Search

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.

Objectives:The optimal timing of anticoagulation after ischemic stroke in atrial fibrillation (AF) patients is unknown. Our aim was to demonstrate the feasibility and safety of initiating dabigatran therapy within 14 days of transient ischemic attack (TIA) or minor stroke in AF patients.Patients and Methods:A prospective, multi-center registry (NCT02415855) in patients with AF treated with dabigatran within 14 days of acute ischemic stroke/TIA (National Institutes of Health Stroke Scale (NIHSS) ≤ 3) onset. Baseline and follow-up computed tomography (CT) scans were assessed for hemorrhagic transformation (HT) and graded by using European Cooperative Acute Stroke Study criteria.Results:One hundred and one patients, with a mean age of 72.4 ± 11.5 years, were enrolled. Median infarct volume was 0 ml. Median time from index event onset to dabigatran initiation was 2 days, and median baseline NIHSS was 1. Pre-treatment HT was present in seven patients. No patients developed symptomatic HT. On the day 7 CT scan, HT was present in six patients (one progressing from baseline hemorrhagic infarction type 1). Infarct volume was a predictor of incident HT (odds ratio = 1.063 [1.020–1.107], p < 0.003). All six (100%) patients with new/progressive HT were functionally independent (modified Rankin Scale (mRS) = 0–2) at 30 days, which was similar to those without HT (90%, p = 0.422). Recurrent ischemic events occurred within 30 days in four patients, two of which were associated with severe disability and death (mRS 5 and 6, respectively).Conclusion:Early dabigatran treatment did not precipitate symptomatic HT after minor stroke. Asymptomatic HT was associated with larger baseline infarct volumes. Early recurrent ischemic events may be clinically more important.

Background and Purpose— Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods— DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results— A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0–2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778–6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03–1.12]; P =0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions— Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02295826.

Background: Transient ischaemic attack (TIA) and minor ischaemic stroke patients are at high risk for recurrent events. Anticoagulants are associated with reduced recurrent ischemic stroke rates, but also increased risk of haemorrhagic transformation (HT). Dabigatran, a novel oral anticoagulant associated with reduced risk of intracranial bleeding compared with warfarin in atrial fibrillation patients, has not been assessed in acute brain ischemia. We hypothesised that HT rates are not increased by dabigatran relative to aspirin after acute ischaemic stroke/TIA. Methods: DAbigatran Treatment of Acute Stroke II (DATAS II) was a prospective, randomised open label, blinded endpoint trial of dabigatran versus aspirin in acute stroke/TIA (clinicatrials.gov NCT02295826). Non-cardio-embolic stroke/TIA patients (NIHSS score ≤9, infarct volume < 25 ml) who did not receive thrombolytic therapy or thrombectomy were randomised 1:1 to dabigatran 150 mg BID (110 mg BID in patients ≥80 or if CrCl

Background and Purpose— Cognitive changes after ischemic stroke are often overlooked, particularly acutely and in patients with mild or transient deficits. We assessed patients with transient ischemic attack (TIA)/minor stroke with serial cognitive screening tests. We tested the hypothesis that mild acute deficits are transient and improve after TIA/minor stroke. Methods— Patients with acute TIA/minor ischemic stroke, without a history of cognitive impairment, presenting with a National Institute of Health Stroke Scale score ≤3 were assessed Results— One hundred patients with a median (interquartile range) National Institute of Health Stroke Scale score of 1 (2) and median age of 68 (20) years were included. Baseline median MoCA score (26 [4]) was lower than the MMSE (29 [2]; P P =0.001) with MMSE. MoCA scores improved at day 7 (27 [5]), day 30 (28 [2]), and day 90 (28 [2]; P Conclusions— Acute temporary cognitive impairment after TIA/minor stroke is common. The MoCA is sensitive to these changes, but the MMSE is not. Routine cognitive assessment after TIA/minor stroke may be warranted and relevant to return to activities even when other neurological deficits are not evident.

Chronic cerebrovascular disease and large ischemic stroke are both associated with cognitive impairment. Much less is known about the acute cognitive sequelae of transient ischemic attack (TIA). Although often overlooked, there is increasing evidence that cognitive impairment does occur following TIA. In some patients, cognitive changes persist after resolution of focal neurological deficits, but the temporal profile of these symptoms is unknown. In addition, clinical and imaging correlates of cognitive impairment after TIA have not been systematically studied. This under-studied and recognized problem has significant implications for TIA patient management. In this review, we summarize the evidence currently available and identify future research priorities.

Background and Purpose— Acute ischemic stroke patients are at risk of early recurrence. We tested the feasibility and safety of initiating dabigatran in patients, within 24 hours of minor stroke in patients without atrial fibrillation. Methods— Minor stroke patients (National Institutes of Health Stroke Scale score ≤3) without atrial fibrillation and evidence of acute infarction on magnetic resonance imaging were treated with dabigatran. Treatment began within 24 hours of onset and was continued for 30 days. The primary end point was symptomatic hemorrhagic transformation. Results— A total of 53 patients with median (interquartile range) age of 68 (57–77) years and National Institutes of Health Stroke Scale score of 1 (0–2) were enrolled. Baseline diffusion-weighted imaging volume was 0.8 (0.3–2.4) mL. No patients experienced symptomatic hemorrhagic transformation. Three patients had evidence of asymptomatic petechial hemorrhagic transformation on day 7, which remained stable at day 30, while continuing dabigatran. Conclusions— Dabigatran treatment within 24 hours of minor stroke is feasible. A larger randomized trial is required to confirm the safety and efficacy of this treatment approach. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT 01769703.

Background. Use of complementary and alternative medicine (CAM) by children with cancer is high; however, pediatric best cases are rare.Objectives. To investigate whether best cases exist in pediatric oncology using a three-phase approach and to compare our methods with other such programs.Methods. In phase I, Children’s Oncology Group (COG) oncologists were approached via email and asked to recall patients who were (i) under 18 when diagnosed with cancer, (ii) diagnosed between 1990 and 2006, (iii) had unexpectedly positive clinical outcome, and (iv) reported using CAM during or after cancer treatment. Phase II involved partnering with CAM research networks; patients who were self-identified as best cases were asked to submit reports completed in conjunction with their oncologists. Phase III extended this partnership to 200 CAM associations and training organizations.Results. In phase I, ten cases from three COG sites were submitted, and most involved use of traditional Chinese medicine to improve quality of life. Phases II and III did not yield further cases.Conclusion. Identification of best cases has been suggested as an important step in guiding CAM research. The CARE Best Case Series Program had limited success in identifying pediatric cases despite the three approaches we used.

Introduction: Early anticoagulation after cardioembolic stroke remains controversial, due to the potential for symptomatic hemorrhagic transformation (HT). The safety profile of rivaroxaban within 14 days of cardioembolic stroke onset has not been assessed prospectively. Methods: We conducted a prospective, open label study of patients with atrial fibrillation treated with rivaroxaban ≤14 days of mild/moderate ischemic stroke/TIA (NIHSS score≤8) onset. Informed consent was obtained after the decision to treat with rivaroxaban was made by the treating physician. All patients underwent MRI, including susceptibility-weighted sequences, within 24 hours of rivaroxaban initiation and at day 7, with clinical assessment at 90 days. HT was classified using ECASS criteria (hemorrhagic infarct (HI) 1/2, or parenchymal hemorrhage (PH) 1/2). The primary endpoint was symptomatic HT (defined as PH2 associated with an NIHSS increase ≥4 within the study period). Secondary outcomes included any PH at day 7 and recurrent stroke within 90 days of enrolment. Results: Sixty patients were enrolled (mean±SD age 71±19 years, 82% stroke/18% TIA). Median (IQR) time from onset to first rivaroxaban dose was 3(5) days. At treatment initiation, median NIHSS was 2(4) and median DWI volume was 7.9(13.7) ml (range 0-175 ml). Baseline DWI volume was correlated with time to first dose (r=0.58, p Conclusion: These data support the safety of rivaroxaban initiation within 14 days of mild/moderate cardioembolic stroke/TIA. MRI evidence of petechial HT, which is common, does not appear to increase the risk of symptomatic HT.

Background and Purpose— Diffusion-weighted imaging (DWI) lesion volume on magnetic resonance imaging is increasingly being used as a surrogate outcome measure in clinical trials. We aimed to characterize the evolution of DWI lesion volumes within 30 days of symptom onset after minor stroke. Methods— Minor stroke patients with DWI lesions on magnetic resonance imaging within 48 hours of symptom onset were prospectively followed with magnetic resonance imaging brain scan at 7 and 30 days. Change in the lesion volume was defined as the difference between day 30 Fluid-Attenuated Inversion Recovery and baseline DWI lesion volumes. Results— Three patterns of infarct evolution were observed: reduction (72 [63%]), no change (26 [23%]), and growth (16 [14%]). Patients with infarct reduction at 30 days had larger baseline DWI lesion volumes (2.5 [0.9–8.5] mL) than those with stable infarcts (0.5 [0.3–0.9] mL; P =0.01). Complete DWI reversal at day 30, was seen in only 6 (5.3%) patients. Conclusions— The most common pattern of infarct evolution in patients with minor stroke is a reduction in volume, but complete resolution is uncommon.

Background and Purpose— Diffusion-weighted imaging (DWI) lesions have been identified both inside and outside the perihematoma region. We tested the hypotheses that larger hematoma volumes and blood pressure reduction are associated with DWI lesions. Methods— Hematoma and perihematoma edema volumes were measured using planimetric techniques in 117 intracerebral hemorrhage (ICH) patients who underwent DWI. Perihematoma and remote DWI lesion volumes were measured using apparent diffusion coefficient thresholds for moderate (−6 mm/s) and severe (−6 mm/s) ischemia. Acute blood pressure change over the first 24 hours was calculated. Results— The median (interquartile range) time to magnetic resonance imaging was 2 (1–5) days. Median hematoma volume was 9.8 (2.6–23.0) mL, and median perihematoma edema volume was 7.0 (2.9–18.6) mL. A small portion of the perihematoma region contained tissue below the thresholds for moderate (8.0 [2.9–14.5]%) and severe ischemia (1.1 [0.3–3.5]%). Ischemic perihematoma tissue volumes were correlated with hematoma volumes ( R =0.52, P R =−0.09, P =0.38). Remote DWI lesions were found in 17 (14.5%) patients (mean volume=0.44±0.3 mL). Patients with remote DWI lesions had higher rates of antiplatelet use ( P =0.01), prior ICH ( P =0.03), lobar ICH (0.04), and larger leukoaraiosis volumes ( P =0.02). Maximal systolic blood pressure drop at 24 hours was similar in patients with (−20.5 [−55, −10] mm Hg) and without remote DWI lesions (−27 [−46, −13] mm Hg, P =0.96). Conclusions— Small DWI lesions within and outside the perihematoma region are common in primary ICH. Perihematoma DWI lesions were independently associated with larger hematoma volumes. Remote DWI lesions may be an epiphenomenon associated with the underlying microvascular pathogenesis. These data do not support a hemodynamic mechanism of ischemic injury after primary ICH.

We thank Dr Regal for his interest and comments regarding our article.1 It is important to consider delirium in the differential diagnosis of stroke and to recognize that delirium can occur in the acute phase of ischemic stroke.2 We do agree that delirium and transient ischemic attack/minor stroke patients both exhibit rapid early neurological improvement. As pointed out by Dr Regal, these conditions are distinct from dementia and minimal cognitive impairment. Unlike the patients included in Dr Regal’s study, however, our patients demonstrated …

Introduction: Evidence of infarction on MRI is predictive of early stroke recurrence after TIA/minor stroke. It has recently been reported that diffusion-weighted imaging (DWI) changes are not associated with evidence of infarction on Fluid Attenuated Inverse Recovery (FLAIR) sequences 90 days later in 30% of patients. We completed a serial MRI study to determine the time course of infarct resolution. We tested the hypothesis that acute DWI lesion volume predicts infarct disappearance by 30 days. Methods: Acute TIA/minor stroke patients (NIHSS≤3) were prospectively imaged at baseline, 7 and 30 days after symptom onset. Lesion volumes were measured planimetrically by a blinded rater at each time point on DWI and FLAIR sequences. Mean and relative (to contralateral tissue) Apparent Diffusion Coefficient ((r)ADC) values were also calculated. Results: Acute DWI lesions were found in 94/172 patients. Median time between symptom onset and baseline MRI was 20.9(19.3) h. DWI volume decreased from baseline (1.51 ml (4.36)) at 7 days (1.13 ml (2.96), P =0.001) and at 30 days (0.40 ml (0.97), P P =0.64). Baseline rADC was similar in FLAIR+ (0.84(0.17)) and FLAIR– patients (0.89(0.21), P =0.155). Baseline DWI volumes were larger in FLAIR+ (2.08 ml (6.9)) than FLAIR– patients (0.69 ml (0.95), P =0.007). ROC analysis indicated that a baseline DWI volume P =0.339). Conclusion: Acute DWI lesions are transient and not always associated with visible infarction on FLAIR, even as early as 7 days after symptom onset. Delaying MRI results in a failure to demonstrate evidence of infarction in the majority of patients, particularly those with DWI lesion volumes below 2 ml.

Background: Cognitive changes have been described in subacute TIA/minor stroke (TIA/MIS), but the temporal profile is unknown. We tested the hypothesis that TIA/MIS patients experience transient cognitive impairment, and that this can be predicted by Diffusion-Weighted Imaging (DWI) lesion volume. Methods: Acute TIA/MIS stroke (NIH stroke scale score ≤3) patients with no history of cognitive impairment were prospectively recruited within 72 h of onset. Patients underwent Montreal Cognitive Assessment (MoCA), Mini-Mental Status Examination (MMSE) and MRI, including DWI and Fluid-Attenuated Inverse Recovery (FLAIR) sequences, at baseline, days 7 and 30. DWI lesion and FLAIR chronic white matter hyperintensity (WMH) volumes were measured planimetrically. Results: Fifty patients (mean age 68 ±15.1 years) were imaged at a median (IQR) of 26.5 (28.5) h after onset. Cognitive impairment (scores ≤26) was detected more frequently with MoCA (31/50, 62%) than MMSE (13/50, 26%, p=0.009). Acute ischemic lesions (DWI) were present in 33 (66%) patients. Mean DWI volume at baseline was 4.5 ± 11.1ml. Patients with DWI lesions (22/33, 67%) had similar impairment rates as those without (9/17, 53%; p=0.34). Linear regression indicated no relationship between acute DWI lesion volume (log transformed) and baseline MoCA scores (β=0.028, 95% CI [-2.09, 2.44]). Impaired patients had larger WMH volumes (13.6 ± 21.9 ml) than unaffected patients (2.6 ± 3.2 ml, p=0.01). Log transformed WMH volumes were inversely predictive of baseline MoCA scores (β=-0.54, 95% CI [-7.84, -2.28]). Median MoCA scores improved over time (27(5) at day 7 and 28(5) at day 30). Patients with baseline impairment and an increase of ≥2 points on MoCA by day 30 were defined as reverters (N=20). DWI lesion frequency was similar in reverters and those with persisting impairment (75% vs 64%, p= 0.50), as was DWI (6.9 ±14.3 ml vs 1.2 ±1.9 ml; p= 0.113) and WMH lesion volume (17.0 ± 26.2 ml vs 8.1 ± 8.1 ml; p= 0.18). Conclusions: Most TIA/MIS patients have evidence of temporary acute cognitive impairment when assessed with MoCA. Deficits are correlated with chronic WMH, suggesting an unmasking of subclinical cognitive impairment. Temporary cognitive deficits should be considered in the management of TIA/MIS patients.

Background Temporary and permanent cognitive changes following transient ischemic attack/minor stroke have been described previously. It is unknown if persisting cognitive deficits in these patients are correlated with acute infarction identified using magnetic resonance imaging. Aims We tested the hypothesis that persistent cognitive impairment after transient ischemic attack/minor stroke can be predicted by the volume of diffusion-weighted imaging lesions. Methods Acute transient ischemic attack/minor stroke (NIH stroke scale score ≤ 3) patients were prospectively recruited within 72 h of onset. Patients underwent Montreal cognitive assessment and magnetic resonance imaging, including diffusion-weighted imaging and Fluid-Attenuated Inverse Recovery sequences, at baseline, days 7 and 30. Cognitive testing was repeated at day 90. Diffusion-weighted imaging lesion and Fluid-Attenuated Inverse Recovery chronic white matter hyperintensity volumes were measured planimetrically. Cognitive impairment was defined a priori as Montreal cognitive assessment score Results One hundred fifteen patients were imaged at a median (inter-quartile range) of 24.0 (16.6) h after onset. Acute ischemic lesions were present in 91 (79%) patients. Cognitive impairment rates were similar in patients with (47/91, 52%) and without diffusion-weighted imaging lesions (13/24, 54%; p = 0.83). Although linear regression indicated no relationship between acute diffusion-weighted imaging lesion volume and day 30 Montreal cognitive assessment scores (β = −0.163, [−2.243, 0.334], p = 0.144), white matter hyperintensity volumes at baseline were predictive of persistent cognitive deficits after 30 days (β = 2.24, [1.956, 45.369], p = 0.005). Conclusions In most transient ischemic attack/minor stroke patients who suffer acute cognitive impairment post event, deficits are temporary. Deficits after 30 days of onset are correlated with chronic white matter hyperintensity, suggesting subclinical cognitive impairment and/or impaired ability to compensate for the effects of acute ischemic infarcts.