Clot Burden Score and Early Ischemia Predict Intracranial Hemorrhage following Endovascular Therapy.

BACKGROUND AND PURPOSE: Intracranial hemorrhage is a known complication following endovascular thrombectomy. The radiologic characteristics of a CT scan may assist with hemorrhage risk stratification. We assessed the radiologic predictors of intracranial hemorrhage following endovascular therapy using data from the INTERRSeCT (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) study. MATERIALS AND METHODS: Patients undergoing endovascular therapy underwent baseline imaging, postprocedural angiography, and 24-hour follow-up imaging. The primary outcome was any intracranial hemorrhage observed on follow-up imaging. The secondary outcome was symptomatic hemorrhage. We assessed the relationship between hemorrhage occurrence and baseline patient characteristics, clinical course, and imaging factors: baseline ASPECTS, thrombus location, residual flow grade, collateralization, and clot burden score. Multivariable logistic regression with backward selection was used to adjust for relevant covariates. RESULTS: Of the 199 enrolled patients who met the inclusion criteria, 46 (23%) had an intracranial hemorrhage at 24 hours. On multivariable analysis, postprocedural hemorrhage was associated with pretreatment ASPECTS (OR, 1.56 per point lost; 95% CI, 1.12-2.15), clot burden score (OR, 1.19 per point lost; 95% CI, 1.03-1.38), and ICA thrombus location (OR, 3.10; 95% CI, 1.07-8.91). In post hoc analysis, clot burden scores of ≤3 (sensitivity, 41%; specificity, 82%; OR, 3.12; 95% CI, 1.36-7.15) and pretreatment ASPECTS ≤ 7 (sensitivity, 48%; specificity, 82%; OR, 3.17; 95% CI, 1.35-7.45) robustly predicted hemorrhage. Residual flow grade and collateralization were not associated with hemorrhage occurrence. Symptomatic hemorrhage was observed in 4 patients. CONCLUSIONS: Radiologic factors, early ischemia on CT, and increased CTA clot burden are associated with an increased risk of intracranial hemorrhage in patients undergoing endovascular therapy.

Aneurysmal SubArachnoid Hemorrhage-Red Blood Cell Transfusion And Outcome (SAHaRA): a pilot randomised controlled trial protocol.

INTRODUCTION: Anaemia is common in aneurysmal subarachnoid haemorrhage (aSAH) and is a potential critical modifiable factor affecting secondary injury. Despite physiological evidence and management guidelines that support maintaining a higher haemoglobin level in patients with aSAH, current practice is one of a more restrictive approach to transfusion. The goal of this multicentre pilot trial is to determine the feasibility of successfully conducting a red blood cell (RBC) transfusion trial in adult patients with acute aSAH and anaemia (Hb ≤100 g/L), comparing a liberal transfusion strategy (Hb ≤100 g/L) with a restrictive strategy (Hb ≤80 g/L) on the combined rate of death and severe disability at 12 months. METHODS: Design This is a multicentre open-label randomised controlled pilot trial at 5 academic tertiary care centres. Population We are targeting adult aSAH patients within 14 days of their initial bleed and with anaemia (Hb ≤110 g/L). Randomisation Central computer-generated randomisation, stratified by centre, will be undertaken from the host centre. Randomisation into 1 of the 2 treatment arms will occur when the haemoglobin levels of eligible patients fall to ≤100 g/L. Intervention Patients will be randomly assigned to either a liberal (threshold: Hb ≤100 g/L) or a restrictive transfusion strategy (threshold: Hb ≤80 g/L). Outcome Primary: Centre randomisation rate over the study period. Secondary: (1) transfusion threshold adherence; (2) study RBC transfusion protocol adherence; and (3) outcome assessment including vital status at hospital discharge, modified Rankin Score at 6 and 12 months and Functional Independence Measure and EuroQOL Quality of Life Scale scores at 12 months. Outcome measures will be reported in aggregate. ETHICS AND DISSEMINATION: The study protocol has been approved by the host centre (OHSN-REB 20150433-01H). This study will determine the feasibility of conducting the large pragmatic RCT comparing 2 RBC transfusion strategies examining the effect of a liberal strategy on 12-month outcome following aSAH. TRIAL REGISTRATION NUMBER: NCT02483351; Pre-results.

Cerebral Perfusion Pressure is Maintained in Acute Intracerebral Hemorrhage: A CT Perfusion Study.

BACKGROUND AND PURPOSE: Although blood pressure reduction has been postulated to result in a fall in cerebral perfusion pressure in patients with intracerebral hemorrhage, the latter is rarely measured. We assessed regional cerebral perfusion pressure in patients with intracerebral hemorrhage by using CT perfusion source data. MATERIALS AND METHODS: Patients with acute primary intracerebral hemorrhage were randomized to target systolic blood pressures of <150 mm Hg (n = 37) or <180 mm Hg (n = 36). Regional maps of cerebral blood flow, cerebral perfusion pressure, and cerebrovascular resistance were generated by using CT perfusion source data, obtained 2 hours after randomization. RESULTS: Perihematoma cerebral blood flow (38.7 ± 11.9 mL/100 g/min) was reduced relative to contralateral regions (44.1 ± 11.1 mL/100 g/min, P = .001), but cerebral perfusion pressure was not (14.4 ± 4.6 minutes(-1) versus 14.3 ± 4.8 minutes(-1), P = .93). Perihematoma cerebrovascular resistance (0.34 ± 0.11 g/mL) was higher than that in the contralateral region (0.30 ± 0.10 g/mL, P < .001). Ipsilateral and contralateral cerebral perfusion pressure in the external (15.0 ± 4.6 versus 15.6 ± 5.3 minutes(-1), P = .15) and internal (15.0 ± 4.8 versus 15.0 ± 4.8 minutes(-1), P = .90) borderzone regions were all similar. Borderzone cerebral perfusion pressure was similar to mean global cerebral perfusion pressure (14.7 ± 4.7 minutes(-1), P ≥ .29). Perihematoma cerebral perfusion pressure did not differ between blood pressure treatment groups (13.9 ± 5.5 minutes(-1) versus 14.8 ± 3.4 minutes(-1), P = .38) or vary with mean arterial pressure (r = -0.08, [-0.10, 0.05]). CONCLUSIONS: Perihematoma cerebral perfusion pressure is maintained despite increased cerebrovascular resistance and reduced cerebral blood flow. Aggressive antihypertensive therapy does not affect perihematoma or borderzone cerebral perfusion pressure. Maintenance of cerebral perfusion pressure provides physiologic support for the safety of blood pressure reduction in intracerebral hemorrhage.

Computed tomography angiography intraluminal filling defect is predictive of internal carotid artery free-floating thrombus.

INTRODUCTION: Filling defects at the internal carotid artery (ICA) origin in the work-up of stroke or transient ischemic attack may be an ulcerated plaque or free-floating thrombus (FFT). This may be challenging to distinguish, as they can appear morphologically similar. This is an important distinction as FFT can potentially embolize distally, and its management differs. We describe a series of patients with suspected FFT and evaluate its imaging appearance, clinical features, and evolution with therapy. METHODS: Between 2008 and 2013, we prospectively collected consecutive patients with proximal ICA filling defects in the axial plane surrounded by contrast on CT/MR angiography. We defined FFT as a filling defect that resolved on follow-up imaging. We assessed the cranial-caudal dimension of the filling defect and receiver operating characteristics to identify clinical and radiological variables that distinguished FFT from complex ulcerated plaque. RESULTS: Intraluminal filling defects were identified in 32 patients. Filling defects and resolved or decreased in 25 patients (78 %) and felt to be FFT; there was no change in 7 (22 %). Resolved defects and those that decreased in size extended more cranially than those that remained unchanged: 7.3 mm (4.2-15.9) versus 3.1 mm (2.7-3.7; p = 0.0038). Receiver operating characteristic analysis established a threshold of 3.8 mm (filling defect length), sensitivity of 88 %, specificity of 86 %, and area under the curve of 0.86 (p < 0.0001) for distinguishing FFT from plaque. CONCLUSION: Filling defects in the proximal ICA extending cranially >3.8 mm were more likely to be FFT than complex ulcerated plaque. Further studies evaluating filling defect length as a predictor for FFT are warranted.

Dynamic 'Spot Sign' Resolution following INR Correction in a Patient with Warfarin-Associated Intracerebral Hemorrhage.

Hematoma expansion in intracerebral hemorrhage is associated with poor clinical outcome. The 'spot sign' is a radiological marker that is associated with hematoma expansion, and thought to represent active extravasation of contrast. This case demonstrates the use of dynamic CT angiography in identifying the time-dependent appearance of a spot sign in a patient with warfarin-associated intracerebral hemorrhage. Repeat imaging is also presented which verified cessation of the spot sign after INR correction.

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.

Pre admission antithrombotics are associated with improved outcomes following ischaemic stroke: a cohort from the Registry of the Canadian Stroke Network.

BACKGROUND: Several studies have attempted to identify predictors of outcome following ischaemic stroke. Reduced stroke severity has been reported with pre admission ASA use, and improved outcomes have been reported with pre admission statin treatment. The interaction between pre treatment medications and clinical response to tPA is less clear. The objective of our study was to assess clinical outcomes in patients with acute ischaemic stroke with respect to pre treatment medications. METHODS: The Registry of the Canadian Stroke Network collected pre morbid and prospective outcome data on 5568 patients with ischaemic stroke. We applied multivariate analyses to correlate pre admission medications with stroke severity on presentation, in-hospital mortality, and modified Rankin at discharge. Analyses were adjusted for age, gender, medical history, tPA administration, blood pressure, and glucose on presentation. RESULTS: Pre admission treatment with ASA and clopidogrel was associated with less severe stroke upon presentation. A similar trend was seen with dipyridamole and ticlopidine, but did not reach statistical significance. Pre treatment with ASA and warfarin was associated with improved Rankin scores at discharge. There was no interaction between tPA treatment and pre admission antiplatelets with respect to in-hospital mortality or disability at discharge, although tPA treatment was independently associated with improved Rankin at discharge. Pre treatment antiplatelet use did not result in increased intracerebral haemorrhage following tPA administration. CONCLUSIONS: Patients with acute ischaemic stroke taking antithrombotic medications at hospital admission have improved functional outcomes. No interaction is noted between use of these medications and outcome following thrombolysis. This large prospective cohort study is consistent with previous published reports, and supports the notion that pre admission antithrombotics may mitigate brain injury during acute stroke.

Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium.

There is an established relationship between the monoaminergic neurotransmitter system and mood disorders. In an attempt to define further the pathophysiology of mood disorders, research is focussing on intracellular second messenger systems, including cyclic adenosine 3',5'-monophosphate (cAMP) and the polyphosphoinositol generated second messengers. The availability of tissue from the Stanley Foundation Neuropathology Consortium has offered us the opportunity to make a number of observations with respect to these second messenger systems in tissue from patients with major depressive disorder and bipolar affective disorder. There is evidence that antidepressants stimulate components of the cAMP pathway in patients with depression while mood stabilizers blunt the same pathway in patients with bipolar disorder. Furthermore, downstream targets of this pathway appear to be altered in patients with mood disorders. The relations between changes in second messenger systems, gene transcription, and clinical effects of current therapeutic regimens has implications for development of novel treatments of mood disorders.

Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.

BACKGROUND: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. METHODS: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. CONCLUSIONS: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.

Increased hippocampal supragranular Timm staining in subjects with bipolar disorder.

Biochemical and structural abnormalities have been reported in hippocampus of subjects with mood disorders. This study examined the organization of mossy fibers in anterior hippocampus of subjects obtained from the Stanley Neuropathology Consortium. Frozen postmortem hippocampal sections from subjects with major depression, bipolar disorder, schizophrenia and non-psychiatric controls were stained using the Neo-Timm procedure, which selectively stains mossy fibers. Increased Timm staining in the supragranular layer was found in subjects with bipolar disorder relative to control subjects. These results are suggestive of neuronal sprouting in hippocampus of subjects with bipolar disorder. There were no significant associations between supragranular Timm staining and suicide, length illness or drug treatment at the time of death.

G Protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders: effects of diagnosis, suicide, and treatment at the time of death.

Components of cyclic AMP (cAMP) signaling were examined in postmortem cerebral cortex of a well characterized group of patients with mood disorders and nonpsychiatric control subjects. We measured G protein levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of the subjects with respect to diagnosis, treatment, and suicide. There was no effect of diagnosis on any measure, except for a trend toward decreased stimulated AC activity in subjects with mood disorders relative to control subjects. We also detected a significant effect of suicide on temporal cortex CREB levels in subjects that died as a result of suicide relative to those that did not, which was more evident in patients with major depressive disorder. Bipolar disorder (BD) subjects treated with anticonvulsants at the time of death had decreased temporal cortex CREB levels relative to those not receiving anticonvulsants. Furthermore, we found a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects treated with lithium. These results support the hypothesis of altered cAMP signaling in mood disorders and raise the possibility that factors other than diagnosis, such as treatment and suicide, may be relevant to cell-signaling abnormalities reported in the literature.

Life events and social stress in puerperal psychoses: absence of effect.

Thirty-three patients admitted to hospital with severe early onset puerperal psychiatric disorders were compared with matched normal puerperal controls. Interviews, which were administered after recovery, covered life events in the previous thirteen months and detailed assessment of previous and personal history, pregnancy and labour, other aspects of stress, social support, and marital relationships. No differences, except for previous history of psychiatric disorder, were found between patients and controls or between patients with depressive and with other diagnoses. These findings of absence of social stress contrast with previous studies of milder post-partum depression and of disorders with onset during pregnancy, and suggest that the aetiology of severe post-partum disorders is predominantly biological.

Knowledge profile and control in diabetic patients.

Knowledge about diabetes was assessed using a previously described interactive computer-based questionnaire in 79 patients with insulin-dependent (IDDM) and 72 with non-insulin-dependent (NIDDM) diabetes mellitus routinely attending a single diabetic clinic. Simple linear correlation of total knowledge score with glycosylated haemoglobin (HbA1c) showed no significant relationship for either IDDM (r = 0.12: p = 0.18) or NIDDM (r = 0.15: p = 0.1). However, quintile grouping of knowledge scores showed the mean HbA1c to be significantly higher in the lowest scoring NIDDM quintile (10.6 +/- 0.5: +/- SE) with respect to the pooled mean of all the higher scoring quintiles (9.0 +/- 0.3) (p = 0.027). Mean HbA1c (9.6 +/- 0.5) was also higher in the least knowledgeable IDDM quintile than any other quintile group (range 8.8-9.0) but this was not significant with respect to the pooled mean of higher scoring patients (p greater than 0.1). The mean age of the lowest scoring IDDM quintile group (60.5 +/- 13.9 years) was significantly higher (p less than 0.01) than higher scoring IDDM groups (mean age range 36.5-43.3 years) but age was not significantly related to HbA1c in IDDM subjects. IDDM showed greater knowledge of diabetes than NIDDM but ignorance in key areas was unacceptably high in both diabetic subtypes, indicating that regular knowledge assessment and educational reinforcement may be essential for good diabetic control as well as patient safety, particularly in older IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of computer-based learning on diabetes knowledge and control.

Two interactive computer-based systems have been evaluated: a teaching program with text and animated graphics and a multiple-choice knowledge-assessment program (KAP) with optional prescriptive feedback. One hundred seventy-four routine-attending insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) patients were allocated to active and control groups to determine the effect of these programs on knowledge and control after a 4- to 6-mo follow-up period. Interactive computer teaching (ICT) resulted in a significant knowledge increment in both IDDM and NIDDM patients (P less than .05), together with a mean fall of 0.8 and 0.7%, respectively, in HbA1c (P less than .05 and P greater than .1), but no changes were observed in respective control groups. The KAP with feedback also produced a significant knowledge increment in both IDDM and NIDDM patients (P less than .05), of similar magnitude to the ICT program, and a mean fall in HbA1c of 1.2 and 1.3%, respectively (P less than .05), with no changes in the corresponding control groups. Even when KAP was used without prescriptive feedback, smaller but significant mean falls in HbA1c of 0.7 and 0.8% (P less than .05) were seen in IDDM and NIDDM patients, respectively, suggesting a motivational effect resulting from program participation.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer based learning and assessment for diabetic patients.

A comparatively inexpensive microcomputer-based system of programmed diabetic instruction is described, matched to an interactive knowledge assessment questionnaire with or without prescriptive feedback. This provides an educational and assessment package for newly diagnosed and established diabetics, with additional analytical potential. The system is well accepted, demonstrates major areas of defective knowledge and allows cost-effective handling of large numbers of patients.