Dar Dowlatshahi

Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study

BACKGROUND In patients with intracerebral haemorrhage (ICH), early haemorrhage expansion affects clinical outcome. Haemostatic treatment reduces haematoma expansion, but fails to improve clinical outcomes in many patients. Proper selection of patients at high risk for haematoma expansion seems crucial to improve outcomes. In this study, we aimed to prospectively validate the CT-angiography (CTA) spot sign for prediction of haematoma expansion. METHODS PREDICT (predicting haematoma growth and outcome in intracerebral haemorrhage using contrast bolus CT) was a multicentre prospective observational cohort study. We recruited patients aged 18 years or older, with ICH smaller than 100 mL, and presenting at less than 6 h from symptom onset. Using two independent core laboratories, one neuroradiologist determined CTA spot-sign status, whereas another neurologist masked for clinical outcomes and imaging measured haematoma volumes by computerised planimetry. The primary outcome was haematoma expansion defined as absolute growth greater than 6 mL or a relative growth of more than 33% from initial CT to follow-up CT. We reported data using standard descriptive statistics stratified by the CTA spot sign. Mortality was assessed with Kaplan-Meier survival analysis. FINDINGS We enrolled 268 patients. Median time from symptom onset to baseline CT was 135 min (range 22-470), and time from onset to CTA was 159 min (32-475). 81 (30%) patients were spot-sign positive. The primary analysis included 228 patients, who had a follow-up CT before surgery or death. Median baseline ICH volume was 19·9 mL (1·5-80·9) in spot-sign-positive patients versus 10·0 mL (0·1-102·7) in spot-sign negative patients (p<0·001). Median ICH expansion was 8·6 mL (-9·3 to 121·7) for spot-sign positive patients and 0·4 mL (-11·7 to 98·3) for spot-negative patients (p<0·001). In those with haematoma expansion, the positive predictive value for the spot sign was61% (95% CI 47–73) for the positive predictive value and 78% (71–84) for the negative predictive value, with 51% (39–63) sensitivity and 85% (78–90) specificity[corrected]. Median 3-month modified Rankin Scale (mRS) was 5 in CTA spot-sign-positive patients, and 3 in spot-sign-negative patients (p<0·001). Mortality at 3 months was 43·4% (23 of 53) in CTA spot-sign positive versus 19·6% (31 of 158) in CTA spot-sign-negative patients (HR 2·4, 95% CI 1·4-4·0, p=0·002). INTERPRETATION These findings confirm previous single-centre studies showing that the CTA spot sign is a predictor of haematoma expansion. The spot sign is recommended as an entry criterion for future trials of haemostatic therapy in patients with acute ICH. FUNDING Canadian Stroke Consortium and NovoNordisk Canada.

Increased temporal cortex CREB concentrations and antidepressant treatment in major depression

There was no correlation between temporal cortex CREB concentration and age (r =0·046, p=0·73) or postmortem interval (r = 0·039, p=0·77). In the MDD group, higher temporal cortex CREB concentrations were found in patients treated with antidepressants at the time of death (figure) than in untreated patients (p=0·01). Furthermore, MDD patients not on antidepressants at the time of death had lower CREB concentrations than controls (p=0·02), whereas treated patients did not differ from the control group (p=0·17). There were no differences in the occipital cortex, which suggests that the effects of antidepressants may be regional. There were no differences in CREB concentrations between patients with bipolar disorder or schizophrenia and controls or between treated and untreated patients with bipolar disorder and schizophrenia, which suggests that this drug effect may be specific to MDD. Downstream changes in the cAMP pathway may occur in patients with MDD and antidepressant treatment may be associated with a return to normal temporal cortex of CREB in patients with MDD. The cAMP pathway might ultimately be one of many intracellular pathways contributing to the pathophysiology of depression and its

Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes.

Background: Hematoma expansion (HE) is a surrogate marker in intracerebral hemorrhage (ICH) trials. However, the amount of HE necessary to produce poor outcomes in an individual is unclear; there is no agreement on a clinically meaningful definition of HE. We compared commonly used definitions of HE in their ability to predict poor outcome as defined by various cutpoints on the modified Rankin Scale (mRS). Methods: In this cohort study, we analyzed 531 patients with ICH from the Virtual International Stroke Trials Archive. Primary outcome was mRS at 90 days, dichotomized into 0–3 vs 4–6. Secondary outcomes included other mRS cutpoints and mRS “shift analysis.” Sensitivity, specificity, and predictive values for commonly used HE definitions were calculated. Results: Between 13% and 32% of patients met the commonly used HE definitions. All definitions independently predicted poor outcome; positive predictive values increased with higher growth cutoffs but at the expense of lower sensitivities. All HE definitions showed higher specificity than sensitivity. Absolute growth cutoffs were more predictive than relative cutoffs when mRS 5–6 or 6 was defined as “poor outcome.” Conclusion: HE robustly predicts poor outcome regardless of the growth definition or the outcome definition. The highest positive predictive values are obtained when using an absolute growth definition to predict more severe outcomes. Given that only a minority of patients may have clinically relevant HE, hemostatic ICH trials may need to enroll a large number of patients, or select for a population that is more likely to have HE.

Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal

Background and Purpose Anticoagulant-associated intracranial hemorrhage (aaICH) presents with larger hematoma volumes, higher risk of hematoma expansion, and worse outcome than spontaneous intracranial hemorrhage. Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of anticoagulation after aaICH. Given the lack of randomized controlled trial evidence of efficacy, and the potential for thrombotic complications, we aimed to determine outcomes in patients with aaICH treated with PCC. Methods We conducted a prospective multicenter registry of patients treated with PCC for aaICH in Canada. Patients were identified by local blood banks after the release of PCC. A chart review abstracted clinical, imaging, and laboratory data, including thrombotic events after therapy. Hematoma volumes were measured on brain CT scans and primary outcomes were modified Rankin Scale at discharge and in-hospital mortality. Results Between 2008 and 2010, 141 patients received PCC for aaICH (71 intraparenchymal hemorrhages). The median age was 78 years (interquartile range, 14), 59.6% were male, and median Glasgow Coma Scale was 14. Median international normalized ratio was 2.6 (interquartile range, 2.0) and median parenchymal hematoma volume was 15.8 mL (interquartile range, 31.8). Median post-PCC therapy international normalized ratio was 1.4: 79.5% of patients had international normalized ratio correction (<1.5) within 1 hour of PCC therapy. Patients with intraparenchymal hemorrhage had an in-hospital mortality rate of 42.3% with median modified Rankin Scale of 5. Significant hematoma expansion occurred in 45.5%. There were 3 confirmed thrombotic complications within 7 days of PCC therapy. Conclusions PCC therapy rapidly corrected international normalized ratio in the majority of patients, yet mortality and morbidity rates remained high. Rapid international normalized ratio correction alone may not be sufficient to alter prognosis after aaICH.

Analysis of Workflow and Time to Treatment on Thrombectomy Outcome in the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) Randomized, Controlled Trial

Background— The Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial used innovative imaging and aggressive target time metrics to demonstrate the benefit of endovascular treatment in patients with acute ischemic stroke. We analyze the impact of time on clinical outcome and the effect of patient, hospital, and health system characteristics on workflow within the trial. Methods and Results— Relationship between outcome (modified Rankin Scale) and interval times was modeled by using logistic regression. Association between time intervals (stroke onset to arrival in endovascular-capable hospital, to qualifying computed tomography, to groin puncture, and to reperfusion) and patient, hospital, and health system characteristics were modeled by using negative binomial regression. Every 30-minute increase in computed tomography-to-reperfusion time reduced the probability of achieving a functionally independent outcome (90-day modified Rankin Scale 0–2) by 8.3% (P=0.006). Symptom onset-to-imaging time was not associated with outcome (P>0.05). Onset-to-endovascular hospital arrival time was 42% (34 minutes) longer among patients receiving intravenous alteplase at the referring hospital (drip and ship) versus direct transfer (mothership). Computed tomography-to-groin puncture time was 15% (8 minutes) shorter among patients presenting during work hours versus off hours, 41% (24 minutes) shorter in drip-ship patients versus mothership, and 43% (22 minutes) longer when general anesthesia was administered. The use of a balloon guide catheter during endovascular procedures shortened puncture-to-reperfusion time by 21% (8 minutes). Conclusions— Imaging-to-reperfusion time is a significant predictor of outcome in the ESCAPE trial. Inefficiencies in triaging, off-hour presentation, intravenous alteplase administration, use of general anesthesia, and endovascular techniques offer major opportunities for improvement in workflow. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Certainty of Stroke Diagnosis: Incremental Benefit with CT Perfusion over Noncontrast CT and CT Angiography

PURPOSE To systematically evaluate the diagnostic benefits and inter- and intraobserver reliability of an incremental computed tomographic (CT) protocol in the confirmation of clinically suspected stroke, with combined imaging and clinical data as the reference standard. MATERIALS AND METHODS Institutional review board approval was obtained, and participants gave informed consent. A total of 191 patients (mean age, 67 years +/- 16 [standard deviation]; 105 men) with strokelike symptoms of no more than 3 hours duration were recruited. Blinded review was performed by four readers with limited stroke imaging experience. Diagnostic confidence was recorded on a five-point scale. Logistic regression analysis was used to calculate the difference between the real and observed diagnoses, adjusting for confidence. Predictive effects of observed diagnostic performance and confidence score were quantified with the entropy r(2) value. Sensitivity, specificity, and confidence intervals were calculated while accounting for multiple reader assessments. Receiver operating characteristic (ROC) analyses, including area under the ROC curve, were conducted for three modalities in combination with confidence score. Inter- and intraobserver agreement was established with the Cohen kappa statistic. RESULTS The final diagnosis was infarct in 64% of the patients, transient ischemic attack in 18%, and stroke mimic in 17%. Large-vessel occlusion occurred in 70% of the patients with an infarct. Sensitivity for stroke determination with noncontrast CT, CT angiography, and CT perfusion increased by 12.4% over that with noncontrast CT and CT angiography and by 18.2% over that with only noncontrast CT for a confidence level of 4 or higher. The incremental protocol was more likely to enable confirmation of clinical stroke diagnosis (odds ratio, 13.3) than was noncontrast CT and CT angiography (odds ratio, 6.4) or noncontrast CT alone (odds ratio, 3.3), The area under the ROC curve was 0.67 for the combination of noncontrast CT and confidence score, 0.72 for the combination of CT angiography and confidence score, and 0.81 for the combination of CT perfusion and confidence score. Inter- and intraobserver agreement increased with progressive sequence use. CONCLUSION An incremental stroke protocol that includes CT perfusion increases diagnostic performance for stroke diagnosis and inter- and intraobserver agreement.

Postcontrast CT Extravasation Is Associated With Hematoma Expansion in CTA Spot Negative Patients

BACKGROUND AND PURPOSE The purpose of this study was to assess the effect of postcontrast CT (PCCT) leakage (PCL) on hematoma growth in CTA spot negative patients. METHODS A retrospective study of 61 patients presenting within 6 hours of primary ICH onset imaged with CT angiography (CTA) and PCCT. Presence of CTA spot sign and PCL were documented. PCL was defined as the presence of contrast extravasation on the PCCT study at a location remote from the CTA spot sign if present. Hematoma expansion was defined as >6 mL or 30% hematoma enlargement. Patients were dichotomized by CTA spot sign presence and PCL and compared for baseline demographic data, hematoma size, and growth using the unpaired t test and Mann-Whitney test for continuous and categorical data, respectively. A probability value <0.05 was considered significant. RESULTS PCL was present in 11/61 patients (18%), occurring in 5 without a spot sign (45%). Spot negative PCL patients demonstrated larger absolute (P=0.02) and percentage hematoma growth (P=0.02) compared to those without PCL. The mean volume and percent increase was 6.7 mL and 26%, respectively. Inclusion of PCL together with CTA spot sign as risk factor for hematoma expansion increased sensitivity from 0.78 (95% CI; 0.52 to 0.94) to 0.94 (95% CI; 0.72 to 1.00) and NPV from 0.90 (95% CI; 0.76 to 0.97) to 0.97 (95% CI; 0.85 to 1.00). CONCLUSIONS Inclusion of PCCT in the investigation of ICH patients allows detection of PCL which, together with the CTA spot sign, increases sensitivity and negative predictive value for predicting hematoma expansion. This finding should be validated in larger studies.

Canadian stroke best practice recommendations: Stroke rehabilitation practice guidelines, update 2015:

Stroke rehabilitation is a progressive, dynamic, goal-orientated process aimed at enabling a person with impairment to reach their optimal physical, cognitive, emotional, communicative, social and/or functional activity level. After a stroke, patients often continue to require rehabilitation for persistent deficits related to spasticity, upper and lower extremity dysfunction, shoulder and central pain, mobility/gait, dysphagia, vision, and communication. Each year in Canada 62,000 people experience a stroke. Among stroke survivors, over 6500 individuals access in-patient stroke rehabilitation and stay a median of 30 days (inter-quartile range 19 to 45 days). The 2015 update of the Canadian Stroke Best Practice Recommendations: Stroke Rehabilitation Practice Guidelines is a comprehensive summary of current evidence-based recommendations for all members of multidisciplinary teams working in a range of settings, who provide care to patients following stroke. These recommendations have been developed to address both the organization of stroke rehabilitation within a system of care (i.e., Initial Rehabilitation Assessment; Stroke Rehabilitation Units; Stroke Rehabilitation Teams; Delivery; Outpatient and Community-Based Rehabilitation), and specific interventions and management in stroke recovery and direct clinical care (i.e., Upper Extremity Dysfunction; Lower Extremity Dysfunction; Dysphagia and Malnutrition; Visual-Perceptual Deficits; Central Pain; Communication; Life Roles). In addition, stroke happens at any age, and therefore a new section has been added to the 2015 update to highlight components of stroke rehabilitation for children who have experienced a stroke, either prenatally, as a newborn, or during childhood. All recommendations have been assigned a level of evidence which reflects the strength and quality of current research evidence available to support the recommendation. The updated Rehabilitation Clinical Practice Guidelines feature several additions that reflect new research areas and stronger evidence for already existing recommendations. It is anticipated that these guidelines will provide direction and standardization for patients, families/caregiver(s), and clinicians within Canada and internationally.

Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis

BACKGROUND The clinical armamentarium for anticoagulation has expanded substantially since the recent approval of dabigatran, rivaroxaban and apixaban for the prevention of stroke in atrial fibrillation. However, patients in the general population often differ from participants in clinical trials. In this study, we assessed the uptake of these novel oral anticoagulants in Ontario, Canada, within the first 2 years after dabigatrans approval for this indication. METHODS Using data on province-wide prescription volumes, we conducted a time-series analysis of prescription trends between October 2010 and September 2012 for all orally administered anticoagulants (warfarin, dabigatran and rivaroxaban) that were available in this period. We stratified dabigatran prescription rates by age group (20-39, 40-59, 60-64, 65-84 and ≥ 85 yr). We compared the proportion of dabigatran prescriptions to patients aged 65 or older with similar data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. RESULTS Over the 24-month study period, we found that prescriptions for the novel anticoagulants rose more than 20-fold, to represent 21.1% of all prescriptions of oral anticoagulants by September 2012. The rise in prescriptions was due primarily to an increase in dabigatran use. Prescription rates of dabigatran were highest among people aged 85 years or more, a group at increased risk of bleeding who are markedly older than the average participant in the clinical trial in which the drug was tested (71 yr). In September 2012, most of the dabigatran prescriptions were for the lower-dose formulation (110 mg) in the older groups (58.8% of dabigatran prescriptions in the 65-84 age group and 93.6% in the oldest group). INTERPRETATION We observed rapid growth in the uptake of the novel oral anticoagulants since their approval for use in patients with atrial fibrillation, especially among those aged 85 years or more. This increase in use in the oldest group, a population at high risk of bleeding, signals the need to evaluate outcomes of use of novel oral anticoagulants in the clinical setting.

Stratified, Urgent Care for Transient Ischemic Attack Results in Low Stroke Rates

Background and Purpose— Transient ischemic attack (TIA) is a marker for early risk of stroke. No previous studies have assessed the use of urgent stroke prevention clinics for emergency department (ED) patients with TIA. We hypothesized that an ABCD2-based ED triaging tool for TIA with outpatient management would be associated with lower 90-day stroke rate than that predicted by ABCD2. Methods— A cohort of prospectively identified patients presenting with symptoms suggestive of TIA seen in 2 tertiary-care EDs. These patients were divided into 3 strata based on their ACBD2 score, and triage targets were set for each stratum. All patients received the same standard of care in the Stroke Clinic regardless of their risk score. Primary outcome was stroke by 90 days of index TIA. Secondary outcomes were subsequent TIA, myocardial infarction, or death. Results— One-thousand ninety-three patients met the inclusion criteria; 982 patients completed 90-day follow-up and comprised the final cohort. After stratification, 32%, 49%, and 19% of patients were categorized as low-, moderate-, or high-risk, respectively. The overall 90-day risk of stroke in all patients was 3.2%, compared with the ABCD2-predicted risk of 9.2%. Only 1.6% of patients with TIA/minor stroke were admitted from the ED. The risk of subsequent TIA, myocardial infarction, or death by 90 days was 5.5%, 0.1%, and 1.7%, respectively. Conclusion— Outpatient care in a rapid-access stroke prevention clinic using the ABCD2 score for triage resulted in a low 90-day stroke rate for patients in the ED with TIA. Benefit occurred without requiring admission for most patients.