Depression one year after hemorrhagic stroke is associated with late worsening of outcomes.

BACKGROUND: Poststroke depression is the most common psychiatric sequelae of stroke, and it's independently associated with increased morbidity and mortality. Few studies have examined depression after intracranial hemorrhage (ICH). OBJECTIVE: To investigate the relationship between depression, ICH and outcomes. METHODS: A substudy of the prospective Diagnostic Accuracy of MRI in Spontaneous Intracerebral Hemorrhage (DASH) study, we included 89 subjects assessed for depression 1 year after hemorrhage. A Hamilton Depression Rating Scale score >10 defined depression. Univariate, multivariable, and trend analyses evaluated relationships between depression, clinical, radiographic, and inflammatory factors and modified Rankin score (mRS) at 90 days and one year. RESULTS: Prevalence of depression at one year was 15%. Depression was not associated with hematoma volumes, presence of IVH or admission NIHSS, nor with demographic factors. Despite this, depressed patients had worse 1-year outcomes (p = 0.004) and were less likely to improve between 3 and 12 months, and more likely to worsen (p = 0.042). CONCLUSION: This is the first study to investigate depression one year after ICH. Post-ICH depression was common and associated with late worsening of disability unrelated to initial hemorrhage severity. Further research is needed to understand whether depression is caused by worsened disability, or whether the converse is true.

Bleeding and infection with external ventricular drainage: a systematic review in comparison with adjudicated adverse events in the ongoing Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-III IHV) trial.

BACKGROUND: Retrospective series report varied rates of bleeding and infection with external ventricular drainage (EVD). There have been no prospective studies of these risks with systematic surveillance, threshold definitions, or independent adjudication. OBJECTIVE: To analyze the rate of complications in the ongoing Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) trial, providing a comparison with a systematic review of complications of EVD in the literature. METHODS: Patients were prospectively enrolled in the CLEAR III trial after placement of an EVD for obstructive intraventricular hemorrhage and randomized to receive recombinant tissue-type plasminogen activator or placebo. We counted any detected new hemorrhage (catheter tract hemorrhage or any other distant hemorrhage) on computed tomography scan within 30 days from the randomization. Meta-analysis of published series of EVD placement was compiled with STATA software. RESULTS: Growing or unstable hemorrhage was reported as a cause of exclusion from the trial in 74 of 5707 cases (1.3%) screened for CLEAR III. The first 250 patients enrolled have completed adjudication of adverse events. Forty-two subjects (16.8%) experienced ≥1 new bleeds or expansions, and 6 of 250 subjects (2.4%) suffered symptomatic hemorrhages. Eleven cases (4.4%) had culture-proven bacterial meningitis or ventriculitis. CONCLUSION: Risks of bleeding and infection in the ongoing CLEAR III trial are comparable to those previously reported in EVD case series. In the present study, rates of new bleeds and bacterial meningitis/ventriculitis are very low despite multiple daily injections, blood in the ventricles, the use of thrombolysis in half the cases, and generalization to >60 trial sites.

Natural history and prognostic value of corticospinal tract Wallerian degeneration in intracerebral hemorrhage.

BACKGROUND: The purpose of this study was to define the incidence, imaging characteristics, natural history, and prognostic implication of corticospinal tract Wallerian degeneration (CST-WD) in spontaneous intracerebral hemorrhage (ICH) using serial MR imaging. METHODS AND RESULTS: Consecutive ICH patients with supratentorial ICH prospectively underwent serial MRIs at 2, 7, 14, and 21 days. MRIs were analyzed by independent raters for the presence and topographical distribution of CST-WD on diffusion-weighted imaging (DWI). Baseline demographics, hematoma characteristics, ICH score, and admission National Institute of Health Stroke Score (NIHSS) were systematically recorded. Functional outcome at 3 months was assessed by the modified Rankin Scale (mRS) and the motor-NIHSS. Twenty-seven patients underwent 93 MRIs; 88 of these were serially obtained in the first month. In 13 patients (48%), all with deep ICH, CST-WD changes were observed after a median of 7 days (interquartile range, 7 to 8) as reduced diffusion on DWI and progressed rostrocaudally along the CST. CST-WD changes evolved into T2-hyperintense areas after a median of 11 days (interquartile range, 6 to 14) and became atrophic on MRIs obtained after 3 months. In univariate analyses, the presence of CST-WD was associated with poor functional outcome (ie, mRS 4 to 6; P=0.046) and worse motor-NIHSS (5 versus 1, P=0.001) at 3 months. CONCLUSIONS: Wallerian degeneration along the CST is common in spontaneous supratentorial ICH, particularly in deep ICH. It can be detected 1 week after ICH on DWI and progresses rostrocaudally along the CST over time. The presence of CST-WD is associated with poor motor and functional recovery after ICH.

Magnetic resonance imaging profile of blood-brain barrier injury in patients with acute intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is associated with blood-brain barrier (BBB) injury, which is a poorly understood factor in ICH pathogenesis, potentially contributing to edema formation and perihematomal tissue injury. We aimed to assess and quantify BBB permeability following human spontaneous ICH using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). We also investigated whether hematoma size or location affected the amount of BBB leakage. METHODS AND RESULTS: Twenty-five prospectively enrolled patients from the Diagnostic Accuracy of MRI in Spontaneous intracerebral Hemorrhage (DASH) study were examined using DCE MRI at 1 week after symptom onset. Contrast agent dynamics in the brain tissue and general tracer kinetic modeling were used to estimate the forward leakage rate (K(trans)) in regions of interest (ROI) in and surrounding the hematoma and in contralateral mirror-image locations (control ROI). In all patients BBB permeability was significantly increased in the brain tissue immediately adjacent to the hematoma, that is, the hematoma rim, compared to the contralateral mirror ROI (P<0.0001). Large hematomas (>30 mL) had higher K(trans) values than small hematomas (P<0.005). K(trans) values of lobar hemorrhages were significantly higher than the K(trans) values of deep hemorrhages (P<0.005), independent of hematoma volume. Higher K(trans) values were associated with larger edema volumes. CONCLUSIONS: BBB leakage in the brain tissue immediately bordering the hematoma can be measured and quantified by DCE MRI in human ICH. BBB leakage at 1 week is greater in larger hematomas as well as in hematomas in lobar locations and is associated with larger edema volumes.

Anemia and hematoma volume in acute intracerebral hemorrhage.

OBJECTIVE: Anemia increases risk of bleeding complications in the critically ill. In primary intracerebral hemorrhage (ICH), the most fatal type of stroke, outcome is largely dependent on the volume of hemorrhage into the brain. We investigated the relationship between anemia and clinical course of acute ICH. METHODS: Six hundred ninety-four consecutive subjects were identified from an ongoing single-center prospective cohort study of nontraumatic ICH during a 6-year period. Anemia was defined according to World Health Organization criteria. Study end points were ICH volume, as measured on the baseline computed tomography scan, and 30-day mortality. RESULTS: Anemia was present in 177 (25.8%) patients on admission. Patients with anemia were older (p = 0.005) and more likely to have coronary artery disease (p < 0.0001). In multivariable analysis, anemia (p = 0.009), lobar location of ICH (p < 0.001), white blood cell count (p < 0.001), and admission diastolic blood pressure (p < 0.001) were associated with larger ICH volume. Although after accounting for ICH volume, none of these variables was a significant predictor of 30-day mortality in multivariable analysis, the size of the marginal reduction in the odds ratio for anemia suggests that it may have a small effect on mortality through mechanisms in addition to ICH volume. CONCLUSIONS: Anemia is common in acute ICH and its presence at admission is an independent predictor of larger volume of ICH. Given the central role of ICH volume in outcome, clarification of the mechanisms underlying this relationship may offer novel therapeutic targets for reducing ICH morbidity and mortality.

Risk of thromboembolism following acute intracerebral hemorrhage.

INTRODUCTION: Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulant therapy (OAT). While anticoagulated patients have increased severity of bleeding following ICH, they may also be at increased risk for thromboembolic events (TEs) given that they had been prescribed OAT prior to their ICH. We hypothesized that TEs are relatively common following ICH, and that anticoagulated patients are at higher risk for these complications. METHODS: Consecutive patients with primary ICH presenting to a tertiary care hospital from 1994 to 2006 were prospectively characterized and followed. Hospital records were retrospectively reviewed for clinically relevant in-hospital TEs and patients were prospectively followed for 90 day mortality. RESULTS: For 988 patients of whom 218 (22%) were on OAT at presentation, median hospital length of stay was 7 (IQR 4-13) days and 90-day mortality was 36%. TEs were diagnosed in 71 patients (7.2%) including pulmonary embolism (1.8%), deep venous thrombosis (1.1%), myocardial ischemia (1.6%), and cerebrovascular ischemia (3.0%). Mean time to event was 8.4 +/- 7.0 days. Rates of TE were 5% among those with OAT-related ICH and 8% among those with non-OAT ICH (P = 0.2). After multivariable Cox regression, the only independent risk factor for developing a TE was external ventricular drain placement (HR 2.1, 95% CI 1.1-4.1, P = 0.03). TEs had no effect on 90-day mortality (HR 0.7, 95% CI 0.5-1.1, P = 0.1). CONCLUSIONS: The incidence of TEs in an unselected ICH population was 7.2%. Patients with OAT-related ICH were not at increased risk of TEs.

Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is the most fatal and disabling stroke subtype. Widely used tools for prediction of mortality are fundamentally limited in that they do not account for effects of withdrawal of care and are not designed to predict functional recovery. We developed an acute clinical score to predict likelihood of functional independence. METHODS: We prospectively characterized 629 consecutive patients with ICH at hospital presentation. Predictors of functional independence (Glasgow Outcome Score > or = 4) at 90 days were used to develop a logistic regression-based risk stratification scale in a random subset of two thirds and validated in the remaining one third of the cohort. RESULTS: At 90 days, 162 (26%) patients achieved independence. Age, Glasgow Coma Scale, ICH location, volume (all P<0.0001), and pre-ICH cognitive impairment (P=0.005) were independently associated with Glasgow Outcome Score > or = 4. The FUNC score was developed as a sum of individual points (0-11) based on strength of association with outcome. In both the development and validation cohorts, the proportion of patients who achieved Glasgow Outcome Score > or = 4 increased steadily with FUNC score. No patient assigned a FUNC score < or = 4 achieved functional independence, whereas > 80% with a score of 11 did. The predictive accuracy of the FUNC score remained unchanged when restricted to ICH survivors only, consistent with absence of confounding by early withdrawal of care. CONCLUSIONS: FUNC score is a valid clinical assessment tool that identifies patients with ICH who will attain functional independence and thus, can provide guidance in clinical decision-making and patient selection for clinical trials.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

BACKGROUND AND PURPOSE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. METHODS: We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. RESULTS: Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). CONCLUSIONS: Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.

Early edema in warfarin-related intracerebral hemorrhage.

BACKGROUND AND PURPOSE: The pathophysiology and clinical significance of perihematomal edema (PHE), a cause of secondary neuronal injury after intracerebral hemorrhage (ICH), is poorly understood. A leading theory proposes that early PHE results from activation of the clotting cascade. We sought to test this theory by examining the relationship between early PHE and warfarin use in ICH patients. METHODS: ICH and PHE volumes were measured in consecutive patients with warfarin-related ICH and compared to those of controls with non-coagulopathic ICH. Subjects were identified from a prospective database of ICH patients. Clinical and radiological predictors of PHE volume and relative PHE (PHE volume/ICH volume) were identified. The relationship between PHE volume and 90-day mortality was determined. RESULTS: For the 49 consecutive warfarin-related ICH patients and 49 matched controls: median INRs (interquartile ranges) were 3.2 (2.3, 4.1) and 1.1 (1.08, 1.2); median hematoma volumes were 37.8 cm(3) (6.7, 102.9) and 18.1 cm(3) (9, 51) (P = 0.18); median PHE volumes were 12 cm(3) (3.7, 36.7), and 11 cm(3) (4.1, 24) (P = 0.87); and median relative PHE was 0.38 (0.28, 0.52) and 2 (1.37, 3.06), respectively. In multivariable analysis, ICH volume and warfarin use independently predicted PHE volume. There was an association between higher PHE volume and decreased 90-day mortality. CONCLUSIONS: Warfarin-related ICH is associated with less early relative edema than non-coagulopathic ICH. This is consistent with the theory that coagulation contributes to early edema. Early edema may be associated with improved functional outcome.

Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Anticoagulation-related intracerebral hemorrhage (ICH) is often fatal, and rapid reversal of anticoagulation is the most appealing strategy currently available for treatment. We sought to determine whether particular emergency department (ED) interventions are effective in reversing coagulopathy and improving outcome. METHODS: Consecutive patients with warfarin-related ICH presenting to an urban tertiary care hospital from 1998 to 2004 were prospectively captured in a database. ED records were retrospectively reviewed for dose and timing of fresh-frozen plasma (FFP) and vitamin K, as well as serial coagulation measures. After excluding patients with incomplete ED records, do-not-resuscitate orders established in the ED, initial international normalized ratio (INR) < or =1.4, and for whom no repeat INR was performed, 69 patients were available for analysis. The primary outcome was a documented INR < or =1.4 within 24 hours of ED presentation. RESULTS: Patients whose INR was successfully reversed within 24 hours had a shorter median time from diagnosis to first dose of FFP (90 minutes versus 210 minutes; P=0.02). In multivariable analysis, shorter time to vitamin K, as well as FFP, predicted INR correction. Every 30 minutes of delay in the first dose of FFP was associated with a 20% decreased odds of INR reversal within 24 hours (odds ratio, 0.8; 95% CI, 0.63 to 0.99). Dosing of FFP and vitamin K had no effect. No ED intervention was associated with improved clinical outcome. CONCLUSIONS: Time to treatment is the most important determinant of 24-hour anticoagulation reversal. Although additional study is required to determine the clinical benefit of rapid reversal of anticoagulation, minimizing delays in FFP administration is a prudent first step in emergency management of warfarin-related ICH.