Rapid tumor DNA analysis of cerebrospinal fluid accelerates treatment of central nervous system lymphoma.

ABSTRACT: Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown cause. Participants underwent genotyping of CSF-derived DNA using a quantitative polymerase chain reaction-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF, and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma, and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7 of 33 cases (21.2%) of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median, 3 vs 12 days; P = .027). This assay was then implemented in a Clinical Laboratory Improvement Amendments environment, with 2-day median turnaround for diagnosis of CNS lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

Complications of Carotid Interventions for Symptomatic Lesions after Systemic Thrombolysis.

BACKGROUND: Series detailing complications after carotid endarterectomy (CEA) and transfemoral carotid stenting (tfCAS) for patients presenting with neurologic symptoms that are treated with systemic thrombolysis (ST) are sparse. We sought to determine if treatment with ST was associated with a higher rate of post-carotid intervention complications. METHODS: A multispecialty, institutional, prospectively maintained database was queried for symptomatic patients treated with CEA or tfCAS from 2007 to 2019. The primary outcomes of interest were bleeding complications (access/wound complications, hematuria, intracranial hemorrhage) or need for reintervention, stroke, and death. We compared rates of these outcomes between patients who were and were not treated with ST. To adjust for preoperative patient factors and confounding variables, propensity scores for assignment to ST and non-ST were calculated. RESULTS: There were 1,139 patients included (949 [82%] CEA and 190 [17%] tfCAS. All treated lesions were symptomatic (550 [48%] stroke, 603 [52%] transient ischemic attack). Fifty-six patients (5%) were treated with ST. Fifteen of 56 patients also underwent catheter-based intervention for stroke. ST was administered 0 to 1 day preoperatively in 21 (38%) patients, 2 to 6 days preoperatively in 27 (48%) patients, and greater than 6 days preoperatively in 8 (14%) patients. ST patients were more likely to present with stroke (93% vs. 45%; P < 0.001) and have higher preoperative Rankin scores. Unadjusted rate of bleeding/return to operating room was 3% for ST group and 3% for non-ST group (P = 0.60). Unadjusted rate of stroke was 4% for ST group and 3% for the non-ST group (P = 0.91), while perioperative mortality was 5% for ST group and 1% for non-ST group (P = 0.009). After adjusting for patient factors, preoperative antiplatelet/anticoagulation, and operative factors, ST was not associated with an increased odds of perioperative bleeding/return to the operating room (odds ratio 0.37; 95% confidence interval: 0.02-1.63; P = 0.309) or stroke (odds ratio 0.62; 95% confidence interval: 0.16-2.40; P = 0.493). CONCLUSIONS: ST does not convey a higher risk of complications after CEA or tfCAS. After controlling for other factors, patients that received ST had similar rates of local complications and stroke when compared to non-ST patients. Early carotid intervention is safe in patients that have received ST, and delays should be avoided in symptomatic patients given the high risk of recurrent stroke.

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

Cerebral arteriopathy and ischemic stroke in a pediatric MYH11 patient.

OBJECTIVES: Mutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2. METHODS: A proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI. RESULTS: A 12-year-old girl presented with a right middle cerebral artery occlusion. She received thrombolysis and underwent mechanical thrombectomy. An extensive stroke work-up was negative. A three-generation pedigree showed a splice site mutation of MYH11 IVS32G>A of the proband and three more family members. A 7T-MRI showed "broomstick-like" straightening of distal arterial segments, a V-shaped anterior corpus callosum and a post-stroke cystic area of encephalomalacia. This vascular appearance and parenchymal abnormalities typically present in patients with an ACTA2 phenotype. 7T-MRI also demonstrated thickening of the right middle cerebral arterial wall. DISCUSSION: This case suggests that MYH11 patients may have a similar angiographic and brain parenchymal phenotype to patients with ACTA2 mutations. This is the first report of arterial wall thickening in a MYH11 stroke patient using 7T-MRI. Patients with MYH11 mutations may display a focal cerebral steno-occlusive arteriopathy that may lead to stroke.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Preoperative antithrombotic treatment in acutely symptomatic carotid artery stenosis.

OBJECTIVES: Early recurrence of cerebral ischemia in acutely symptomatic carotid artery stenosis can precede revascularization. The optimal antithrombotic regimen for this high-risk population is not well established. Although antiplatelet agents are commonly used, there is limited evidence for the use of anticoagulants. We sought to understand the safety and efficacy of short-term preoperative anticoagulants in secondary prevention of recurrent cerebral ischemic events from acutely symptomatic carotid stenosis in patients awaiting carotid endarterectomy (CEA). MATERIALS AND METHODS: A retrospective query of a prospective single institution registry of carotid revascularization was performed. Patients who presented with acute ischemic stroke or transient ischemic attack (TIA) attributable to an ipsilateral internal carotid artery stenosis (ICA) were included. Antiplatelet (AP) only and anticoagulation (AC) treatment arms were compared. The primary outcome was a composite of preoperative recurrent ischemic stroke or TIA. The primary safety outcome was symptomatic intracranial hemorrhage. RESULTS: Out of 443 CEA patients, 342 were in the AC group and 101 in the AP group. Baseline characteristics between groups (AC vs AP) were similar apart from age (71±10.5 vs 73±9.5, p=0.04), premorbid modified Rankin scale (mRS) score (1.0±1.2 vs 1.4±1.3, p=0.03) and stroke as presenting symptom (65.8 vs 53.5%, p=0.02). Patients in the AC group had a lower incidence of recurrent stroke/TIA (3.8 vs 10.9%, p=0.006). One patient had symptomatic intracranial hemorrhage in the AC group, and none in the AP group. In multivariate analysis controlling for age, premorbid mRS, stroke severity, degree of stenosis, presence of intraluminal thrombus (ILT) and time to surgery, AC was protective (OR 0.30, p=0.007). This effect persisted in the cohort exclusively without ILT (OR 0.23, p=0.002). CONCLUSIONS: Short term preoperative anticoagulation in patients with acutely symptomatic carotid stenosis appears safe and effective compared to antiplatelet agents alone in the prevention of recurrent cerebral ischemic events while awaiting CEA.

White Matter Hyperintensities and Blood Pressure Lowering in Acute Intracerebral Hemorrhage: A Secondary Analysis of the ATACH-2 Trial.

BACKGROUND: It is not clear whether subsets of patients with intracerebral hemorrhage (ICH) benefit from intensive blood pressure (BP) lowering. We evaluated whether white matter hyperintensities (WMH) burden influences response to this therapy. METHODS: Retrospective secondary analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. Patients were randomized to intensive (systolic BP target: 110-139 mmHg) versus standard (systolic BP target: 140-179 mmHg) BP treatment with intravenous nicardipine within 4.5 h from onset between May 2011 and September 2015. WMH were rated on magnetic resonance images (fluid-attenuated inversion recovery sequences), defining moderate-severe WMH as total Fazekas scale score ≥ 3 (range 0-6). The main outcome was death or major disability at 90 days (modified Rankin scale ≥ 3). The secondary outcome was ICH expansion, defined as hematoma growth > 33% from baseline to follow-up CT scan. Predictors of the outcomes of interest were explored with multivariable logistic regression. RESULTS: A total of 195/1000 patients had MRI images available for analysis, of whom 161 (82.6%) had moderate-severe WMH. When compared to patients with none-mild WMH, those with moderate-severe WMH did not have an increased risk of death or major disability (adjusted relative risk: 1.83, 95% CI 0.71-4.69) or ICH expansion (adjusted relative risk: 1.14, 95% CI 0.38-3.37). WMH burden did not modify the effect of intensive BP treatment on outcome (all p for interaction ≥ 0.2). CONCLUSION: The majority of acute ICH patients have moderate-severe WMH, but advanced small vessel disease burden marked by WMH does not influence ICH-related outcomes or response to intensive BP reduction.

Accuracy of MRI T2*-weighted sequences (GRE-EPI) compared to CTA for detection of anterior circulation large vessel thrombus.

PURPOSE: Rapid detection of vessel occlusion is pivotal to the management of patients with acute stroke. Magnetic resonance (MR) T2*-weighted (W) sequence has proven its capability to detect intravascular thrombi, but its diagnostic value compared to computed tomography angiography (CTA) is not well established. We aimed to determine the diagnostic performance of fast 1.5-T MR T2*W sequences compared to CTA for the detection of intra-arterial thrombi in patients with acute stroke. METHODS: About 71 consecutive patients with known middle cerebral artery (MCA) territory stroke were identified. Patients with CTA and MR imaging within 12 h of symptom onset were included in the study. Two investigators reviewed the DWI and T2*W sequences for the presence of infarction and susceptibility vessel sign (SVS). A comparison to the corresponding internal carotid artery (ICA) and M1 and M2 segments of the MCA findings on CTA was made. RESULTS: Of the 51 patients included in our study, CTA thrombi were identified 84% patients (43/51). Of these, 77% (33/43) presented a corresponding SVS on T2*W. A total of 29 CTA thrombi were identified in the M1 segment, and of these, 22 patients had a corresponding SVS. Of the patients without M1 thrombus on CTA, no M1-SVS was detected on T2*W sequences. We found an accuracy of 92%, sensitivity of 85%, specificity of 100%, PPV 100%, and NPV of 86% for M1 occlusion. The Kappa coefficient was 0.79. CONCLUSION: Fast T2*W sequences demonstrated very good diagnostic performance and inter-reader agreement for detecting SVS in the M1 segment in patients with acute ischemic stroke.

Multivariable analysis on factors associated with aneurysm rupture in patients with multiple intracranial aneurysms.

PURPOSE: Multiple intracranial aneurysms (MIA) occur in one-third of patients with intracranial aneurysms (IA), and have been previously associated with an overall worse prognosis. Risk factors for IA formation and rupture in patients with a single IA are well-known. However, risk factors associated with rupture in patients with MIA have been less studied. METHODS: We performed a retrospective search of patients with MIA identified by computed tomography angiography (CTA) within a 10-year period. Patients with > 1 saccular aneurysm with size ≥ 2.0 mm were included. The location, size, number, and rupture status of the aneurysms were recorded. Patient demographics and cerebrovascular risk factors were obtained from electronic medical records. The primary endpoint of this study was to determine the association of these factors with aneurysmal rupture. The case-fatality rate was evaluated as a secondary outcome. RESULTS: Of the 2957 patients with IA in our CTA database, 425 patients were diagnosed with MIA and were therefore included in our study. A total of 1082 aneurysms were identified. Predictors of increased risk of aneurysmal rupture were age (OR 0.98, 95% CI, 0.96-0.99), size ≥ 5 mm (OR 4.4, 95% CI 2.76-7.0); and location in the anterior communicating artery complex (AcomC) (OR 2.62, 95% CI, 1.46-4.72) or posterior communicating artery (PCOM) (OR 2.66, 95% CI, 1.45-4.87). CONCLUSIONS: Younger age, aneurysm size ≥ 5 mm, and location in the AcomC and PCOM were independently associated with aneurysmal rupture in patients with MIA. Identifying these features could help recognize patients who might benefit from early intervention.

Spot and Diffuse Signs: Quantitative Markers of Intracranial Hematoma Expansion at Dual-Energy CT.

Purpose To compare dual-energy CT with iodine quantification to single-energy CT for evaluation of the spot sign for intracranial hematoma expansion. Materials and Methods In this retrospective study, 42 patients (mean age, 66 years ± 15 [standard deviation]; 19 women) were referred for dual-energy CT assessment of intracranial hemorrhage from October 2014 to January 2017. A machine learning approach (naive Bayes classifier) was used to identify iodine markers of extravasation for risk of hematoma expansion. Specificity and sensitivity of these markers were then independently validated in 65 new patients from February 2017 to February 2018. Results Analysis of dual-energy CT images identified two features of iodine extravasation: total iodine concentration within the hematoma (Ih) and focal iodine concentration in the brightest spot in the hematoma (Ibs) as predictors of expansion. The I2 score derived from these features provided a measure of expansion probability. Optimal classification threshold was an I2 score of 20 (95% confidence interval [CI]: 18, 23), leading to correct identification of 39 of 46 (85%; 95% CI: 71%, 94%) of the hematomas on the training set (sensitivity of 79% [11 of 14; 95% CI: 57%, 100%] and specificity of 88% [28 of 32; 95% CI: 76%, 99%]), and 62 of 70 (89%; 95% CI: 79%, 95%) of the hematomas on the validation set (sensitivity of 71% [10 of 14; 95% CI: 48%, 95%] and specificity of 93% [52 of 56; 95% CI: 86%, 100%]). Sensitivity, specificity, and accuracy of conventional spot sign were, respectively, 57% (eight of 14), 90% (29 of 32), and 80% (37 of 46) on the training set and 57% (eight of 14), 83% (47 of 56), and 75% (53 of 70) on the validation set. Conclusion This study identified two quantitative markers of intracranial hemorrhage expansion at dual-energy CT of the brain. The I2 score derived from these markers highlights the utility of dual-energy CT measurements of iodine content for high sensitivity risk assessment. © RSNA, 2018 Online supplemental material is available for this article.

Integration of Computed Tomographic Angiography Spot Sign and Noncontrast Computed Tomographic Hypodensities to Predict Hematoma Expansion.

Background and Purpose- Noncontrast computed tomographic (CT) hypodensities represent an alternative to the CT angiography spot sign (SS) to predict intracerebral hemorrhage (ICH) expansion. However, previous studies suggested that these markers predicted hematoma expansion independently from each other. We investigated whether the integration of SS and hypodensity (HD) improved the stratification of ICH expansion risk. Methods- A single-center cohort of consecutive patients with ICH was retrospectively analyzed. Patients with available CT angiography, baseline, and follow-up noncontrast CT images available were included. Trained readers reviewed all the images for SS and HD presence, and the study population was classified into 4 groups: SS and HD negative (SS-HD-), SS positive only (SS+HD-), HD positive only (SS-HD+), and SS and HD positive (SS+HD+). ICH expansion was defined as hematoma growth >33% or >6 mL. The association between SS and HD presence and ICH expansion was investigated with multivariable logistic regression. Results- A total of 745 subjects qualified for the analysis (median age, 73 years; 54.1% men). The rates of ICH expansion were 9.3% in SS-HD-, 25.8% in SS+HD-, 27.4% in SS-HD+, and 55.6% in SS+HD+ patients ( P<0.001). After adjustment for potential confounders and keeping SS-HD- subjects as reference, the risk of ICH expansion was increased in SS+HD- and SS-HD+ patients (odds ratio, 2.93, P=0.002 and odds ratio, 3.02, P<0.001, respectively). SS+HD+ subjects had the highest risk of hematoma growth (odds ratio, 9.50; P<0.001). Conclusions- Integration of SS and HD improves the stratification of hematoma growth risk and may help the selection of patients with ICH for antiexpansion treatment in clinical trials.

Predicting Intracerebral Hemorrhage Expansion With Noncontrast Computed Tomography: The BAT Score.

BACKGROUND AND PURPOSE: Although the computed tomographic angiography spot sign performs well as a biomarker for hematoma expansion (HE), computed tomographic angiography is not routinely performed in the emergency setting. We developed and validated a score to predict HE-based on noncontrast computed tomography (NCCT) findings in spontaneous acute intracerebral hemorrhage. METHODS: After developing the score in a single-center cohort of patients with intracerebral hemorrhage (n=344), we validated it in a large clinical trial population (n=954) and in a multicenter intracerebral hemorrhage cohort (n=241). The following NCCT markers of HE were analyzed: hypodensities, blend sign, hematoma shape and density, and fluid level. HE was defined as hematoma growth >6 mL or >33%. The score was created using the estimates from multivariable logistic regression after final predictors were selected from bootstrap samples. RESULTS: Presence of blend sign (odds ratio, 3.09; 95% confidence interval [CI],1.49-6.40; P=0.002), any intrahematoma hypodensity (odds ratio, 4.54; 95% CI, 2.44-8.43; P<0.0001), and time from onset to NCCT <2.5 hours (odds ratio, 3.73; 95% CI, 1.86-7.51; P=0.0002) were predictors of HE. A 5-point score was created (BAT score: 1 point for blend sign, 2 points for any hypodensity, and 2 points for timing of NCCT <2.5 hours). The c statistic was 0.77 (95% CI, 0.70-0.83) in the development population, 0.65 (95% CI 0.61-0.68) and 0.70 (95% CI, 0.64-0.77) in the 2 validation cohorts. A dichotomized score (BAT score ≥3) predicted HE with 0.50 sensitivity and 0.89 specificity. CONCLUSIONS: An easy to use 5-point prediction score can identify subjects at high risk of HE with good specificity and accuracy. This tool requires just a baseline NCCT scan and may help select patients with intracerebral hemorrhage for antiexpansion clinical trials.

Phantom-based standardization of CT angiography images for spot sign detection.

PURPOSE: The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. METHODS: A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. RESULTS: A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p < 0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. CONCLUSION: Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.

Negative spot sign in primary intracerebral hemorrhage: potential impact in reducing imaging.

Intracerebral hemorrhage (ICH) is one of the most devastating and costly diagnoses in the USA. ICH is a common diagnosis, accounting for 10-15 % of all strokes and affecting 20 out of 100,000 people. The CT angiography (CTA) spot sign, or contrast extravasation into the hematoma, is a reliable predictor of hematoma expansion, clinical deterioration, and increased mortality. Multiple studies have demonstrated a high negative predictive value (NPV) for ICH expansion in patients without spot sign. Our aim is to determine the absolute NPV of the spot sign and clinical characteristics of patients who had ICH expansion despite the absence of a spot sign. This information may be helpful in the development of a cost effective imaging protocol of patients with ICH. During a 3-year period, 204 patients with a CTA with primary intracerebral hemorrhage were evaluated for subsequent hematoma expansion during their hospitalization. Patients with intraventricular hemorrhage were excluded. Clinical characteristics and antithrombotic treatment on admission were noted. The number of follow-up NCCT was recorded. Of the resulting 123 patients, 108 had a negative spot sign and 7 of those patients subsequently had significant hematoma expansion, 6 of which were on antithrombotic therapy. The NPV of the CTA spot sign was calculated at 0.93. In patients without antithrombotic therapy, the NPV was 0.98. In summary, the negative predictive value of the CTA spot sign for expansion of ICH, in the absence of antithrombotic therapy and intraventricular hemorrhage (IVH) on admission, is very high. These results have the potential to redirect follow-up imaging protocols and reduce cost.

Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. METHODS: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 µg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms. CONCLUSIONS: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Predicting Intracerebral Hemorrhage Growth With the Spot Sign: The Effect of Onset-to-Scan Time.

BACKGROUND AND PURPOSE: Hematoma expansion after acute intracerebral hemorrhage is common and is associated with early deterioration and poor clinical outcome. The computed tomographic angiography (CTA) spot sign is a promising predictor of expansion; however, frequency and predictive values are variable across studies, possibly because of differences in onset-to-CTA time. We performed a patient-level meta-analysis to define the relationship between onset-to-CTA time and frequency and predictive ability of the spot sign. METHODS: We completed a systematic review for studies of CTA spot sign and hematoma expansion. We subsequently pooled patient-level data on the frequency and predictive values for significant hematoma expansion according to 5 predefined categorized onset-to-CTA times. We calculated spot-sign frequency both as raw and frequency-adjusted rates. RESULTS: Among 2051 studies identified, 12 met our inclusion criteria. Baseline hematoma volume, spot-sign status, and time-to-CTA were available for 1176 patients, and 1039 patients had follow-up computed tomographies for hematoma expansion analysis. The overall spot sign frequency was 26%, decreasing from 39% within 2 hours of onset to 13% beyond 8 hours (P<0.001). There was a significant decrease in hematoma expansion in spot-positive patients as onset-to-CTA time increased (P=0.004), with positive predictive values decreasing from 53% to 33%. CONCLUSIONS: The frequency of the CTA spot sign is inversely related to intracerebral hemorrhage onset-to-CTA time. Furthermore, the positive predictive value of the spot sign for significant hematoma expansion decreases as time-to-CTA increases. Our results offer more precise risk stratification for patients with acute intracerebral hemorrhage and will help refine clinical prediction rules for intracerebral hemorrhage expansion.

CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The computed tomography angiography (CTA) spot sign is a validated predictor of hematoma expansion and poor outcome in supratentorial intracerebral hemorrhage (ICH), but patients with brainstem ICH have typically been excluded from the analyses. We investigated the frequency of spot sign and its relationship with hematoma expansion and outcome in patients with primary pontine hemorrhage (PPH). METHODS: We performed a retrospective analysis of PPH cases obtained from a prospectively collected cohort of consecutive ICH patients who underwent CTA. CTA first-pass readings for spot sign presence were analyzed by two trained readers. Baseline and follow-up hematoma volumes on non-contrast CT scans were assessed by semi-automated computer-assisted volumetric analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratio, and accuracy of spot sign for prediction of in-hospital mortality were calculated. RESULTS: 49 subjects met the inclusion criteria of whom 11 (22.4 %) showed a spot sign. In-hospital mortality was higher in spot sign-positive versus spot sign-negative subjects (90.9 vs 47.4 %, p = 0.020). Spot sign showed excellent specificity (95 %) and PPV (91 %) in predicting in-hospital mortality. Absolute hematoma growth, defined as parenchymal and intraventricular hematoma expansion of any amount, was significantly higher in spot sign-positive versus spot sign-negative subjects (13.72 ± 20.93 vs 3.76 ± 8.55 mL, p = 0.045). CONCLUSIONS: As with supratentorial ICH, the CTA spot sign is a common finding and is associated with higher risk of hematoma expansion and mortality in PPH. This marker may assist clinicians in prognostic stratification.