective cohort study was conducted at a single centre in people with Type 2 diabetes referred to our department between January 2000 and December 2007. In 517 consecutive people without any history, signs or symptoms of atrial fibrillation at baseline, the association between baseline B-type natriuretic peptide level and future atrial fibrillation incidence was examined, with adjustments for other potentially confounding factors. RESULTS: A total of 28 people were diagnosed with new-onset atrial fibrillation during a median 6-year follow-up. When people were categorized into three groups according to B-type natriuretic peptide clinical thresholds (20 and 100 pg/ml), hazard ratios for the development of atrial fibrillation in the middle and highest B-type natriuretic peptide groups were 2.8 and 9.4, respectively, compared with the lowest B-type natriuretic peptide group. Time-dependent receiver-operating curve analysis identified a threshold for B-type natriuretic peptide to detect atrial fibrillation development of 52.8 pg/ml (sensitivity 75.2%, specificity 68.8%). The B-type natriuretic peptide predictive value was independent of and similar to that of left atrial size and ventricular dimension. CONCLUSION: In people with Type 2 diabetes, high baseline B-type natriuretic peptide levels were significantly associated with future atrial fibrillation development.

The relationship between the pre-admission CHA2DS2-VASc score and proximal artery occlusion in patients with acute stroke and atrial fibrillation.

BACKGROUND AND PURPOSE: The CHA2DS2-VASc score is associated with severity and outcome of ischaemic stroke in patients with atrial fibrillation (AF). It was hypothesized that a high CHA2DS2-VASc score was related to severity and outcome because of its association with proximal artery occlusion (PAO). This study aimed to elucidate the relationship between the CHA2DS2-VASc score and PAO and to determine whether the effect of the CHA2DS2-VASc score on severity or outcome is independent of PAO. METHODS: Acute stroke patients with AF were retrospectively enrolled. PAO was defined as occlusion at the internal carotid artery or proximal middle cerebral artery on admission magnetic resonance angiography. Multivariable analyses were performed to identify independent factors associated with PAO and determine the associations of the CHA2DS2-VASc score with the initial National Institutes of Health Stroke Scale (NIHSS) score and poor functional outcome (discharge modified Rankin scale score 4-6). RESULTS: In all, 213 patients [102 women; median age 80 (interquartile range 71-86) years; NIHSS score 16 (9-22)] were enrolled. On multivariable analysis, the CHA2DS2-VASc score (odds ratio 1.40, 95% confidence interval 1.12-1.76 per 1 point) was independently associated with PAO and correlated with the initial NIHSS score (standardized coefficient 0.198, P = 0.017). This association was not significant after further adjustment for PAO (0.080, P = 0.241). The CHA2DS2-VASc score was independently related to poor outcome even adjusted for PAO (odds ratio 1.39, 95% confidence interval 1.03-1.88). CONCLUSION: The CHA2DS2-VASc score was associated with PAO in acute ischaemic stroke patients with AF. The CHA2DS2-VASc score may be correlated with the NIHSS score through the presence of PAO and with poor functional outcome independently of PAO.

Simple clinical predictors of stroke outcome based on National Institutes of Health Stroke scale score during 1-h recombinant tissue-type plasminogen activator infusion.

BACKGROUND AND PURPOSE: An index for predictors of stroke outcome was determined based on the National Institutes of Health Stroke Scale (NIHSS) scores during 1-h intravenous administration of recombinant tissue-type plasminogen activator (rt-PA). METHODS: Stroke patients with baseline NIHSS score ≥8 and occlusion at the internal carotid or middle cerebral arteries (ICA, MCA) were retrospectively studied from a prospective single-center registry. NIHSS scores and inverse change from baseline scores (ΔNIHSS) were assessed at 30 min and 1 h after rt-PA infusion. Patients were divided into two groups according to arterial occlusion sites: group P, ICA or proximal M1; and group D, distal M1 or M2. A modified Rankin Scale score of 2-6 at 3 months was defined as an unfavorable outcome. RESULTS: In all 108 patients, the cutoff NIHSS score predicting unfavorable outcome was ≥12 and cutoff ΔNIHSS scores were ≤2 at both 30 min and 1 h. In group P (n = 36), the cutoff NIHSS score was ≥14 at both 30 min and 1 h and cutoff ΔNIHSS scores were ≤1 at 30 min and ≤2 at 1 h. Unfavorable outcome was seen in all patients with NIHSS1 h ≥ 14, ΔNIHSS30 min ≤ 1 and ΔNIHSS1 h ≤ 2. In group D (n = 72), the cutoff NIHSS scores were ≥12 at both 30 min and 1 h, and cutoff ΔNIHSS scores were ≤2 at 30 min and ≤7 at 1 h; 90% of patients with unfavorable outcome showed ΔNIHSS1 h ≤ 7. CONCLUSION: NIHSS and ΔNIHSS during 1-h rt-PA infusion seemed predictive of 3-month outcome when the site of arterial occlusion was identified prior to rt-PA.

Intravenous thrombolysis for patients with reverse magnetic resonance angiography and diffusion-weighted imaging mismatch: SAMURAI and NCVC rt-PA Registries.

BACKGROUND AND PURPOSE: The characteristics of reverse magnetic resonance angiography and diffusion-weighted imaging (MRA-DWI) mismatch (RMM), defined as a large DWI lesion in the absence of major artery occlusion (MAO), remain unknown, especially in patients treated with intravenous recombinant tissue plasminogen activator (rt-PA). METHODS: Patients with stroke in the middle cerebral artery territory were included. Early ischaemic changes (EIC) were assessed with the Alberta Stroke Program Early CT Score on DWI (DWI-ASPECTS). All patients were divided into four groups based on the presence of MAO and a DWI-ASPECTS cut-off value of <7. RMM was defined as DWI-ASPECTS <7 without MAO. Clinical characteristics, symptomatic intracerebral hemorrhage (sICH) and favorable functional outcome (modified Rankin Scale score 0-2) at 90 days were compared amongst the four groups. RESULTS: Of the 486 patients enrolled (167 women, median age 74 years, median initial National Institutes of Health Stroke Scale score 13), reverse MRA-DWI mismatch was observed in 24 (5%). Of the clinical characteristics, cardioembolism was the only factor that was independently associated with RMM [odds ratio (OR) 5.49, 95% confidence interval (CI) 1.25-24.1]. Multivariable analyses revealed that patients with RMM more commonly had sICH than those with DWI-ASPECTS ≥ 7 irrespective of the presence (OR 5.44, 95% CI 1.13-26.1) or absence (13.1, 2.07-83.3) of MAO, and they had a more favorable functional outcome than those with DWI-ASPECTS < 7 plus MAO (7.45, 2.39-23.2). CONCLUSION: RMM was observed in 5% of patients treated with rt-PA and associated with cardioembolism. Patients with RMM may benefit from thrombolysis compared with those with EIC with MAO, although increment in the rate of sICH is a concern.

A study of vertebrobasilar artery dissection with subarachnoid hemorrhage.

We retrospectively studied clinical characteristics of 368 patients with cerebral artery dissections who were diagnosed in 172 Japanese hospitals. Of these patients, 130 (35%) presented with subarachnoid hemorrhage, 217 (59%) with cerebral infarctions, and 21 (6%) with transient ischemic attacks. We analyzed 109 (84%) subarachnoid hemorrhage cases caused by vertebrobasilar artery dissection to evaluate conservative and surgical treatment from the viewpoint of postoperative rerupture and infarction.Subsequent ruptures were observed in 14% of the 21 cases with nonsurgical treatment. For the preventive purpose of rerupture, 88 patients received surgical interventions: 68 trappings, 13 proximal occlusions, 6 aneurysmal sac occlusions and 1 stenting. Rerupture was experienced in 33% of the aneurysmal sac occlusion patients while not occurring in the other three surgical interventions. In the group without vascular anastomosis, postoperative cerebral infarction was observed in 25% of the trapping, none of the proximal occlusion and 33% of the aneurysmal sac occlusion cases.In this study, aneurysmal sac occlusion treatments were more frequently complicated by rerupture or cerebral infarction postoperatively than the other treatment methods. It was difficult to determine which surgical treatment can achieve better surgical outcome among the proximal occlusion and trapping with or without vascular anastomosis.

Association between signal hyperintensity on T1-weighted MR imaging of carotid plaques and ipsilateral ischemic events.

BACKGROUND AND PURPOSE: To investigate associations between cerebral ischemic events and signal hyperintensity in T1-weighted MR imaging (T1WI) of carotid plaque according to stenosis severity and to estimate persistence of T1WI signal hyperintensity. METHODS: A total of 222 patients (392 atherosclerotic carotid arteries) underwent plaque imaging using 3D inversion-recovery-based T1WI (magnetization-prepared rapid acquisition with gradient-echo [MPRAGE]). Carotid plaque with intensity on MPRAGE of >200% that of adjacent muscle was categorized as "high signal intensity" and correlated with ipsilateral ischemic events within the previous 6 months. A total of 58 arteries (35 patients) underwent repeat MR imaging a total of 70 times at a median interval of 279 days (range, 10-1037 days). RESULTS: Ipsilateral ischemic events were more frequent in patients with MPRAGE high signals than in patients with low signals in the 0%-29%, 30%-69%, and 70%-99% stenosis groups: Relative risk (95% confidence interval) was 2.50 (0.96-6.51), 7.55 (1.84-31.04), and 1.98 (1.01-3.90), respectively. In the 70 cases of repeat MR imaging, 29 of 30 cases with high signals on the preceding MR imaging maintained high signals. Of the 58 arteries that underwent repeat MR imaging, 4 of 22 carotid arteries with high signals developed ipsilateral subsequent ischemic events within 1 year, whereas none with low signals developed subsequent events. CONCLUSIONS: Carotid plaque signal hyperintensity on T1WI is strongly associated with previous ipsilateral ischemic events, persisting over a period of months, and may indicate risk of subsequent events. Larger clinical trials are warranted to clarify associations between signal hyperintensity and risk of subsequent cerebral ischemic events.

Risk Factors.

Studies investigating risk factors for intracranial atherosclerosis (ICAS) have been infrequent. However, due to recent availability of non-invasive vascular imaging techniques that can assess intracranial cerebral arteries, there are a growing number of studies on risk factors for ICAS. Conventional vascular risk factors such as hypertension, diabetes, hypercholesterolemia and cigarette smoking are risk factors for ICAS. However, it remains uncertain whether there is a difference in risk factors between ICAS and extracranial atherosclerosis (ECAS). It also remains unclear why ICAS is more common in Asians and Blacks than in Caucasians. Although we reviewed available evidences on these differences, the review was limited because studies were heterogeneous in the definition of risk factors, diagnostic method, and characteristics of study subjects (hospitalized vs. community) or cerebral vessels (symptomatic vs. asymptomatic). Nevertheless, it seems that hypercholesterolemia is more closely associated with ECAS than ICAS. The difference in hypercholesterolemia prevalence is one of the main reasons for racial differences in the location of cerebral atherosclerosis. Intracranial arteries contain higher antioxidant level than extracranial arteries and may be more vulnerable to risk factors that deplete antioxidants (e.g., metabolic syndrome and diabetes mellitus). Intracranial arteries may be more vulnerable to factors associated with hemodynamic stress (e.g., advanced, salt-retaining hypertension and arterial tortuosity) because of a smaller diameter, thinner media and adventitia, and fewer elastic medial fibers than extracranial arteries. Additionally, non-atherosclerotic arterial diseases (e.g., moyamoya disease) that commonly occur in the intracranial arteries of East Asians may contaminate the reports of ICAS cases. Various genes, including RNF 213, might also explain racial differences in atherosclerotic location. Prospective, well-designed risk factor and genetic studies should be performed in a homogeneous group of patients with diverse ethnicities. These efforts are essential in the prevention of atherosclerotic diseases based on adequate knowledge of the risk factors and pathogenesis.

Acetazolamide reactivity on 123I-IMP single photon emission computed tomography in patients with major cerebral artery occlusive disease: correlation with positron emission tomography parameters.

Single photon emission computed tomography (SPECT) with acetazolamide challenge has increasingly been used for evaluating hemodynamic reserve in stroke patients. The accuracy of this test, however, has not been validated with positron emission tomography (PET). In 14 patients who had occlusive disease of the internal carotid artery or the trunk of the middle cerebral artery (MCA) with minimal or no infarction on computed tomography (CT) and magnetic resonance imaging (MRI), we compared acetazolamide reactivity on SPECT with N-isopropyl-p-[123I]-iodoamphetamine to hemodynamic parameters determined with gas inhalation labeled 15O steady-state PET studies. The asymmetry index (AI)--i.e., the percentage of the activity rate of the ischemic MCA territory versus the contralateral one, was determined by SPECT. Acetazolamide reactivity expressed as delta AI, or change in AI after acetazolamide challenge, was significantly lower in seven patients than -8.4%, the lower limit of the 95% confidence interval for the normal reactivity. Values of ipsilateral CBF, cerebral blood volume (CBV)/CBF, and oxygen extraction fraction (OEF) and contralateral OEF were significantly different between patients with normal and reduced acetazolamide reactivity. Values of delta AI were correlated with OEF (r = -0.87; p < 0.001) and CBV/CBF (r = -0.56; p < 0.05). All patients with OEF > 0.52, the mean + 2 SD calculated from five normal volunteers, also had reduced acetazolamide reactivity, while the patients with normal OEF values had normal reactivity. The present study has demonstrated that SPECT studies with an acetazolamide challenge can detect the Stage II hemodynamic failure.

Positron emission tomography for quantitative determination of glucose metabolism in normal and ischemic brains in rats: an insoluble problem by the Harderian glands.

To examine the reliability of quantitative positron emission tomography studies in the rat (Rat-PET), we assessed the influence of radioactivity accumulated in the Harderian glands on PET CMRglc determination. We measured CMRglc by PET and ex vivo dissection methods by using 2-[18F]fluoro-2-deoxy-D-glucose in rats with and without focal brain ischemia. The CMRglc values obtained by PET, after correcting with recovery coefficients, were higher than those measured by the ex vivo method at rostral slices, and reduction of the CMRglc in the ischemic brain was not demonstrated by PET in the frontal cortex. The radioactivity accumulated in the Harderian glands prevents the quantitative determination of CMRglc using Rat-PET.

Serial changes in cerebral blood flow and flow-metabolism uncoupling in primates with acute thromboembolic stroke.

The authors recently developed a primate thromboembolic stroke model. To characterize the primate model, the authors determined serial changes in cerebral blood flow (CBF) and the relation between CBF and cerebral metabolic rate of glucose (CMRglc) using high-resolution positron emission tomography. Thromboembolic stroke was produced in male cynomolgus monkeys (n = 4). Acute obstruction of the left middle cerebral artery was achieved by injecting an autologous blood clot into the left internal carotid artery. Cerebral blood flow was measured with [15O]H2O before and 1, 2, 4, 6, and 24 hours after embolization. CMRglc was measured with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) 24 hours after embolization. Lesion size and location 24 hours after embolization was determined by the 2,3,5-triphenyltetrazolium chloride (TTC) staining method. The results are summarized as follows: (1) 1 hour after embolization, CBF in the temporal cortex and the basal ganglia decreased to < 40% of the contralateral values. In these regions, regarded as an ischemic core, CBF decreased further with time and CMRglc at 24 hours also decreased. Infarcted lesions as indicated by being unstained with TTC were consistently observed in these regions. (2) In the parietal cortex and several regions surrounding the ischemic core, CBF was > 40% of the contralateral values 1 hour after embolization and recovered gradually with time (ischemic penumbra). In these regions, CMRglc at 24 hours increased compared with that in the contralateral regions, indicating an uncoupling of CBF and CMRglc. No obvious TTC-unstained lesions were detected in these regions. The authors demonstrated a gradual recovery of reduced CBF, an elevated CMRglc and a CBF-CMRglc uncoupling in the penumbra regions of the primate model. Positron emission tomography investigations using this model will provide better understanding of the pathophysiology of thromboembolic stroke in humans.

'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.

The duration of symptoms in transient ischemic attack.

BACKGROUND: The majority of TIAs last from 2 to 15 minutes, although some may be of long duration. OBJECTIVE: We examined factors related to the duration of TIAs to identify the relationship to clinical characteristics. METHODS: We performed brain imaging studies as well as angiographic and cardiac examinations in 81 consecutive patients (64 men and 17 women, age 65.8+/-9.9 years) with carotid TIAs. We evaluated risk factors (hypertension, diabetes mellitus, hyperlipidemia, alcohol consumption, and smoking), potential cardiac sources of emboli, and arterial stenosis > or =50% in diameter in the carotid or middle cerebral arteries. Recent infarcts were assessed with CT or MRI. We correlated duration of symptoms with clinical data. RESULTS: The presence of emboligenic cardiac or arterial diseases was significantly related to the duration of symptoms. With sensitivity-specificity curve analysis for detecting such diseases, the duration of symptoms could be divided into short-duration TIAs (<60 minutes, n = 41) or long-duration TIAs (> or =60 minutes, n = 40). Patients with long-duration TIAs had emboligenic cardiac or arterial diseases more frequently than those with short-duration TIAs (86% versus 46%, p < 0.001). Recent infarcts were also more frequent in patients with long-duration TIAs than they were in patients with short-duration TIAs (45% versus 21%, p < 0.05). CONCLUSIONS: Short-duration and long-duration TIAs can be separated based on symptom duration of < 1 hour or > or = 1 hour. Patients with long-duration TIAs should be examined more closely for the presence of cardiac and arterial diseases than those with short-duration TIAs.

Diffusion-weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia.

We examined serial changes of diffusion- (DWI) and T2-weighted (T2WI) magnetic resonance images 30 minutes to 3 hours after intraluminal suture occlusion of the middle cerebral artery (MCA) in eight rats and after sham occlusion in four. We correlated the abnormal areas on DWI and T2WI with postmortem areas of infarction determined by 2,3,5-triphenyltetrazolium chloride (TTC), 24 hours after the operation. The 30-minute DWI in each MCA-occluded rat demonstrated increased signal intensity in the ipsilateral MCA territory, while T2WI showed no changes. At 3 hours, the ipsilateral DWI signal intensity increased further and the area of abnormality slightly increased. In some animals, the 3-hour T2WI disclosed an area of hyperintensity significantly smaller than that seen on the 30-minute DWI. TTC staining demonstrated an extensive MCA infarction in all rats with permanent MCA occlusion, confirmed by hematoxylin and eosin staining. The percent infarcted area of coronal brain sections, as determined by TTC staining, correlated significantly with areas on similar DWI sections at both 30 minutes and 3 hours. Sham-occluded control animals did not display any changes on DWI, T2WI, or TTC staining. The present study suggests that DWI is a very sensitive modality for detecting early ischemic brain injury, being highly correlated with post-mortem area of infarction, and may be useful to assess pharmacologic intervention.

Medial medullary infarction: analyses of eleven patients.

Of 2,130 consecutive patients admitted to two hospitals with acute brain infarction, we examined 11 patients (0.52%) with medial medullary infarction. The infarcts documented by MRI were unilateral in 9 patients and bilateral in 2 patients, and located in the anteromedial arterial territory of the upper or middle part of the medulla. Atherosclerosis of the vertebral arteries was the predominant vascular pathology. The vertebral artery was occluded at its terminal portion in 7 patients. Nine patients had hypertension, and 8 of these had additional risk factors. Male gender (10 patients) and smoking habits (7 patients) were more prevalent compared with patients with pontine infarction. One patient had a medial medullary infarction attributed to dissection of the vertebral arteries following blunt head injury. Limb weakness was the major symptom in all patients, and gaze-evoked nystagmus was also frequent (6 patients). Tongue weakness ipsilateral to the infarct, the classic sign of medial medullary syndrome, was evident in only 3 patients. The outcome was usually excellent.

Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion-weighted MRI.

We employed diffusion-weighted MRI (DWI) to identify regions of focal brain ischemia during the first 3 hours after permanent occlusion of the middle cerebral artery in rats. Using DWI as early as 30 minutes after the onset of ischemia, it was possible to identify the areas of brain destined to progress to infarction over the next 24 hours in untreated animals, as demonstrated by postmortem evaluation. DWI studies revealed the cerebroprotective effects of a noncompetitive N-methyl-D-aspartate receptor antagonist, CNS 1102, administered 15 minutes postocclusion, both on the cortical and caudoputaminal regions during the initial 3 hours of ischemia. Although the treatment effect lessened over the next 21 hours in a few animals with lower plasma drug levels at 3 hours, postmortem studies demonstrated a 66% reduction in the total volume of infarcted tissue with the treatment and confirmed the DWI results. T2-weighted MRI obtained at similar times revealed little or no abnormality. These results suggest that DWI provides a sensitive in vivo measure of focal cerebral ischemic injury and can assess the beneficial effects of cytoprotective therapy. DWI may be useful in the early evaluation of human stroke patients and in monitoring the effects of cerebroprotective therapies in the clinical setting.

Population-based distribution of plasminogen activity and estimated prevalence and relevance to thrombotic diseases of plasminogen deficiency in the Japanese: the Suita Study.

Reduced plasminogen activity with a normal level of antigen is commonly observed in Japanese individuals. The first reported patient with plasminogen deficiency was accompanied with deep vein thrombosis. The present study examines whether heterozygous or homozygous deficiency of plasminogen is a risk factor for thrombotic disease. This study measures the plasminogen activity of 4517 individuals in the general population, determines the cut-off to define plasminogen deficiency, and identifies plasminogen deficiencies in the control groups and thrombotic disease groups. In another study, we examined the phenotypes of consecutive patients with homozygous plasminogen deficiency detected in our hospital. We found 173 and two of 4517 individuals to have heterozygous and homozygous deficiency with normal plasminogen antigen level, respectively, and 19 to have heterozygous deficiency with reduced antigen levels. The incidence of plasminogen deficiency in an age- and sex-matched control group (13/324, 4.01% for deep vein thrombosis or 13/330, 3.94% for stroke) selected from the 4517 individuals was not significantly different from those in patients with deep vein thrombosis (3/108, 2.78%) or cardioembolic stroke (6/110, 5.55%). Among 19 patients with homozygous plasminogen deficiency showing about 10% plasminogen activity, none had deep vein thrombosis. These findings indicate that neither heterozygous nor homozygous plasminogen deficiency constitutes a significant risk factor for thrombotic disease.

Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model.

The neuroprotective effects of YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist with high water solubility, were examined in rats with transient middle cerebral artery (MCA) occlusion. The right MCA of male SD rats was occluded for 3 h using the intraluminal suture occlusion method. YM872 significantly reduced the infarct volume 24 hours after occlusion, at dosages of 20 and 40 mg/kg/h (iv infusion) when given for 4 h immediately after occlusion. Furthermore, delayed administration of YM872 (20 mg/kg/h iv infusion for 4 h, starting 2 or 3 h after the occlusion) also reduced the infarct volume and the neurological deficits measured at 24 h. Additionally, the therapeutic efficacy of YM872 persisted for at least seven days after MCA occlusion in animals treated with YM872 for 4 h starting 2 h after MCA occlusion. These data demonstrate that AMPA receptors contribute to the development of neuronal damage after reperfusion as well as during ischemia in the focal ischemia models and that the acute effect of the blockade of AMPA receptors persists over a long time period. YM872 shows promise as an effective treatment for patients suffering from acute stroke.

Experimental thromboembolic stroke in cynomolgus monkey.

To develop an experimental model of thromboembolic stroke without intracranial surgery, an autologous blood clot was delivered to the middle cerebral artery (MCA) via the internal carotid artery in cynomolgus monkeys. Male cynomolgus monkeys, in which a chronic catheter had been earlier implanted in the left internal carotid artery, were used. The clot was flushed into the internal carotid artery under sevofluorane anesthesia. A neurologic deficit score was assigned after MCA embolization. After 24 h, cerebral infarct size and location were determined by the TTC staining method. Cerebral blood flow (CBF) was measured prior to and after MCA embolization, using positron emission tomography (PET). After embolization, long-lasting and profound extensor hypotonia of the contralateral upper and lower limbs, and mild to severe incoordination were observed. Contralateral hemiplegia was observed over the following 24 h. In gross morphologic observation of the brain, the lesions involved mostly the caudate nucleus, putamen, globus pallidus and insular cortex. CBF was maximally reduced in the left MCA territory, but not in the right MCA territory. This model is relevant to thromboembolic stroke in human in neurologic dysfunction and histopathologic brain damage.

A novel AMPA receptor antagonist, YM872, reduces infarct size after middle cerebral artery occlusion in rats.

The neuroprotective effect of YM872 ([2.3-dioxo-7-(1H-imidazol-1-yl) 6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist with improved water solubility, was examined in a rat focal cerebral ischemia model. Rats were subjected to permanent middle cerebral artery (MCA) occlusion using the intraluminal suture occlusion method for 24 h. YM872 was intravenously infused for 4 h (20 and 40 mg/kg/h) or 24 h (10 and 20 mg/kg/h), starting 5 min after the MCA occlusion, to investigate the effect of prolonged duration of the treatment on infarct volume. In the 4 h infusion study, YM872 reduced the cortical infarct volume by 48% at a dose of 40 mg/kg/h. YM872 did not significantly reduce the infarct at 20 mg/kg/h for 4 h. In the 24 h infusion study, however, YM872 markedly reduced the cortical infarct volume by 62%, even at 20 mg/kg/h. The present study indicates that the neuroprotective effect of YM872 is enhanced by extending the duration of treatment, and demonstrates the benefit of the prolonged treatment with AMPA antagonists following focal cerebral ischemia. YM872, a highly water soluble compound, is applicable to investigate the role of AMPA receptors in ischemic models without concern about nephrotoxicity and could be useful in the treatment of human stroke.