Small vessel occlusion is a high-risk etiology for early recurrent stroke after transient ischemic attack.

BACKGROUND: Recent prospective registration studies of transient ischemic attack in Western countries demonstrated that large artery atherosclerosis is the highest risk etiology for early stroke recurrence under urgent evaluation and treatment. On the other hand, some limited transient ischemic attack studies from East Asian countries showed transient ischemic attack patients due to small vessel occlusion were at a higher early stroke risk. AIMS: We aimed to assess the risk for early stroke in small vessel occlusion-transient ischemic attack patients in a Japanese large transient ischemic attack registry. METHODS: We analyzed the data of a prospective Japanese transient ischemic attack registry including 1320 transient ischemic attack patients within seven days after onset. Small vessel occlusion-transient ischemic attack was defined as the presence of lacunar transient ischemic attack syndrome, without other etiologies. The outcome measure was recurrent stroke within 30 days after transient ischemic attack. The predictors of 30-day recurrent stroke were estimated using the Cox proportional hazards model. RESULTS: The study population had a mean age of 69 ± 12 years and 470 were women. Recurrent stroke was observed in 61 patients (4.6%), and the highest rate was observed with small vessel occlusion-transient ischemic attack (7.8%), followed by large artery atherosclerosis (5.4%). In multivariate analysis, recurrent stroke was independently associated with small vessel occlusion-transient ischemic attack (hazard ratio (HR): 2.01, 95% confidence interval (CI): 1.19-3.35), higher systolic blood pressure (HR: 1.18, 95% CI: 1.08-1.28), and presentation within 3 h after onset (HR: 2.21, 95% CI: 1.27-4.04). Furthermore, small vessel occlusion-transient ischemic attack with acute small deep infarct on diffusion-weighted imaging was a stronger predictor of recurrent stroke (HR: 4.87, 95% CI: 2.09-10.0). CONCLUSION: Small vessel occlusion-transient ischemic attack, especially with acute small deep infarct, had a higher early stroke risk compared with other etiologies in Japanese transient ischemic attack patients who received early management.

Significance of Nonfocal Symptoms in Patients With Transient Ischemic Attack.

Background and Purpose- Patients with transient ischemic attack (TIA) occasionally show nonfocal symptoms, such as unconsciousness, amnesia, and unsteadiness. The purpose of this study was to clarify the characteristics and prognosis of patients with TIA with nonfocal symptoms, using data from the PROMISE-TIA (Prospective Multicenter Registry to Identify Subsequent Cardiovascular Events After Transient Ischemic Attack). Methods- Patients with TIA within 7 days of onset were consecutively enrolled in the Japanese nationwide registry. Factors associated with nonfocal symptoms and 1-year risks of ischemic stroke and coronary artery diseases were assessed in multivariate-adjusted models. Results- We studied 1362 patients with TIA (879 men; mean age, 69±12 years), including 219 (16%) with nonfocal symptoms. Patients with TIA with nonfocal symptoms were more likely to show acute ischemic lesions in the posterior circulation on diffusion-weighted imaging (multivariate-adjusted odds ratio, 3.07; 95% confidence interval, 1.57-5.82) and arterial stenosis or occlusion in the posterior circulation on vascular examination (odds ratio, 1.94; 95% confidence interval, 1.19-3.09) than those without nonfocal symptoms. Although 1-year risk of ischemic stroke did not differ significantly between groups (adjusted hazard ratio, 0.79; 95% confidence interval, 0.42-1.37), risk of coronary artery disease was higher in patients with TIA with nonfocal symptoms (hazard ratio, 3.37; 95% confidence interval, 1.14-9.03). Conclusions- Both acute ischemic lesions and arterial stenosis and occlusion in the posterior circulation were more frequently observed in patients with TIA with nonfocal symptoms.

Comparison of Clinical Characteristics among Subtypes of Visual Symptoms in Patients with Transient Ischemic Attack: Analysis of the PROspective Multicenter registry to Identify Subsequent cardiovascular Events after TIA (PROMISE-TIA) Registry.

BACKGROUND: A transient visual symptom (TVS) is a clinical manifestation of transient ischemic attack (TIA). The aim of this study was to investigate differences in clinical characteristics among subtypes of TVS using multicenter TIA registry data. MATERIALS AND METHODS: Patients with TIA visiting within 7 days of onset were prospectively enrolled from 57 hospitals between June 2011 and December 2013. Clinical characteristics were compared between patients with 3 major subtypes of TVS (transient monocular blindness [TMB], homonymous lateral hemianopia [HLH], and diplopia). RESULTS: Of 1365 patients, 106 (7.8%) had TVS, including 40 TMB (38%), 34 HLH (32%), 17 diplopia (16%), and 15 others/unknown (14%). Ninety-one patients with 1 of the 3 major subtypes of TVS were included. Symptoms persisted on arrival in 12 (13%) patients. Isolated TVS was significantly more common in TMB than in HLH and diplopia (88%, 62%, and 0%, respectively; P < .001). Duration of symptoms was shorter in patients with TMB than those with HLH (P = .004). The ABCD2 score was significantly lower in patients with TMB compared with those with HLH and diplopia (median 2 [interquartile range 2-3] versus 3 [2-4] and 4 [2-5], respectively; P = .005). Symptomatic extracranial internal carotid artery stenosis or occlusion was seen in 14 (16%) patients, and was more frequent in TMB than in HLH and diplopia (28%, 9%, and 0%, respectively; P = .015). CONCLUSIONS: TVS was an uncommon symptom in our TIA multicenter cohort. Some differences in clinical characteristics were found among subtypes of TVS.

Incidence, predictors, and etiology of subsequent ischemic stroke within one year after transient ischemic attack.

Background Incidence and predictors of ischemic stroke in patients with transient ischemic attack (TIA) have not been fully clarified outside Europe and North America. Aims We undertook the present prospective, multicenter study to clarify the incidence, predictors, and etiology of ischemic stroke within one year of TIA onset in Japan. Methods The study subjects were patients within seven days of TIA onset who were enrolled in a prospective register from 57 hospitals between June 2011 and December 2013. The primary endpoint was occurrence of ischemic stroke. Results Of 1365 consecutive patients, 1245 were followed for one year after TIA onset; 101 (8.1%) experienced ischemic stroke during follow-up. The leading subtype of ischemic stroke was small-vessel occlusion (SVO) followed by large-artery atherosclerosis (LAA) attributable to intracranial artery diseases. When dividing ischemic stroke events between those occurring within the first 90 days after TIA onset and those occurring after the first 90 days, the leading subtype of ischemic stroke within the first 90 days after TIA onset was SVO, followed by LAA attributable to intracranial artery diseases. In comparison, the subtypes most commonly seen beyond the first 90 days after TIA onset were cardioembolic and LAA attributable to intracranial artery disease. The one-year risk of ischemic stroke increased significantly as ABCD2 score increased, at 6.2% for 0-3 points, 7.2% for 4-5 points, and 11.6% for 6-7 points. Conclusions The one-year ischemic stroke risk after TIA was about 8% and was associated with the ABCD2 score. The most common subtype of subsequent ischemic stroke was SVO.

Differences in Clinical Characteristics between Patients with Transient Ischemic Attack Whose Symptoms Do and Do Not Persist on Arrival.

BACKGROUND: Symptoms of transient ischemic attack (TIA) persist on arrival and subsequently resolve in some patients admitted to hospitals early after onset. Differences in clinical characteristics between patients with acute TIA whose symptoms do and do not persist on arrival remain unclear. METHODS: We retrospectively extracted data of consecutive TIA patients with an onset-to-door time (ODT) of 24 hours or less and without a history of stroke from a multicenter TIA database. Clinical characteristics were compared between patients with and without persisting symptoms on arrival. RESULTS: Two hundred sixty-six patients (158 men, 68.0 ± 12.9 years) were included. Of the total number of patients, 105 (39.5%) had persisting symptoms with a mean National Institutes of Health Stroke Scale score of 2.4 (median, 1.0). Patients with persisting symptoms were more likely to have sensory disorder, ambulance-transported admission, long-duration TIA (≥60 minutes), and shorter ODT than those without. Multivariate analysis showed that sensory disorder (odds ratio [OR] 2.52, 95% confidence interval [CI] 1.35-4.77), ambulance-transported admission (OR 1.80, 95% CI 1.00-3.28), and long-duration TIA (OR 3.96, 95% CI 2.12-7.71) were positively associated and that an ODT of more than 12 hours (OR .18, 95% CI .04-.63) was inversely associated with the presence ofpersisting symptoms. Patients with persisting symptoms were more likely to be examined by a stroke physician at first (69% versus 57%, P = .049) and then hospitalized in a stroke unit (59% versus 43%, P = .010). CONCLUSION: Clinical manifestations and management after admission might differ between patients with acute TIA whose symptoms do and do not persist on arrival.

Clinical Characteristics of Transient Ischemic Attack Patients with Atrial Fibrillation: Analyses of a Multicenter Retrospective Study.

BACKGROUND: Atrial fibrillation (AF) is an important risk factor for transient ischemic attack (TIA). However, little is known about the characteristics of TIA patients with AF. This study investigated the characteristics of such patients, using data from a retrospective, observational, multicenter study. METHODS: TIA patients admitted to 13 stroke centers in Japan within 7 days of onset between January 2008 and December 2009 were included. The present analyses compared baseline characteristics, clinical symptoms, findings from diffusion-weighted imaging (DWI), and clinical outcomes between patients with and without AF (AF and non-AF groups). RESULTS: A total of 464 patients (292 men; mean age 68.5 ± 13.2 years) were registered. Of these, 79 patients (17%) had AF. Patients in the AF group were older (73.9 ± 9.1 vs. 67.4 ± 13.6 years, p < 0.001) and more likely to show disturbance of consciousness (13 vs. 6%, p = 0.046) and aphasia (9 vs. 3%, p = 0.007) than patients in the non-AF group. Although no difference in the overall DWI-positive rate was seen between the groups (28 vs. 20%, p = 0.102), a single lesion (23 vs. 10%, p < 0.001), a lesion ≥15 mm (11 vs. 4%, p = 0.006), and a single lesion ≥15 mm (11 vs. 2%, p < 0.001) on DWI were more frequent in the AF group. Multivariate logistic regression analysis identified increased age [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.02-1.07] and DWI single lesion ≥15 mm (OR 5.67; 95% CI 1.92-16.7) as independently associated with the presence of AF. CONCLUSIONS: In this study, 17% of our TIA patients had AF. We found an association between the acute ischemic lesion pattern on DWI of a single lesion ≥15 mm and AF in TIA patients. These results might lead to a better diagnosis of TIA patients with AF.

Incidence and predictors of ischemic stroke events during hospitalization in patients with transient ischemic attack.

BACKGROUND: The purpose of this study was to elucidate the incidence and predictors of ischemic stroke or recurrent transient ischemic attack (TIA) during acute hospitalization in patients with TIA. METHODS: We carried out a multicenter retrospective study to clarify the characteristics of in-patients with TIA. The subjects of this study were TIA patients admitted to 13 stroke hospitals within 7 days after onset between 2008 and 2009. TIA was defined as focal neurologic symptoms ascribable to a vascular etiology lasting less than 24 h. We investigated the incidence and predictors of ischemic events including ischemic stroke or recurrent TIA during hospitalization. RESULTS: A total of 464 patients with TIA (292 men, 69 ± 13 years) were registered. Of those, 400 (86.2%) were admitted within 24 h of TIA onset. The mean length of hospital stay was 13 days. During hospitalization, 8 patients had ischemic strokes and 26 had recurrent TIAs. The leading subtype of 8 ischemic strokes was small vessel disease (n = 3) followed by cardioembolism (n = 2). Multiple logistic regression analysis showed that hypertension (OR: 3.41; 95% CI: 1.23-12.3), MRI-diffusion-weighted image positivity (OR: 2.49; 95% CI: 1.15-5.25), and hemiparesis (OR: 2.30; 95% CI: 1.02-5.88) were independently associated with ischemic events during hospitalization. CONCLUSIONS: In this study, 1.7% of patients with TIA had ischemic stroke during acute hospitalization, and the most common subtype was small vessel disease. Subsequent ischemic stroke and recurrent TIA were associated with hypertension, positive DWI findings, and hemiparesis.

Factors associated with onset-to-door time in patients with transient ischemic attack admitted to stroke centers.

BACKGROUND AND PURPOSE: The aim of this study was to elucidate the factors associated with the time from symptom onset to arrival at a stroke center (onset-to-door time [ODT]) in patients with classically defined transient ischemic attack using data from a multicenter, retrospective study. METHODS: The subjects were patients with transient ischemic attack admitted to 13 stroke centers in Japan within 7 days of onset between 2008 and 2009. A total of 464 patients registered (292 men, 68.5±13.2 years old), and 421 of them (268 men, 68.8±13.1 years old) were included in the analyses. ODT was classified into the following 5 categories: <3 hours, 3 to 6 hours, 7 to 12 hours, 13 to 24 hours, and >24 hours. RESULTS: There were 233 patients (55.3%) who visited a stroke center within 3 hours of symptom onset. Multiple ordinal logistic regression analysis revealed that motor weakness, speech disturbance, and duration of symptoms >10 minutes were independently associated with a short ODT. Furthermore, a history of transient ischemic attack and hypertension and a referral from another medical facility were independently associated with a long ODT. Patients with a higher ABCD2 score were likely to arrive at a stroke center more quickly. CONCLUSIONS: We identified several factors that were positively and negatively associated with the ODT in patients with transient ischemic attack.

Features of patients with transient monocular blindness: a multicenter retrospective study in Japan.

BACKGROUND: Transient monocular blindness (TMB) is associated with a transient ischemic attack (TIA). The purpose of this study was to investigate the features of TMB in the Japanese population using data from a multicenter retrospective study of TIA. METHODS: The subjects were consecutive TIA patients admitted to 13 stroke centers within 7 days after symptom onset. We compared clinical characteristics of patients with TMB and those without TMB who had other symptoms of cerebral TIA. RESULTS: A total of 464 patients were registered between January 2008 and December 2009, and 444 patients (283 men, mean age: 68.5 years) were included in the analysis. Thirteen patients (2.9%) presented with TMB. Patients with TMB were less likely to arrive at the specialized stroke center quickly than those without TMB (P = .013). Stenotic lesions in the extracranial internal carotid artery were more common in patients with TMB (33.3% versus 9.1%, P = .022). CONCLUSIONS: TMB was not common in our TIA inpatients. This study suggests that patients with TMB should immediately undergo a diagnostic workup, including brain and vessel imaging, and cardiac evaluation, as is performed in patients with other cerebral TIA symptoms. A larger, prospective cohort is needed to confirm the risks and outcomes of patients with TMB in the Japanese population.

Examination timing and lesion patterns in diffusion-weighted magnetic resonance imaging of patients with classically defined transient ischemic attack.

BACKGROUND: This study investigated factors associated with the presence of acute ischemic lesions after transient ischemic attack (TIA), using diffusion-weighted imaging (DWI) data from a multicenter retrospective, observational study. METHODS: Of the 464 patients admitted to 13 stroke centers in Japan within 7 days after TIA onset, 458 patients underwent a DWI examination in this registry. Patients were divided into those with acute ischemic lesions and those without. We analyzed associations between DWI lesions and baseline characteristics, including age, sex, comorbidities, large artery atherosclerosis (LAA), type and duration of symptoms, the presence of multiple occurrences of TIA within 90 days before hospital visits (multiple TIAs) and the time from symptom onset to DWI examination (time-to-DWI). RESULTS: Among the 458 patients (291 men, 68.4±13.2 years old), 374 (81.7%) underwent a DWI examination within the initial 24 hours after the symptom onset. DWI lesions were found in 96 patients (21.0%), and divided into a single lesion (56 patients, 12.2%) or multiple lesions (40 patients, 8.7%). The presence of DWI lesions had an association with male sex (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.07-3.29), time-to-DWI longer than 24 hours (OR 2.96; CI 1.57-5.52), and intracranial LAA (OR 1.99; CI 1.02-3.79). The presence of a single DWI lesion had an association with atrial fibrillation (OR 2.70; CI 1.41-5.03), and multiple DWI lesions did with time-to-DWI longer than 24 hours (OR 6.20; CI 2.60-15.20), multiple TIAs (OR 3.04; CI 1.35-6.76), intracranial LAA (OR 3.63; CI 1.44-8.89), and extracranial LAA (OR 3.53; CI 1.08-10.78). CONCLUSIONS: Acute ischemic lesions on DWI were associated with time-to-DWI and LAA in patients with classically defined TIA. Additionally, we identified some differences in relating factors between patients with single and multiple DWI lesions. These results indicate that time-to-DWI and DWI lesion pattern may be important for the diagnosis and management of TIA.

Thrombosis in Japanese patients with Fabry disease.

Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme alpha-galactosidase (alpha-Gal) A. It has been postulated that the accumulation of globotriaosylceramide in the endothelial cells of blood vessels may lead to thrombosis of the brain and other tissues. Recently, enzyme replacement therapy (ERT) for Fabry disease is available. A high incidence of thrombotic accidents in Fabry disease has been postulated. However, a systemic study on thrombosis in cases of Fabry disease has not been undertaken. To clarify the incidence of thrombosis in Fabry disease, we screened 65 patients with Fabry disease (49 hemizygotes and 16 heterozygotes) from 39 unrelated Japanese families. We found that ten patients with Fabry disease (7 hemizygous males and 3 heterozygous females) had experienced thrombotic accidents, under 45-years-old in 8 cases. These 10 patients showed the gene mutations of classical Fabry disease. Nine of these thrombotic patients developed brain infarctions, one man who had the complication of recurrent thrombophlebitis, and the remaining woman showed central retinal artery occlusion and thrombophlebitis. We demonstrated a high incidence of thrombosis in Fabry disease (15%). ERT should be performed in patients not only in hemizygous males but also in heterozygous females and started at their early ages.

Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis.

BACKGROUND: Arteriosclerosis obliterans (ASO) is a serious complication in patients with end-stage renal disease (ESRD) caused by diabetic nephropathy. Adsorption of low-density lipoprotein (LDL) has been performed to treat ASO. While efficacy of this treatment has been reported in limb ischemia, the mechanism underlying the benefit remains unclear. We investigated how LDL adsorption affected soluble adhesion molecules; P-selectin, an endothelial and platelet activation marker; inflammatory cytokines such as interleukin (IL)-1beta, IL-6 and tissue necrosis factor (TNF)-alpha; and lipids in serum. METHODS: Selective LDL adsorption by dextran sulfate columns (LDL apheresis) was performed weekly for 10 weeks to treat eight hemodialysis patients with ASO, ESRD, and type 2 diabetes mellitus. Serum was sampled before and immediately after apheresis. RESULTS: LDL apheresis was performed safely. After LDL apheresis lipid concentrations were significantly reduced and clinical findings, such as Fontaine's classification and ankle brachial pressure index values, were improved. Pretreatment concentrations of soluble intercellular and vascular cell adhesion molecules (sICAM-1 and sVCAM-1) and also P-selectin were higher in patients than healthy controls. After apheresis these decreased, especially P-selectin. IL-1beta, IL-6, and TNF-alpha concentrations before apheresis were similar to those in controls and were unaffected by treatment. CONCLUSION: Effectiveness of LDL apheresis against ASO may involve decreased endothelial cell and platelet activation.

Enzyme replacement therapy for Fabry disease: morphologic and histochemical changes in the urinary sediments.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme alpha-galacotsidase A. Accumulation of glycosphingolipids, especially globotriaosylceramide, leads to renal damage in Fabry disease. In patients with Fabry disease, the urinary sediment contains excreted glycosphingolipids. With enzyme replacement therapy for Fabry disease now currently available, we examined whether the urinary sediment could be used to noninvasively monitor effectiveness of enzyme replacement therapy. METHODS: Four male patients with hemizygous classical Fabry disease received recombinant alpha-galactsidase A biweekly, and urinary sediments were assessed at 3-month intervals. RESULTS: The morphologic and immunohistochemical changes in urinary sediment at 6 and 18 months suggested that accumulations of glycosphingolipids in renal tissues were cleared by enzyme replacement. CONCLUSION: Examination of urinary sediments could serve as noninvasive monitoring of the effect of therapy in patients with Fabry disease.

The effect of ozagrel sodium on photochemical thrombosis in rat: therapeutic window and combined therapy with heparin sodium.

The therapeutic efficacy of ozagrel sodium (ozagrel), alone and in combination with heparin, and its therapeutic time window were studied in a photochemically induced thrombotic cerebral infarction rat model. Cerebral artery thrombosis was induced by irradiating the brain with green light through intact skull using rose bengal as the photosensitizing dye. One set of animals was treated immediately after thrombosis with (1) vehicle, (2) 10 mg/kg ozagrel in saline, intravenously (i.v.), (3) 150 U/kg unfractioned heparin, subcutaneously (s.c.), or (4) ozagrel, i.v. plus heparin, s.c. Infarct volume was significantly smaller and edema was reduced in the ozagrel-treated groups compared to the vehicle-treated group; heparin did not convey additional benefit. In another set of animals, rats were given either vehicle or 10 mg/kg ozagrel in saline, i.v., 60 min or 120 min after induction of thrombosis. Ozagrel reduced infarct volume, but its effect diminished with delayed administration. The therapeutic window was determined to be less than 60 minutes after induction of thrombosis.