Acute Hyperglycemia and In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage.

Hyperglycemia is reported to predict worse outcome in patients with stroke, including intracerebral hemorrhage (ICH). In 83 consecutive cases of ICH at a tertiary stroke center, hyperglycemia (serum glucose >7 mmol/L) compared to normoglycemia at presentation was associated with higher rates of in-hospital mortality (51.2% vs. 26.2%, OR 2.3, CI 1.2-7.6, p = 0.02). The association with in-hospital mortality withstood adjustment for age, ICH volume, intraventricular hemorrhage, and infratentorial ICH location, but not baseline Glasgow Coma Scale. Acute hyperglycemia is associated with in-hospital mortality in spontaneous ICH patients, though this may be an indirect, rather than a causal relationship.

PRES and RCVS: Two Distinct Entities or a Spectrum of the Same Disease?

OBJECTIVES: To report a case of a patient with overlapping posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), and review the existing literature emphasizing the pathophysiological overlap of these two entities. MATERIALS AND METHODS: We conducted a literature search in electronic database PubMed identifying studies reporting the overlap of PRES and RCVS. RESULTS: PRES and RCVS are two increasingly recognized entities that share similar clinical and imaging features. PRES is characterized by vasogenic edema predominantly in the parieto-occipital regions, associated with acute onset of neurological symptoms including encephalopathy, seizures, headaches, and visual disturbances. RCVS is characterized by reversible segmental and multifocal vasoconstriction of the cerebral arteries and classically presents with thunderclap headache, with or without associated focal neurological deficits and seizures. PRES is frequently associated with uncontrolled hypertension but can also be seen in the setting of renal failure, exposure to cytotoxic agents, or pre-eclampsia. RCVS is often triggered by exposure to vasoactive agents, postpartum state, or immunosuppression. We report a case of a patient presenting with vision changes and hemiparesis, and found to have extensive cytotoxic and vasogenic edema involving the cortex and subcortical white matter on brain imaging. These changes were primarily noted in the parieto-occipital and brainstem regions, along with features of reversible vasculopathy on vascular imaging suggestive of coexisting PRES and RCVS. CONCLUSIONS: PRES and RCVS share precipitating factors, clinical and radiological features, and frequently co-exist, suggesting a common pathophysiological mechanism related to reversible dysregulation of cerebral vasculature, endothelial dysfunction, and breakdown of the blood-brain barrier.

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Calculation of Prognostic Scores, Using Delayed Imaging, Outperforms Baseline Assessments in Acute Intracerebral Hemorrhage.

Background and Purpose- Patients with intracerebral hemorrhage (ICH) are often subject to rapid deterioration due to hematoma expansion. Current prognostic scores are largely based on the assessment of baseline radiographic characteristics and do not account for subsequent changes. We propose that calculation of prognostic scores using delayed imaging will have better predictive values for long-term mortality compared with baseline assessments. Methods- We analyzed prospectively collected data from the multicenter PREDICT study (Prediction of Hematoma Growth and Outcome in Patients With Intracerebral Hemorrhage Using the CT-Angiography Spot Sign). We calculated the ICH Score, Functional Outcome in Patients With Primary Intracerebral Hemorrhage (FUNC) Score, and modified ICH Score using imaging data at initial presentation and at 24 hours. The primary outcome was mortality at 90 days. We generated receiver operating characteristic curves for all 3 scores, both at baseline and at 24 hours, and assessed predictive accuracy for 90-day mortality with their respective area under the curve. Competing curves were assessed with nonparametric methods. Results- The analysis included 280 patients, with a 90-day mortality rate of 25.4%. All 3 prognostic scores calculated using 24-hour imaging were more predictive of mortality as compared with baseline: the area under the curve was 0.82 at 24 hours (95% CI, 0.76-0.87) compared with 0.78 at baseline (95% CI, 0.72-0.84) for ICH Score, 0.84 at 24 hours (95% CI, 0.79-0.89) compared with 0.76 at baseline (95% CI, 0.70-0.83) for FUNC, and 0.82 at 24 hours (95% CI, 0.76-0.88) compared with 0.74 at baseline (95% CI, 0.67-0.81) for modified ICH Score. Conclusions- Calculation of the ICH Score, FUNC Score, and modified ICH Score using 24-hour imaging demonstrated better prognostic value in predicting 90-day mortality compared with those calculated at presentation.

Redefining Hematoma Expansion With the Inclusion of Intraventricular Hemorrhage Growth.

Background and Purpose- Definitions of significant hematoma expansion traditionally focus on changes in intraparenchymal volume. The presence of intraventricular hemorrhage (IVH) is a predictor of poor outcome, but current definitions of hematoma expansion do not include IVH expansion. We evaluated whether including IVH expansion to current definitions of hematoma expansion improves the ability to predict 90-day outcome. Methods- Using data from the PREDICT-ICH study (Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT), we compared a standard definition of hematoma expansion (≥6 mL or ≥33%) to revised definitions that includes new IVH development or expansion (≥6 mL or ≥33% or any IVH; ≥6 mL or ≥33% or IVH expansion ≥1 mL). The primary outcome was poor clinical outcome (modified Rankin Scale score, 4-6) at 90 days. Diagnostic accuracy measures were calculated for each definition, and C statistics for each definition were compared using nonparametric methods. Results- Of the 256 patients eligible for primary analysis, 127 (49.6%) had a modified Rankin Scale score of 4 to 6. Sensitivity and specificity for the standard definition (n=80) were 45.7% (95% CI, 36.8-54.7) and 82.9% (95% CI, 75.3-88.9), respectively. The revised definition, ≥6 mL or ≥33% or any IVH (n=113), possessed a sensitivity of 63.8% (95% CI, 54.8-72.1) and specificity of 75.2% (95% CI, 66.8-82.4). Overall accuracy was significantly improved with the revised definition (P=0.013) and after adjusting for relevant covariates, was associated with a 2.55-fold increased odds (95% CI, 1.31-4.94) of poor outcome at 90 days. A second revised definition, ≥6 mL or ≥33% or IVH expansion ≥1 mL, performed similarly (sensitivity, 56.7% [95% CI, 47.6-65.5]; specificity, 78.3% [95% CI, 40.2-85.1]; aOR, 2.40 [95% CI, 1.23-4.69]). Conclusions- In patients with mild-to-moderate ICH, including IVH expansion to the definition of hematoma expansion improves sensitivity with only minimal decreases to specificity and improves overall prediction of 90-day outcome.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

Temporal Trends in Ischemic Stroke Incidence in Younger Adults in the Framingham Study.

Background and Purpose- Stroke at midlife has a disproportionately large impact on disability-adjusted life-years lost. Ischemic stroke incidence may be increasing at this age. We investigated long-term trends in ischemic stroke incidence and changes in stroke risk factors in a community sample stratified by stroke onset at middle and older age. Methods- In the Framingham Study, surveillance for incident stroke is ongoing since 1948. We examined age-adjusted and sex-adjusted 10-year incidence of ischemic stroke using Cox models in persons aged 35 to 54 and ≥55 years at start of follow-up. Tests for linear trend were performed over 4 epochs, controlling for the distance in time between intervals. Further, we calculated the mean 10-year risk of stroke at each epoch and for both age groups, based on vascular risk factors from the Framingham Stroke Risk Profile. Results- There were 153, 197, 176, and 165 incident ischemic strokes within each epoch beginning in 1962 (n=3966), 1971 (n=5779), 1987 (n=5133), and 1998 (n=6964). Most ischemic strokes at midlife (n=71) were because of atherosclerotic brain infarction (n=50) or cardioembolism (n=19). Using the risk in the 1962 epoch as the reference, the risk of ischemic stroke at midlife did not significantly decline (hazard ratio, 0.87; 95% CI, 0.74-1.02; P trend =0.09). Incidence of ischemic stroke declined in the older group (hazard ratio, 0.82; 95% CI, 0.77-0.88; P trend <0.001). Between epochs 1 and 4, the average 10-year risk of stroke, as estimated by the Framingham Stroke Risk Profile, declined by 0.7% at midlife and 1.1% at older age. Conclusions- Long-term rates of ischemic stroke declined in our community sample; the decline was greater in older as compared with younger adults. Early prevention, focused on modification of cardiovascular risk factors, is important to see sustained declines in stroke incidence and mortality at midlife.

Independent Validation of the Hematoma Expansion Prediction Score: A Non-contrast Score Equivalent in Accuracy to the Spot Sign.

BACKGROUND AND PURPOSE: The computed tomography angiography (CTA) spot sign is widely used to assess the risk of hematoma expansion following acute intracerebral hemorrhage (ICH). However, not all patients can receive intravenous contrast nor are all hospital systems equipped with this technology. We aimed to independently validate the Hematoma Expansion Prediction (HEP) Score, an 18-point non-contrast prediction scale, in an external cohort and compare its diagnostic capability to the CTA spot sign. METHODS: We performed a retrospective analysis of the predicting hematoma growth and outcome in intracerebral hemorrhage using contrast bolus CT (PREDICT) Cohort Study. Primary outcome was significant hematoma expansion (≥ 6 mL or ≥ 33%). We generated a receiver operating characteristic (ROC) curve comparing the HEP score to significant expansion. We calculated sensitivity, specificity, positive and negative predictive values (PPV/NPV) for each score point. We determined independent predictors of significant hematoma expansion via logistic regression. RESULTS: A total of 292 patients were included in primary analysis. Hematoma growth of ≥ 6 mL or ≥ 33% occurred in 94 patients (32%). The HEP score was associated with significant expansion (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.01-1.30). ROC curves comparing HEP score to significant expansion had an area under the curve of 0.64 (95% CI 0.57-0.71). Youden's method showed an optimum score of 4. HEP Scores ≥ 4 (n = 100, sensitivity 49%, specificity 73%, PPV 46%, NPV 75%, aOR 1.99, 95% CI 1.09-3.64) accurately predicted significant expansion. PPV increased with higher HEP scores, but at the cost of lower sensitivity. The diagnostic characteristics of the spot sign (n = 82, Sensitivity 49%, Specificity 81%, PPV 55%, NPV 76%, aOR 2.95, 95% CI 1.61-5.42) were similar to HEP scores ≥ 4. CONCLUSION: The HEP score is predictive of significant expansion (≥ 6 mL or ≥ 33%) and is comparable to the spot sign in diagnostic accuracy. Non-contrast prediction tools may have a potential role in the recruitment of patients in future intracerebral hemorrhage trials.

Revised Framingham Stroke Risk Profile to Reflect Temporal Trends.

BACKGROUND: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies. METHODS: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks. RESULTS: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks. CONCLUSIONS: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.

APOE and the Association of Fatty Acids With the Risk of Stroke, Coronary Heart Disease, and Mortality.

Background and Purpose- The role of dietary fat on cardiovascular health and mortality remains under debate. Because the APOE is central to the transport and metabolism of lipids, we examined associations between plasma fatty acids and the risk of stroke, coronary heart disease, and mortality by APOE-ε4 genotype. Methods- We included 943 FHS (Framingham Heart Study) and 1406 3C (Three-City) Bordeaux Study participants. Plasma docosahexaenoic, linoleic, arachidonic, and palmitic fatty acids were measured at baseline by gas chromatography. All-cause stroke, ischemic stroke, coronary heart disease, and all-cause mortality events were identified prospectively using standardized protocols. Each cohort used Cox models to separately relate fatty acid levels to the risk of developing each event during ≤10 years of follow-up adjusting for potential confounders and stratifying by APOE genotype (ε4 carriers versus noncarriers). We then meta-analyzed summary statistics using random-effects models. Results- On average, participants had a mean age of 74 years, 61% were women, and 21% (n=483) were APOE-ε4 carriers. Meta-analysis results showed that, only among APOE-ε4 carriers, every SD unit increase in linoleic acid was associated with a reduced risk of all-cause stroke (hazard ratio [HR], 0.54 [95% CI, 0.38-0.78]), ischemic stroke (HR, 0.48 [95% CI, 0.33-0.71]), and all-cause mortality (HR, 0.70 [95% CI, 0.57-0.85]). In contrast, every SD unit increase in palmitic acid was related to an increased risk of all-cause stroke (HR, 1.58 [95% CI, 1.16-2.17]), ischemic stroke (HR, 1.76 [95% CI, 1.26-2.45]), and coronary heart disease (HR, 1.48 [95% CI, 1.09-2.01]), also in APOE-ε4 carriers only. Results for docosahexaenoic acid and arachidonic acid were heterogeneous between cohorts. Conclusions- These exploratory results suggest that APOE-ε4 carriers may be more susceptible to the beneficial or adverse impact of fatty acids on cardiovascular disease and mortality. In this subgroup, higher linoleic acid was protective for stroke and mortality, whereas palmitic acid was a risk factor for stroke and coronary heart disease. The mechanisms underlying these novel findings warrant further investigation.

Do Intracerebral Hemorrhage Nonexpanders Actually Expand Into the Ventricular Space?

BACKGROUND AND PURPOSE: The computed tomographic angiography spot sign as a predictor of hematoma expansion is limited by its modest sensitivity and positive predictive value. It is possible that hematoma expansion in spot-positive patients is missed because of decompression of intracerebral hemorrhage (ICH) into the ventricular space. We hypothesized that revising hematoma expansion definitions to include intraventricular hemorrhage (IVH) expansion will improve the predictive performance of the spot sign. Our objectives were to determine the proportion of ICH nonexpanders who actually have IVH expansion, determine the proportion of false-positive spot signs that have IVH expansion, and compare the known predictive performance of the spot sign to a revised definition incorporating IVH expansion. METHODS: We analyzed patients from the multicenter PREDICT ICH spot sign study. We defined hematoma expansion as ≥6 mL or ≥33% ICH expansion or >2 mL IVH expansion and compared spot sign performance using this revised definition with the conventional 6 mL/33% definition using receiver operating curve analysis. RESULTS: Of 311 patients, 213 did not meet the 6-mL/33% expansion definition (nonexpanders). Only 13 of 213 (6.1%) nonexpanders had ≥2 mL IVH expansion. Of the false-positive spot signs, 4 of 40 (10%) had >2 mL ventricular expansion. The area under the curve for spot sign to predict significant ICH expansion was 0.65 (95% confidence interval, 0.58-0.72), which was no different than when IVH expansion was added to the definition (area under the curve, 0.66; 95% confidence interval, 0.58-0.71). CONCLUSIONS: Although IVH expansion does indeed occur in a minority of ICH nonexpanders, its inclusion into a revised hematoma expansion definition does not alter the predictive performance of the spot sign.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke.

Lack of Early Improvement Predicts Poor Outcome Following Acute Intracerebral Hemorrhage.

OBJECTIVES: There are limited data as to what degree of early neurologic change best relates to outcome in acute intracerebral hemorrhage. We aimed to derive and validate a threshold for early postintracerebral hemorrhage change that best predicts 90-day outcomes. DESIGN: Derivation: retrospective analysis of collated clinical stroke trial data (Virtual International Stroke Trials Archive). VALIDATION: retrospective analysis of a prospective multicenter cohort study (Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign [PREDICT]). SETTING: Neurocritical and ICUs. PATIENTS: Patients with acute intracerebral hemorrhage presenting less than 6 hours. Derivation: 552 patients; validation: 275 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We generated a receiver operating characteristic curve for the association between 24-hour National Institutes of Health Stroke Scale change and clinical outcome. The primary outcome was a modified Rankin Scale score of 4-6 at 90 days; secondary outcomes were other modified Rankin Scale score ranges (modified Rankin Scale, 2-6, 3-6, 5-6, 6). We employed Youden's J Index to select optimal cut points and calculated sensitivity, specificity, and predictive values. We determined independent predictors via multivariable logistic regression. The derived definitions were validated in the PREDICT cohort. Twenty-four-hour National Institutes of Health Stroke Scale change was strongly associated with 90-day outcome with an area under the receiver operating characteristic curve of 0.75. Youden's method showed an optimum cut point at -0.5, corresponding to National Institutes of Health Stroke Scale change of greater than or equal to 0 (a lack of clinical improvement), which was seen in 46%. Early neurologic change accurately predicted poor outcome when defined as greater than or equal to 0 (sensitivity, 65%; specificity, 73%; positive predictive value, 70%; adjusted odds ratio, 5.05 [CI, 3.25-7.85]) or greater than or equal to 4 (sensitivity, 19%; specificity, 98%; positive predictive value, 91%; adjusted odds ratio, 12.24 [CI, 4.08-36.66]). All definitions reproduced well in the validation cohort. CONCLUSIONS: Lack of clinical improvement at 24 hours robustly predicted poor outcome and showed good discrimination for individual patients who would do poorly. These findings are useful for prognostication and may also present as a potential early surrogate outcome for future intracerebral hemorrhage treatment trials.

Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, mortality, and treatment interactions.

OBJECTIVE: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment. METHODS: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs <130mmHg; open label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1,278 trial participants who had a baseline axial T2*-weighted gradient echo MRI sequence allowing for CMB detection. RESULTS: CMBs were present in 30% of 1,278 patients (mean age = 63 years). Male gender (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.3), history of hypertension (OR = 1.6, 95% CI = 1.2-2.3), increased systolic blood pressure (1.2 per 20mmHg, 95% CI = 1.1-1.4), nondiabetic status (OR = 1.4, 95% CI = 1.1-1.9), multiple old lacunar infarcts (OR = 1.9, 95% CI = 1.5-2.5), and moderate (OR = 1.7, 95% CI = 1.2-2.3) or severe (OR = 4.2, 95% CI = 3.0-5.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 years, overall stroke recurrence was 2.5% per patient-year. Patients with CMBs had an adjusted 2-fold increased risk of recurrent stroke (hazard ratio = 2.1, 95% CI = 1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments. INTERPRETATION: Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies. Ann Neurol 2017;82:196-207.

Cerebral Microbleeds as Predictors of Mortality: The Framingham Heart Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) represent a common magnetic resonance imaging marker of cerebral small vessel disease, increasingly recognized as a subclinical marker of stroke and dementia risk. CMB detection may reflect the cumulative effect of vascular risk burden and be a marker of higher mortality. We investigated the relation of CMB to risk of death in community dwelling participants free of stroke and dementia. METHODS: We evaluated 1963 Framingham Original and Offspring Cohort participants (mean age 67 years; 54% women) with available brain magnetic resonance imaging and mortality data. Using Cox proportional hazards models, we related CMB to all-cause, cardiovascular, and stroke-related mortality. RESULTS: Participants with CMB (8.9%) had higher prevalence of cardiovascular risk factors and use of preventive medications. During a mean follow-up of 7.2±2.6 years, we observed 296 deaths. In age- and sex-adjusted analysis, CMB were associated with increased all-cause mortality (hazards ratio, 1.39; 95% confidence interval 1.03-1.88), a relation that was no longer significant after adjustment for cardiovascular risk and preventive medication use (hazards ratio, 1.15; 95% confidence interval, 0.82-1.63). CONCLUSIONS: CMBs may represent the deleterious effect of cardiovascular risk factors in the cerebral vasculature. Although their presence was associated with increased all-cause mortality, the effect was no longer present after accounting for vascular risk factors and preventive treatment use. Further studies are required to clarify the role of cardiovascular preventive therapies for prevention of mortality in persons with incidental detection of CMB.

Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study.

BACKGROUND AND PURPOSE: Low insulin-like growth factor 1 (IGF-1) has been associated with increased risk of atherosclerosis and atrial fibrillation in cross-sectional studies. Yet, prospective data linking IGF-1 levels to the development of ischemic stroke remain inconclusive. We examined prospectively the association between serum IGF-1 levels and incident ischemic stroke. METHODS: We measured serum IGF-1 levels in 757 elderly individuals (mean age 79±5, 62% women), free of prevalent stroke, from the Framingham original cohort participants at the 22nd examination cycle (1990-1994) and were followed up for the development of ischemic stroke. Cox models were used to relate IGF-1 levels to the risk for incident ischemic stroke, adjusted for potential confounders. RESULTS: During a mean follow-up of 10.2 years, 99 individuals developed ischemic stroke. After adjustment for age, sex, and potential confounders, higher IGF-1 levels were associated with a lower risk of incident ischemic stroke, with subjects in the lowest quintile of IGF-1 levels having a 2.3-fold higher risk of incident ischemic stroke (95% confidence interval, 1.09-5.06; P=0.03) as compared with those in the top quintile. We observed an effect modification by diabetes mellitus and waist-hip ratio for the association between IGF-1 and ischemic stroke (P<0.1). In subgroup analyses, the effects were restricted to subjects with diabetics and those in top waist-hip ratio quartile, in whom each standard deviation increase in IGF-1 was associated with a 61% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P=0.007) and 41% (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P=0.031) lower risk of incident ischemic stroke, respectively. CONCLUSIONS: IGF-1 levels were inversely associated with ischemic stroke, especially among persons with insulin resistance.

Stroke as the Initial Manifestation of Atrial Fibrillation: The Framingham Heart Study.

BACKGROUND AND PURPOSE: To prevent strokes that may occur as the first manifestation of atrial fibrillation (AF), screening programs have been proposed to identify patients with undiagnosed AF who may be eligible for treatment with anticoagulation. However, the frequency with which patients with AF present with stroke as the initial manifestation of the arrhythmia is unknown. METHODS: We estimated the frequency with which AF may present as a stroke in 1809 community-based Framingham Heart Study participants with first-detected AF and without previous strokes, by tabulating the frequencies of strokes occurring on the same day, within 30 days before, 90 days before, and 365 days before first-detected AF. Using previously reported AF incidence rates, we estimated the incidence of strokes that may represent the initial manifestation of AF. RESULTS: We observed 87 strokes that occurred ≤1 year before AF detection, corresponding to 1.7% on the same day, 3.4% within 30 days before, 3.7% within 90 days before, and 4.8% ≤1 year before AF detection. We estimated that strokes may present as the initial manifestation of AF at a rate of 2 to 5 per 10 000 person-years, in both men and women. CONCLUSIONS: We observed that stroke is an uncommon but measureable presenting feature of AF. Our data imply that emphasizing cost-effectiveness of population-wide AF-screening efforts will be important given the relative infrequency with which stroke represents the initial manifestation of AF.

Cerebellar stroke presenting with isolated dizziness: Brain MRI in 136 patients.

OBJECTIVE: To evaluate occurrence of cerebellar stroke in Emergency Department (ED) presentations of isolated dizziness (dizziness with a normal exam and negative neurological review of systems). METHODS: A 5-year retrospective study of ED patients presenting with a chief complaint of "dizziness or vertigo", without other symptoms or signs in narrative history or on exam to suggest a central nervous system lesion, and work-up included a brain MRI within 48h. Patients with symptoms commonly peripheral in etiology (nystagmus, tinnitus, gait instability, etc.) were included in the study. Patient demographics, stroke risk factors, and gait assessments were recorded. RESULTS: One hundred and thirty-six patients, who had a brain MRI for isolated dizziness, were included. There was a low correlation of gait assessment between ED physician and Neurologist (49 patients, Spearman's correlation r2=0.17). Based on MRI DWI sequence, 3.7% (5/136 patients) had acute cerebellar strokes, limited to or including, the medial posterior inferior cerebellar artery vascular territory. In the 5 cerebellar stroke patients, mean age, body mass index (BMI), hemoglobin A1c, gender distribution, and prevalence of hypertension were similar to the non-cerebellar stroke patient group. Mean LDL/HDL ratio was 3.63±0.80 and smoking prevalence was 80% in the cerebellar stroke group compared to 2.43±0.79 and 22% (respectively, p values<0.01) in the non-cerebellar stroke group. CONCLUSIONS: Though there was preselection bias for stroke risk factors, our study suggests an important proportion of cerebellar stroke among ED patients with isolated dizziness, considering how common this complaint is.

Association of Ideal Cardiovascular Health With Vascular Brain Injury and Incident Dementia.

BACKGROUND AND PURPOSE: The American Heart Association developed the ideal cardiovascular health (CVH) index as a simple tool to promote CVH; yet, its association with brain atrophy and dementia remains unexamined. METHODS: Our aim was to investigate the prospective association of ideal CVH with vascular brain injury, including the 10-year risks of incident stroke and dementia, as well as cognitive decline and brain atrophy on magnetic resonance imaging, measured for ≈7 years. We studied 2750 stroke- and dementia-free Framingham Heart Study Offspring cohort participants (mean age, 62±9 years; 45% men). Ideal CVH was quantified on a 7-point scale with 1 point awarded for each of the following: nonsmoking status, ideal body mass index, regular physical activity, healthy diet, as well as optimum blood pressure, cholesterol, and fasting blood glucose. Both recent (baseline) and remote (6.9 years earlier) ideal CVH scores were examined. RESULTS: Recent ideal CVH was associated with stroke (hazard ratio, 0.80; 95% confidence interval, 0.67-0.95), vascular dementia (hazard ratio, 0.49; 95% confidence interval, 0.30-0.81), frontal brain atrophy (P=0.003), and cognitive decline on tasks measuring visual memory and reasoning (P<0.05). In addition to predicting stroke, vascular dementia, whole-brain atrophy, and cognitive decline, remote ideal CVH was associated with the incidence of all-cause dementia (hazard ratio, 0.80; 95% confidence interval, 0.67-0.97) and Alzheimer disease (hazard ratio, 0.79; 95% confidence interval, 0.64-0.98). CONCLUSIONS: Adherence to the American Heart Association's ideal CVH factors and behaviors, particularly in midlife, may protect against cerebrovascular disease and dementia.

Perihematomal Edema Is Greater in the Presence of a Spot Sign but Does Not Predict Intracerebral Hematoma Expansion.

BACKGROUND AND PURPOSE: Perihematomal edema volume may be related to intracerebral hemorrhage (ICH) volume at baseline and, consequently, with hematoma expansion. However, the relationship between perihematomal edema and hematoma expansion has not been well established. We aimed to investigate the relationship among baseline perihematomal edema, the computed tomographic angiography spot sign, hematoma expansion, and clinical outcome in patients with acute ICH. METHODS: Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT) was a prospective observational cohort study of ICH patients presenting within 6 hours from onset. Patients underwent computed tomography and computed tomographic angiography scans at baseline and 24-hour computed tomography scan. A post hoc analysis of absolute perihematomal edema and relative perihematomal edema (absolute perihematomal edema divided by ICH) volumes was performed on baseline computed tomography scans (n=353). Primary outcome was significant hematoma expansion (>6 mL or >33%). Secondary outcomes were early neurological deterioration, 90-day mortality, and poor outcome. RESULTS: Absolute perihematomal edema volume was higher in spot sign patients (24.5 [11.5-41.8] versus 12.6 [6.9-22] mL; P<0.001), but it was strongly correlated with ICH volume (ρ=0.905; P<0.001). Patients who experienced significant hematoma expansion had higher absolute perihematomal edema volume (18.4 [10-34.6] versus 11.8 [6.5-22] mL; P<0.001) but similar relative perihematomal edema volume (1.09 [0.89-1.37] versus 1.12 [0.88-1.54]; P=0.400). Absolute perihematomal edema volume and poorer outcomes were higher by tertiles of ICH volume, and perihematomal edema volume did not independently predict significant hematoma expansion. CONCLUSIONS: Perihematomal edema volume is greater at baseline in the presence of a spot sign. However, it is strongly correlated with ICH volume and does not independently predict hematoma expansion.