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Background: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. Methods: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. Results: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2–2.6). Median time from baseline CT to study drug was 62.5 (55–80) minutes, and from study drug to early post-dose CT was 19 (14.5–30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (−0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8–8.3) in the placebo arm ( P =0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (−2.6 to 8.3) in the rFVIIa arm and 0.7 mL (−1.6 to 2.1) in the placebo arm ( P =0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71–1.43]; P =0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994–1.003]; P =0.50; Table 3). Conclusions: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01359202.

Background The relationship between duration of transient neurological events and presence of diffusion‐weighted lesions by symptom type is unclear. Methods and Results This was a substudy of SpecTRA (Spectrometry for Transient Ischemic Attack Rapid Assessment), a multicenter prospective cohort of patients with minor ischemic cerebrovascular events or stroke mimics at academic emergency departments in Canada. For this study we included patients with resolved symptoms and determined the presence of diffusion‐weighted imaging (DWI) lesion on magnetic resonance imaging within 7 days. Using logistic regression, we evaluated the association between symptom duration and DWI lesion, assessing for interaction with symptom type (focal only versus nonfocal/mixed), and adjusting for age, sex, education, comorbidities, and systolic blood pressure. Of 658 patients included, a DWI lesion was present in 232 (35.1%). There was a significant interaction between symptom duration and symptom type. For those with focal‐only symptoms, there was a continuous increase in DWI probability up to 24 hours in duration (ranging from ≈40% to 80% probability). In stratified analyses, the increase in probability of DWI lesion with increased duration of focal symptoms was seen in women but not men. For those with nonfocal or mixed symptoms, predicted probability of DWI lesion was ≈35% and was greater in men, but did not increase with longer duration. Conclusions Increased duration of neurological deficits is associated with greater probability of DWI lesion in those with focal symptoms only. For individuals with nonfocal or mixed symptoms, about one‐third had DWI lesions, but the probability did not increase with duration. These results may be important to improve risk stratification of transient neurological events.

A German study diagnosed 4% of young cryptogenic ischemic stroke patients with Fabry disease, an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A (α-GAL-A) gene resulting in an accumulation of glycosphingolipids. A lower prevalence was found in other geographic regions.To determine the prevalence of Fabry disease in a Canadian population of young cryptogenic ischemic stroke patients.Patients with cryptogenic ischemic stroke at age 16-55 were retrospectively identified in our institutional stroke database and underwent a focused clinical evaluation. We sequenced the α-GAL-A gene and measured the levels of blood globotriaosylsphingosine in subjects with mutations of undetermined pathogenicity. Fabry disease was diagnosed in patients with pathogenic mutations or increased levels of blood globotriaosylsphingosine.Ninety-three of 100 study subjects had normal α-GAL-A gene polymorphisms. Seven had mutations of undetermined pathogenicity, including one with increased globotriaosylsphingosine (prevalence, 1%; 95% confidence interval,.01%-6%). No subjects had angiokeratomas or other clinical manifestations of Fabry disease. Investigation results suggestive of Fabry disease (idiopathic hypertrophic cardiomyopathy, proteinuria, vertebrobasilar dolichoectasia, and the pulvinar sign) were found only in subjects with normal α-GAL-A genes. Apart from the 100 study subjects, our database included another patient with a family history of Fabry disease and a pathogenic mutation identified before her ischemic stroke presentation as the first clinical manifestation of Fabry disease. Both Fabry patients experienced recurrent ischemic stroke.Fabry disease accounts for a small proportion of young Canadians with cryptogenic ischemic stroke. Identification of Fabry biomarkers remains a research priority to delineate stroke patients disserving routine screening.

Background and Purpose— Minor stroke and transient ischemic attack with an intracranial occlusion are associated with neurological deterioration and disability. Tenecteplase (TNK–tissue-type plasminogen activator) compared with alteplase is easier to administer, has a longer half-life, higher fibrin specificity, possibly a lower rate of intracranial hemorrhage, and may be an ideal thrombolytic agent in this population. Methods— TNK–Tissue-Type Plasminogen Activator Evaluation for Minor Ischemic Stroke With Proven Occlusion (TEMPO-1) was a multicenter, prospective, uncontrolled, TNK–tissue-type plasminogen activator dose-escalation, safety, and feasibility trial. Patients with a National Institutes of Health Stroke Scale ≤5 within 12 hours of symptom onset, intracranial arterial occlusion on computed tomographic angiography and absence of well-evolved infarction were eligible. Fifty patients were enrolled; 25 patients at a dose of 0.1 mg/kg, and 25 patients at 0.25 mg/kg. Primary outcome was the rate of drug-related serious adverse events. Secondary outcomes included recanalization and 90-day neurological outcome (modified Rankin Scale, 0–1). Results— Median baseline National Institutes of Health Stroke Scale was 2.5 (interquartile range, 1), and median age was 71 (interquartile range, 22) years. There were no drug-related serious adverse events in tier 1. In tier 2, there was 1 symptomatic intracranial hemorrhage (4%; 95% confidence interval, 0.01–20.0). Stroke progression occurred in 6% of cases. Overall, 66% had excellent functional outcome (modified Rankin Scale, 0–1) at 90 days. Recanalization rates were high; 0.1 mg/kg (39% complete and 17% partial), 0.25 mg/kg (52% complete and 9% partial). Complete recanalization was significantly related to excellent functional outcome (modified Rankin Scale, 0–1) at 90 days (relative risk, 1.65; 95% confidence interval, 1.09–2.5; P =0.026). Conclusions— Administration of TNK–tissue-type plasminogen activator in minor stroke with intracranial occlusion is both feasible and safe. A larger randomized controlled trial is needed to prove that this treatment is efficacious. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01654445.

ence of an intracranial occlusion (RR 9.6, 95% CI 4–22). Sites of occlusion were as follows: intracranial internal carotid artery (ICA) 12/52 (23%), middle cerebral artery (MCA) 31/52 (60%; MCA-M1 7/52; MCA-M2 15/52; MCA-M3 9/52), posterior cere-bral artery (PCA) 5/52 (10%; PCA-P1 3/52, PCA-P2 2/52), and basilar artery (BA) 2/52 (4%). Detailed sites of occlusion and pro-gression rates are shown in table 1 . Our analysis was limited due to the small number of patients in each group, but neurological worsening was seen in patients with both proximal and distal ves-sel occlusions.In this retrospective sub-study of the CATCH study [2], we did not find any clear pattern in the site of vessel occlusion and risk of stroke progression. This finding leads us to suggest that studies us-ing intracranial occlusion as an entry criterion in a TIA and minor stroke population should not exclude patients based simply on oc-clusion location. Finally, this study did not allow us to determine the mechanism explaining neurological deterioration, although we suspect that hemodynamic fluctuations [7] or support by the col-lateral circulation play a determinant role. Future studies could further analyze the relationship between site of occlusion, collat-eral circulation, and symptom progression. Patients affected by TIA and minor stroke are at a high risk of recurrent events, symptom progression, and disability, especially if an intracranial occlusion is documented on a CT-angiogram (CTA) [1, 2] . Despite a risk of poor outcome, these patients are often excluded from thrombolysis treatment because of mild or improving symptoms [3] . Recurrent events are phenomenologi-cally either distinct recurrent strokes or symptomatic progression of the presenting event [4]. Unlike in major stroke, where proximal occlusion is an independent predictor [5] , it remains unclear whether the exact site of vessel occlusion influences outcome in TIA and minor stroke patients [6]. Our aim was to explore the re- lationship between the location of intracranial occlusion and stroke progression in this population. The CATCH study [2] prospectively enrolled consecutive pa-tients with minor stroke (NIHSS 1 or were treated with thrombolysis for this event. All patients had a brain CT and CTA of neck and circle of Willis within 24 h of symptom onset. A neuroradiologist identified the site of vessel occlusion. Stroke progression was defined as clin-ical worsening referable to the same arterial territory as the base-line symptoms without any imaging evidence of a new infarct sep-arate from the baseline imaging [4] . Experienced stroke neurolo-gists assessed the outcomes within 24 h of the index event. The relationship between vessel occlusion site and stroke progression was explored. If a patient had more than one intracranial occlu-sion, the most proximal site was used for analysis. Fisher’s exact test was used to compare proportions, and interpreted with a Bon-ferroni correction for multiple comparisons. For each individual comparison, patients with other sites of intracranial occlusion were removed from the analysis. 510 patients were enrolled. Intracranial occlusion was ob-served in 10% (52/510) of patients. Overall, stroke progression occurred in 4% (19/510) and was more likely to occur in the pres

Objective: To determine the association between silent ischemic lesions (SILs) on baseline brain MRI and recurrent stroke in young adults with first-ever ischemic stroke. Methods: This was a single-center retrospective study of adult patients aged 18–50 years with first-ever ischemic stroke investigated by brain MRI between 2002 and 2009. Silent brain infarcts (SBIs) were defined as focal T2 hyperintensities ≥3 mm without corresponding focal symptoms, and leukoaraiosis was defined as focal, multifocal, or confluent hyperintensities on T2-weighted sequences. The primary outcome was recurrent stroke. A forward stepwise Cox regression model was used to determine whether SILs were independently associated with recurrent stroke. Results: A total of 271 eligible patients were identified in the database: 89 did not undergo MRI imaging and 12 patients had inadequate follow-up, leaving a study population of 170 patients. MRI demonstrated SILs in 48 of 170 (28.2%) patients. No patients had isolated leukoaraiosis. Hypertension ( p = 0.049), migraine with aura ( p = 0.02), and cardiovascular disease ( p = 0.04) were associated with SIL. Mean follow-up duration was 25 ± 7 months. Among patients with SILs, 11 of 48 (23%) had a recurrent stroke vs 8 of 122 (6.5%) patients without SIL ( p = 0.003). After multivariate Cox regression, SILs remained independently associated with recurrent stroke (hazard ratio [HR] 3.2, 95% confidence interval [CI] 1.2−8.6, p = 0.02), as did the combination of SBIs and leukoaraiosis (HR 7.3, 95% CI 2.3−22.9, p = 0.003). Conclusions: In adults ≤50 years old with first-ever ischemic stroke, SILs are common and independently predict recurrent stroke.