Deidre A. De Silva

Refining the Definition of the Malignant Profile Insights From the DEFUSE-EPITHET Pooled Data Set

Background and Purpose— To refine the definition of the malignant magnetic resonance imaging profile in acute stroke patients using baseline diffusion-weighted magnetic resonance imaging (DWI) and perfusion-weighted magnetic resonance imaging (PWI) findings from the pooled DEFUSE/EPITHET database. Methods— Patients presenting with acute stroke within 3 to 6 hours from symptom onset were treated with tissue plasminogen activator or placebo. Baseline and follow-up DWI and PWI images from both studies were reprocessed using the same software program. A receiver operating characteristic curve analysis was used to identify Tmax and DWI volumes that optimally predicted poor outcomes (modified Rankin Scale 5–6) at 90 days in patients who achieved reperfusion. Results— Sixty-five patients achieved reperfusion and 46 did not reperfuse. Receiver operating characteristic analysis identified a PWI (Tmax>8 s) volume of >85 mL as the optimal definition of the malignant profile. Eighty-nine percent of malignant profile patients had poor outcome with reperfusion versus 39% of patients without reperfusion (P=0.02). Parenchymal hematomas occurred more frequently in malignant profile patients who experienced reperfusion versus no reperfusion (67% versus 11%, P<0.01). DWI analysis identified a volume of 80 mL as the best DWI threshold, but this definition was less sensitive than were PWI-based definitions. Conclusions— Stroke patients likely to suffer parenchymal hemorrhages and poor outcomes following reperfusion can be identified from baseline magnetic resonance imaging findings. The current analysis demonstrates that a PWI threshold (Tmax>8 s) of approximately 100 mL is appropriate for identifying these patients. Exclusion of malignant profile patients from reperfusion therapies may substantially improve the efficacy and safety of reperfusion therapies. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00238537.

RAPID Automated Patient Selection for Reperfusion Therapy: A Pooled Analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study

Background and Purpose— The aim of this study was to determine if automated MRI analysis software (RAPID) can be used to identify patients with stroke in whom reperfusion is associated with an increased chance of good outcome. Methods— Baseline diffusion- and perfusion-weighted MRI scans from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution study (DEFUSE; n=74) and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; n=100) were reprocessed with RAPID. Based on RAPID-generated diffusion-weighted imaging and perfusion-weighted imaging lesion volumes, patients were categorized according to 3 prespecified MRI profiles that were hypothesized to predict benefit (Target Mismatch), harm (Malignant), and no effect (No Mismatch) from reperfusion. Favorable clinical response was defined as a National Institutes of Health Stroke Scale score of 0 to 1 or a ≥8-point improvement on the National Institutes of Health Stroke Scale score at Day 90. Results— In Target Mismatch patients, reperfusion was strongly associated with a favorable clinical response (OR, 5.6; 95% CI, 2.1 to 15.3) and attenuation of infarct growth (10±23 mL with reperfusion versus 40±44 mL without reperfusion; P<0.001). In Malignant profile patients, reperfusion was not associated with a favorable clinical response (OR, 0.74; 95% CI, 0.1 to 5.8) or attenuation of infarct growth (85±74 mL with reperfusion versus 95±79 mL without reperfusion; P=0.7). Reperfusion was also not associated with a favorable clinical response (OR, 1.05; 95% CI, 0.1 to 9.4) or attenuation of lesion growth (10±15 mL with reperfusion versus 17±30 mL without reperfusion; P=0.9) in No Mismatch patients. Conclusions— MRI profiles that are associated with a differential response to reperfusion can be identified with RAPID. This supports the use of automated image analysis software such as RAPID for patient selection in acute stroke trials.Background The aim of this study was to determine if automated MRI Analysis Software (RAPID) can be used to identify stroke patients in whom reperfusion is associated with an increased chance of good outcome.

Pretreatment diffusion- and perfusion-MR lesion volumes have a crucial influence on clinical response to stroke thrombolysis

We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions <18 mL (77% versus 18% placebo, OR=15.0, P<0.001). Benefit from tPA was also seen with DWI lesions up to 25 mL (69% versus 29% placebo, OR=5.5, P=0.03), but not for DWI lesions >25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.

The infarct core is well represented by the acute diffusion lesion: sustained reversal is infrequent

Diffusion-weighted imaging (DWI) is commonly used to assess irreversibly infarcted tissue but its accuracy is challenged by reports of diffusion lesion reversal (DLR). We investigated the frequency and implications for mismatch classification of DLR using imaging from the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) and DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) studies. In 119 patients (83 treated with IV tissue plasminogen activator), follow-up images were coregistered to acute diffusion images and the lesions manually outlined to their maximal visual extent in diffusion space. Diffusion lesion reversal was defined as voxels of acute diffusion lesion that corresponded to normal brain at follow-up (i.e., final infarct, leukoaraiosis, and cerebrospinal fluid (CSF) voxels were excluded from consideration). The appearance of DLR was visually checked for artifacts, the volume calculated, and the impact of adjusting baseline diffusion lesion volume for DLR volume on perfusion-diffusion mismatch analyzed. Median DLR volume reduced from 4.4 to 1.5 mL after excluding CSF/leukoaraiosis. Visual inspection verified 8/119 (6.7%) with true DLR, median volume 2.33 mL. Subtracting DLR from acute diffusion volume altered perfusion—diffusion mismatch (Tmax>6 seconds, ratio>1.2) in 3/119 (2.5%) patients. Diffusion lesion reversal between baseline and 3 to 6 hours DWI was also uncommon (7/65, 11%) and often transient. Clinically relevant DLR is uncommon and rarely alters perfusion—diffusion mismatch. The acute diffusion lesion is generally a reliable signature of the infarct core.

Assessing Reperfusion and Recanalization as Markers of Clinical Outcomes After Intravenous Thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)

Background and Purpose— Reperfusion and recanalization have both been used as surrogate markers of clinical outcome in trials of stroke thrombolysis. We aimed to prove that the beneficial impact of recanalization with intravenous tissue plasminogen activator on clinical outcomes is attributable to reperfusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Methods— EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator in the 3- to 6-hour window. Reperfusion was defined as >90% reduction in magnetic resonance perfusion-weighted imaging lesion volume and recanalization as improvement of MR angiographic Thrombolysis In Myocardial Infarction grading by ≥2 points from baseline to Day 3 to 5. Results— At Day 3 to 5, reperfusion and recanalization with intravenous tissue plasminogen activator were strongly correlated. Reperfusion was associated with improved clinical outcome independent of whether recanalization occurred. In contrast, recanalization was not associated with clinical outcome when reperfusion was included as a covariate in regression analyses. Conclusion— Reperfusion is a surrogate marker of clinical outcomes independent of recanalization based on the criteria applied in EPITHET. The impact of recanalization on clinical outcomes was attributable to reperfusion.

South Asian Patients With Ischemic Stroke Intracranial Large Arteries Are the Predominant Site of Disease

Background and Purpose— South Asians are the most prevalent ethnic group in the world. Intracranial disease is the most common vascular lesion worldwide. Methods— We prospectively studied 200 consecutive ethnic South Asian patients with acute ischemic stroke in Singapore. Results— Intracranial large-artery disease was prevalent among 54% of all stroke subtypes and was independently associated with hypertension and higher serum erythrocyte sedimentation rate. Conclusions— Among ethnic South Asian patients with ischemic stroke, intracranial large arteries are the predominant site of disease.

The Benefits of Intravenous Thrombolysis Relate to the Site of Baseline Arterial Occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)

Background and Purpose— In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Methods— EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3- to 6-hour time window. Arterial obstruction site and degree were rated on magnetic resonance angiography blinded to treatment allocation and outcomes. Results— In 101 EPITHET patients, 87 had adequate quality magnetic resonance angiography, of whom 54 had baseline arterial obstruction. Infarct growth attenuation was greater in those with tPA treatment compared to placebo among patients with middle cerebral artery (MCA) obstruction (P=0.037). The treatment benefit of tPA over placebo in attenuating infarct growth was greater for MCA than internal carotid artery (ICA) obstruction (P=0.060). With tPA treatment, good clinical outcome was more likely with MCA than with ICA obstruction (P=0.005). Most patients with ICA obstruction did not achieve good clinical outcome, whether treated with tPA (100%) or placebo (77%). The study was underpowered to prove any treatment benefit of tPA among patients with any or severe degree of arterial obstruction. Conclusions— Arterial obstruction site strongly predicts outcomes. ICA obstruction carries a uniformly poor prognosis, whereas good outcomes with MCA obstruction are associated with tPA therapy.

Regional Very Low Cerebral Blood Volume Predicts Hemorrhagic Transformation Better Than Diffusion-Weighted Imaging Volume and Thresholded Apparent Diffusion Coefficient in Acute Ischemic Stroke

Background and Purpose— Currently, diffusion-weighted imaging (DWI) lesion volume is the most useful magnetic resonance imaging predictor of hemorrhagic transformation (HT). Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study. Methods— Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the <0, 2.5, 5, and 10th percentiles were created. The volume of tissue with VLCBV was calculated within the acute DWI ischemic lesion. HT was graded as per ECASS criteria. Results— HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression. A cutpoint at 2 mL VLCBV with the <2.5th percentile had 100% sensitivity for PH and, in patients treated with tissue plasminogen activator, defined a population with a 43% risk of PH (95% CI, 23% to 66%, likelihood ratio=16). VLCBV remained an independent predictor of PH in multivariate analysis with traditional clinical risk factors for HT. Conclusions— VLCBV predicted HT after thrombolysis better than did DWI or apparent diffusion coefficient volume in this large patient cohort. The advantage was greatest in patients with smaller DWI volumes. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.

PINK1 mutations in sporadic early‐onset Parkinson's disease

Pathogenic PINK1 mutations have been described in PARK6‐linked Parkinsons disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early‐onset Parkinsons disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1‐positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon–intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1‐positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.

Postthrombolysis Blood Pressure Elevation Is Associated With Hemorrhagic Transformation

Background and Purpose— Reliable predictors of hemorrhagic transformation (HT) after stroke thrombolysis have not been identified. We analyzed hemorrhage in a randomized trial of tissue plasminogen activator (t-PA) vs placebo in ischemic stroke patients. We hypothesized that acute diffusion-weighted imaging (DWI) lesion volumes would be larger and blood pressures would be higher in patients with HT. Methods— HT was assessed 2 to 5 days after treatment in 97 patients. Hemorrhage was assessed by using susceptibility-weighted imaging sequences and was classified as petechial hemorrhagic infarction (HI) or parenchymal hematoma (PH). Results— PH was more frequent in t-PA– (11/49) than in placebo- (4/48) treated patients (P=0.049). Patients with PH had larger DWI lesion volumes (63.1±56.1 mL) than did those without HT (27.6±39.0 mL, P=0.033). There were no differences in baseline systolic blood pressure (SBP) between patients with and without hemorrhage. Weighted average SBP 24 hours after treatment was higher in patients with PH (159.4±18.8 mL, P<0.011) relative to those without HT (143.1±20.0 mL). Multinomial logistic regression indicated that PH was predicted by DWI lesion volume (odds ratio=1.16 per 10 mL; 95% CI, 1.03 to 1.30), atrial fibrillation (odds ratio=9.33; 95% CI, 2.30 to 37.94), and 24-hour weighted average SBP (odds ratio=1.59 per 10 mm Hg; 95% CI, 1.14 to 2.23). Conclusions— Pretreatment DWI lesion volume and postthrombolysis BP are both predictive of HT. Consideration should be given to excluding patients with very large baseline DWI volumes from t-PA therapy and to more stringent BP control after stroke thrombolysis.