Vol 50, No 10 | Stroke

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Background and Purpose—
Genome-wide association studies have identified the HDAC9 (histone deacetylase 9) gene region as a major risk locus for atherosclerotic stroke and coronary artery disease in humans. Previous results suggest a role of altered HDAC9 expression levels as the underlying disease mechanism. rs2107595, the lead single nucleotide polymorphism for stroke and coronary artery disease resides in noncoding DNA and colocalizes with histone modification marks suggestive of enhancer elements.

Methods—
To determine the mechanisms by which genetic variation at rs2107595 regulates HDAC9 expression and thus vascular risk we employed targeted resequencing, proteome-wide search for allele-specific nuclear binding partners, chromatin immunoprecipitation, genome-editing, reporter assays, circularized chromosome conformation capture, and gain- and loss-of-function experiments in cultured human cell lines and primary immune cells.

Results—
Targeted resequencing of the HDAC9 locus in patients with atherosclerotic stroke and controls supported candidacy of rs2107595 as the causative single nucleotide polymorphism. A proteomic search for nuclear binding partners revealed preferential binding of the E2F3/TFDP1/Rb1 complex (E2F transcription factor 3/transcription factor Dp-1/Retinoblastoma 1) to the rs2107595 common allele, consistent with the disruption of an E2F3 consensus site by the risk allele. Gain- and loss-of-function studies showed a regulatory effect of E2F/Rb proteins on HDAC9 expression. Compared with the common allele, the rs2107595 risk allele exhibited higher transcriptional capacity in luciferase assays and was associated with higher HDAC9 mRNA levels in primary macrophages and genome-edited Jurkat cells. Circularized chromosome conformation capture revealed a genomic interaction of the rs2107595 region with the HDAC9 promoter, which was stronger for the common allele as was the in vivo interaction with E2F3 and Rb1 determined by chromatin immunoprecipitation. Gain-of-function experiments in isogenic Jurkat cells demonstrated a key role of E2F3 in mediating rs2107595-dependent transcriptional regulation of HDAC9.

Conclusions—
Collectively, our findings imply allele-specific transcriptional regulation of HDAC9 via E2F3 and Rb1 as a major mechanism mediating vascular risk at rs2107595.

Stroke Incidence and Case Fatality According to Rural or Urban Residence

Results From the French Brest Stroke Registry

Stroke. 2019 | Volume 50, Issue 10: 2661–2667,

originally publishedSeptember 4, 2019,

https://doi.org/10.1161/STROKEAHA.118.024695

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Background and Purpose—
Recent findings suggest that in the United States, stroke incidence is higher in rural than in urban areas. Similar analyses in other high-income countries are scarce with conflicting results. In 2008, the Brest Stroke Registry was started in western France, an area that includes about 366 000 individuals living in various urban and rural settings.

Methods—
All new patients with stroke included in the Brest Stroke Registry from 2008 to 2013 were classified as residing in town centers, suburbs, isolated towns, or rural areas. Poisson regression was used to analyze stroke incidence and 30-day case fatality variations in the 4 different residence categories. Models with case fatality as outcome were adjusted for age, stroke type, and stroke severity.

Results—
In total, 3854 incident stroke cases (n=2039 women, 53%) were identified during the study period. Demographic and socio-economic characteristics and primary healthcare access indicators were significantly different among the 4 residence categories. Patterns of risk factors, stroke type, and severity were comparable among residence categories in both sexes. Age-standardized stroke rates varied from 2.90 per thousand (95% CI, 2.59–3.21) in suburbs to 3.35 (95% CI, 2.98–3.73) in rural areas for men, and from 2.14 (95% CI, 2.00–2.28) in town centers to 2.34 (95% CI, 2.12–2.57) in suburbs for women. Regression models suggested that among men, stroke incidence was significantly lower in suburbs than in town centers (incidence rate ratio =0.87; 95% CI, 0.77–0.99). Case fatality risk was comparable across urban categories but lower in rural patients (relative risk versus town centers: 0.76; 95% CI, 0.60–0.96).

Conclusions—
Stroke incidence was comparable, and the 30-day case fatality only slightly varied in the 4 residence categories despite widely different socio-demographic features covered by the Brest Stroke Registry.

Brain Activity and Cerebral Oxygenation After Perinatal Arterial Ischemic Stroke Are Associated With Neurodevelopment

Stroke. 2019 | Volume 50, Issue 10: 2668–2676,

originally publishedAugust 8, 2019,

https://doi.org/10.1161/STROKEAHA.119.025346

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Background and Purpose—
In infants with perinatal arterial ischemic stroke (PAIS), early prognosis of neurodevelopmental outcome is important to adequately inform parents and caretakers. Early continuous neuromonitoring after PAIS may improve early prognosis. Our aim was to study early cerebral electrical activity and oxygenation measured by amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy in term neonates with PAIS and relate these to the development of cerebral palsy and cognitive deficit.

Methods—
aEEG patterns and regional cerebral oxygen saturation (rScO₂) levels of both hemispheres were studied for 120 hours from the first clinical symptoms of PAIS (ie, seizures) onward. Multivariable analyses were used to investigate the association between aEEG, near-infrared spectroscopy, clinical variables, and neurodevelopmental outcome.

Results—
In 52 patients with PAIS (gestational age, 40.4±1.4 weeks; birth weight, 3282±479 g), median time to a continuous background pattern was longer in the ipsilesional compared with the contralesional hemisphere (13.5 versus 10.0 hours; P<0.05). rScO₂ decreased over time in both hemispheres but less in the ipsilesional one, resulting in a rScO₂ asymmetry ratio of 4.5% (interquartile range, −4.3% to 5.9%; P<0.05) between hemispheres from day 3 after symptoms onward. Both time to normal background pattern and asymmetry in rScO₂ were negatively affected by gestational age, size of the PAIS, use of antiepileptic drugs, and mechanical ventilation. After correction for size of the PAIS on magnetic resonance imaging, a slower recovery of background pattern on ipsilesional aEEG and increased rScO₂ asymmetry between hemispheres was related with an increased risk for cognitive deficit (<−1 SD) at a median of 24.0 (interquartile range, 18.4–24.4) months of age.

Conclusions—
Recovery of background pattern on aEEG and cerebral oxygenation are both affected by PAIS and related to neurocognitive development. Both measurements may provide valuable early prognostic information. Additionally, monitoring cerebral activity and oxygenation may be useful in identifying infants eligible for early neuroprotective interventions and to detect early effects of these interventions.

Blood Pressure Drop and Penumbral Tissue Loss in Nonrecanalized Emergent Large Vessel Occlusion

Stroke. 2019 | Volume 50, Issue 10: 2677–2684,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.025426

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Background and Purpose—
For patients with emergent large vessel occlusion who may not benefit from timely recanalization treatment, maintaining adequate cerebral perfusion to prevent penumbral tissue loss is a key therapeutic strategy. Cerebral perfusion should be proportional to systemic blood pressure (BP) due to the loss of autoregulation properties in ischemic brain tissue. We hypothesized that acute fluctuations in BP would lead to aggravated penumbral tissue loss in persistent large vessel occlusion.

Methods—
A total of 80 patients with persistent large vessel occlusion of internal carotid artery or middle cerebral artery admitted within 24 hours after onset, and with a baseline, National Institutes of Health Stroke Scale score ≥4-point were included. Baseline and follow-up (median 88 hours) magnetic resonance images were analyzed, and penumbra was defined as the T_max>6 s region excluding baseline infarction. The hypoperfusion intensity ratio (T_max>10 s/T_max>6 s) was calculated within the penumbra. Penumbral tissue loss (%) was defined as the proportion of follow-up infarct in the penumbra. With serial BP measurements in the first 24 hours (median 29, interquartile range 26–35), BP and BP variability parameters, including BP_dropmax (change from local maxima to minima), were calculated and compared. Generalized linear models were applied to examine the association between BP parameters and the penumbral tissue loss.

Results—
The median penumbral volume was 79.3 mL (interquartile range, 38.2–129.6) and median penumbral tissue loss was 36.7% (interquartile range, 12.0–56.1). In a multivariable analysis, systolic BP (SBP) SBP_dropmax (β±SE of fourth quartile, 17.82±6.58; P value, 0.01) and diastolic BP (DBP) DBP_dropmax (β±SE of fourth quartile, 14.04±6.38; P value, 0.01) were associated with increasing penumbral tissue loss, independently of age, baseline infarction and hypoperfusion intensity ratio. DBP_incmax, SBP_max, DBP_max, SBP_max-min, DBP_max-min, and most of the DBP variability indices were associated with penumbral tissue loss.

Conclusions—
BP fluctuations, even a brief and drastic BP drop in the first 24 hours, significantly contributed to penumbral tissue loss irrespective of baseline hypoperfusion.

Infection During Delivery Hospitalization and Risk of Readmission for Postpartum Stroke

Stroke. 2019 | Volume 50, Issue 10: 2685–2691,

originally publishedAugust 15, 2019,

https://doi.org/10.1161/STROKEAHA.119.025970

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Background and Purpose—
Most cases of pregnancy-related ischemic stroke (IS) and hemorrhagic stroke (HS) occur postpartum. Infections have been identified as a trigger for strokes in young people and have been associated with strokes during delivery hospitalizations, but a temporal relationship has been difficult to establish. We hypothesized that infections diagnosed during a delivery admission would be associated with an increased risk of readmission for postpartum stroke.

Methods—
We conducted a retrospective cohort study using the Healthcare Cost and Utilization Project’s National Readmissions Database from 2010 to 2014. Using weighted survey design Poisson regression analysis, we calculated adjusted risk ratios (aRR) and 95% CI for the association between infection during delivery admission and 30-day postpartum readmission for IS or HS.

Results—
Out of 17.2 million delivery admissions during the study period, 2128 were readmitted within 30 days for a stroke of any type. There were 1189 HS (intracerebral hemorrhage or subarachnoid hemorrhage) and 720 IS, and the remainder unspecified pregnancy-related stroke. Adjusting for age and comorbidities, women with delivery infections were at higher risk of readmission for postpartum stroke of any type (aRR, 1.19; 95% CI, 1.01–1.41). Women with infections had higher risk of readmission for postpartum IS (aRR, 1.75; 95% CI, 1.37–2.22), but not for postpartum HS (aRR, 0.96; 95% CI, 0.75–1.23). The effect of infection on 30-day IS readmission was larger in women without hypertensive disorders of pregnancy (aRR, 2.0; 95% CI, 1.55–2.69 in women without hypertensive disorders of pregnancy versus aRR, 1.47; 95% CI, 0.9–2.38 in women with hypertensive disorders of pregnancy, P value for interaction=0.09).

Conclusions—
Infection during delivery hospitalization was associated with increased risk of readmission for IS, but not HS, within 30 days postpartum, particularly in women without hypertensive disorders of pregnancy. Infection may play a role in triggering postpartum IS even in the absence of other risk factors.

Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Disease

Classification and Clinical Implications

Stroke. 2019 | Volume 50, Issue 10: 2692–2699,

originally publishedAugust 14, 2019,

https://doi.org/10.1161/STROKEAHA.119.025732

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Background and Purpose—
In patients with symptomatic intracranial atherosclerotic stenosis, identifying the underlying stroke mechanisms may inform secondary prevention. We aimed to propose reproducible classification criteria for stroke mechanisms based on routine neuroimaging in symptomatic intracranial atherosclerotic stenosis and explore their clinical implications.

Methods—
We recruited patients with acute ischemic stroke attributed to 50% to 99% intracranial atherosclerotic stenosis in anterior circulation from 2 centers. Two investigators independently classified probable stroke mechanisms as parent artery atherosclerosis occluding penetrating artery, artery-to-artery embolism, hypoperfusion, and mixed mechanisms, with prespecified criteria based on infarct topography and magnetic resonance/computed tomography angiography. These stroke mechanisms were correlated with features of the patients at baseline and recurrent ischemic stroke in the same territory or relevant transient ischemic attack within 1 year.

Results—
Among 153 patients recruited, the most common stroke mechanisms were isolated hypoperfusion (35.3%) and mixed mechanism of artery-to-artery embolism and hypoperfusion (37.3%) that was associated with higher incidence of dyslipidemia (P=0.045) and hypertension (P=0.033) than patients with other stroke mechanisms. The proposed criteria showed substantial to excellent intrarater and interrater reproducibilities (κ, 0.791–0.908). Overall, 31 patients received interventional treatment of the diseased intracranial artery; 122 received medical treatment, among whom a mixed mechanism of artery-to-artery embolism and hypoperfusion at baseline was associated with higher risk of ischemic stroke in the same territory within 1 year (24.4% versus 7.8%; hazard ratio, 3.40; 95% CI, 1.25–9.20; log-rank P=0.010) than other mechanisms combined.

Conclusions—
Artery-to-artery embolism and hypoperfusion commonly coexist in ischemic stroke attributed to intracranial atherosclerotic stenosis, which may be associated with higher risk of stroke relapse.

Degeneration of the Inferior Cerebellar Peduncle After Middle Cerebral Artery Stroke

Another Perspective on Crossed Cerebellar Diaschisis

Stroke. 2019 | Volume 50, Issue 10: 2700–2707,

originally publishedAugust 26, 2019,

https://doi.org/10.1161/STROKEAHA.119.025723

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Background and Purpose—
Deafferentation of the cortico-ponto-cerebellar pathway has been proposed as a key mechanism of crossed cerebellar diaschisis. Although the cerebellum receives afferent stimuli from both cortico-ponto-cerebellar and spinocerebellar pathways, evidence on whether spinocerebellar deafferentation contributes to a hypofunctional cerebellum is lacking. Therefore, we aimed to determine whether changes in the spinocerebellar pathway occur after middle cerebral artery stroke.

Methods—
Twenty-three patients admitted to our inpatient rehabilitation facility and 23 age-matched healthy controls were retrospectively enrolled. Patients’ functional ambulation category was determined and the Medical Research Council muscle scale test of the lower limb muscles was performed at admission and discharge. The fractional anisotropy (FA) values of the corticospinal tract and the inferior cerebellar peduncle (ICP), as the final route of the dorsal spinocerebellar pathway, were compared between the groups. The FA laterality indices of the ICP and corticospinal tract were calculated as follows: (FA_affected−FA_unaffected)/(FA_affected+FA_unaffected). Pearson correlation analysis and multivariate linear regression models were used to determine the associations between the FA laterality indices and ambulatory function.

Results—
The FAs of the corticospinal tract and ICP were lower in the patient group than in the control group. The FA laterality index of the corticospinal tract was not correlated with the functional ambulation category or Medical Research Council muscle scale score at admission or discharge. The FA laterality index of the ICP at the pontomedullary junction was positively correlated with the functional ambulation category and Medical Research Council muscle scale scores of all hemiplegic lower limb muscles at admission and discharge. The FA laterality index of the ICP at the pontomedullary junction was independently associated with the functional ambulation category according to the multivariate regression models.

Conclusions—
ICP degeneration occurs in the subacute and early chronic phase of middle cerebral artery stroke. The lower FA laterality index of the ICP was indicative of poorer ambulatory and lower limb function.

Collateral Circulation in Moyamoya Disease

A New Grading System

Stroke. 2019 | Volume 50, Issue 10: 2708–2715,

originally publishedAugust 14, 2019,

https://doi.org/10.1161/STROKEAHA.119.024487

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Background and Purpose—
Predicting the risk of stroke and determining intervention indications are highly important for patients with Moyamoya disease (MMD). Here, we evaluated a novel MMD grading system based on collateral circulation and Suzuki stage to evaluate symptoms and predict prognosis.

Methods—
In total, 301 idiopathic MMD patients were retrospectively analyzed between 2014 and 2016. A collateral circulation grading system with scores ranging from 1 to 12 was established: the anatomic extent of pial collateral blood flow from posterior cerebral artery to middle cerebral artery and anterior cerebral artery was scored from 1 to 6; perforator collateral and internal cerebral artery flow were scored as 6 to 1, which corresponded to Suzuki stages 1 to 6. Dynamic susceptibility contrast–magnetic resonance imaging was used to evaluate hemodynamic status. We assessed the association between the grading system and clinical characteristics.

Results—
We analyzed 364 symptomatic hemispheres of 301 patients (146 males, 28±16 years). Ischemic patients who presented with infarction were more likely to score <8 points (P<0.001), whereas those with ischemia symptoms (transient ischemic attack and headache) were more likely to score >8 points. Hemorrhagic patients who presented with intraparenchymal hemorrhage were more likely to score <8 points, whereas those who presented with intraventricular hemorrhage were more likely to score >8 points (P<0.001). According to dynamic susceptibility contrast–magnetic resonance imaging, lower scores were correlated with more severe time to peak delay (P<0.001) and worse relative cerebral blood volume ratio (P=0.016) and cerebral flow ratio (P=0.002). Encephaloduroarteriosynangiosis was performed in 348 symptomatic hemispheres. Patients who had collateral scores <4 points were more likely to have a postoperative stroke and a worse prognosis during the follow-up.

Conclusions—
This new MMD collateral grading system correlated well with clinical symptoms, hemodynamic status, and therapeutic prognosis and may facilitate risk stratification and prognosis predictions in patients with MMD.

Early Fibrinogen Depletion and Symptomatic Intracranial Hemorrhage After Reperfusion Therapy

Stroke. 2019 | Volume 50, Issue 10: 2716–2721,

originally publishedAugust 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.025711

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Background and Purpose—
We aimed to thoroughly investigate the relationship between early fibrinogen depletion and symptomatic intracranial hemorrhage (sICH) in patients receiving reperfusion therapy including intravenous thrombolysis (IVT) with or without endovascular thrombectomy (EVT).

Methods—
This study included 1135 stroke patients with baseline and follow-up fibrinogen levels at 2 hours after the beginning of alteplase infusion for those with IVT only or immediately after the end of EVT for those with combined IVT and EVT. Patients received alteplase up to 9 hours after the onset or on awakening based on automated perfusion imaging. sICH was ascertained using ECASS II (The Second European-Australasian Acute Stroke Study) criteria. Δfibrinogen was calculated as follow-up fibrinogen minus baseline fibrinogen.

Results—
In patients with IVT only, baseline fibrinogen level was 3.36±0.94 g/L and decreased to 2.47±0.80 g/L at 2 hours after the beginning of alteplase infusion. In patients with IVT followed by EVT, baseline fibrinogen level was 3.35±0.82 g/L and decreased to 2.52±0.83 g/L immediately after the end of EVT. sICH was observed in 44 (3.9%) patients. The extent of Δfibrinogen was associated with sICH in patients with IVT only (odds ratio, 1.929; 95% CI, 1.402–2.654; P<0.001) and in those with IVT followed by EVT (odds ratio, 1.765; 95% CI, 1.135–2.743; P=0.012).

Conclusions—
An early decrease in fibrinogen levels was related to sICH after reperfusion therapy with alteplase. More fibrin-specific thrombolytic agents are warranted to be tested in acute ischemic stroke patients.

Clinical Trial Registration—
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03367286.

Impact of Cerebral Small Vessel Disease on Functional Recovery After Intracerebral Hemorrhage

Stroke. 2019 | Volume 50, Issue 10: 2722–2728,

originally publishedAugust 26, 2019,

https://doi.org/10.1161/STROKEAHA.119.025061

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Background and Purpose—
In this study, we aim to investigate the association of computed tomography–based markers of cerebral small vessel disease with functional outcome and recovery after intracerebral hemorrhage.

Methods—
Computed tomographic scans of patients in the ERICH study (Ethnic and Racial Variations of Intracerebral Hemorrhage) were evaluated for the extent of leukoaraiosis and cerebral atrophy using visual rating scales. Poor functional outcome was defined as a modified Rankin Scale (mRS) of ≥3. Multivariable logistic and linear regression models were used to explore the associations of cerebral small vessel disease imaging markers with poor functional outcome at discharge and, as a measure of recovery, change in mRS from discharge to 90 days poststroke.

Results—
After excluding in-hospital deaths, data from 2344 patients, 583 (24.9%) with good functional outcome (mRS of 0–2) at discharge and 1761 (75.1%) with poor functional outcome (mRS of 3–5) at discharge, were included. Increasing extent of leukoaraiosis (P for trend, 0.01) and only severe (grade 4) global atrophy (odds ratio, 2.02; 95% CI, 1.22–3.39, P=0.007) were independently associated with poor functional outcome at discharge. Mean (SD) mRS change from discharge to 90-day follow-up was 0.57 (1.18). Increasing extent of leukoaraiosis (P for trend, 0.002) and severe global atrophy (β [SE], −0.23 [0.115]; P=0.045) were independently associated with less improvement in mRS from discharge to 90 days poststroke.

Conclusions—
In intracerebral hemorrhage survivors, the extent of cerebral small vessel disease at the time of intracerebral hemorrhage is associated with poor functional outcome at hospital discharge and impaired functional recovery from discharge to 90 days poststroke.

Deviation From Personalized Blood Pressure Targets Is Associated With Worse Outcome After Subarachnoid Hemorrhage

Stroke. 2019 | Volume 50, Issue 10: 2729–2737,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.026282

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Background and Purpose—
Optimal blood pressure (BP) management during the early stages of aneurysmal subarachnoid hemorrhage remains uncertain. Observational studies have found worse outcomes in patients with increased hemodynamic variability, suggesting BP optimization as a potential neuroprotective strategy. In this study, we calculated personalized BP targets at which cerebral autoregulation was best preserved. We analyzed how deviation from these limits correlates with functional outcome.

Methods—
We prospectively enrolled 31 patients with aneurysmal subarachnoid hemorrhage. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy (NIRS)-derived tissue oxygenation—a surrogate for cerebral blood flow—as well as intracranial pressure (ICP) in response to changes in mean arterial pressure using time-correlation analysis. The resulting autoregulatory indices were used to identify the upper and lower limit of autoregulation. Percent time that mean arterial pressure exceeded limits of autoregulation was calculated for each patient. Functional outcome was assessed using the modified Rankin Scale at discharge and 90 days. Associations with outcome were analyzed using ordinal multivariate logistic regression.

Results—
Personalized limits of autoregulation were computed in all patients (age 57.5±13.4, 23F, mean World Federation of Neurological Surgeons 2±1, monitoring time 67.8±50.8 hours). Optimal BP and limits of autoregulation were calculated on average for 89.5±6.7% of the total monitoring period. ICP- and NIRS-derived optimal pressures strongly correlated with one another (P<0.0001). Percent time that mean arterial pressure deviated from limits of autoregulation significantly associated with worse functional outcome at discharge (NIRS, P=0.001; ICP, P=0.004) and 90 days (NIRS, P=0.002; ICP, P=0.003), adjusting separately for age, World Federation of Neurological Surgeons, vasospasm, and delayed cerebral ischemia.

Conclusions—
Both invasive (ICP) and noninvasive (NIRS) determination of personalized BP targets after aneurysmal subarachnoid hemorrhage is feasible, and these 2 approaches revealed significant collinearity. Furthermore, exceeding individualized limits of autoregulation was associated with poor functional outcomes.

Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage

Stroke. 2019 | Volume 50, Issue 10: 2738–2744,

originally publishedAugust 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.025682

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Background and Purpose—
Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH), although no effect on long-term functional outcome has been demonstrated. Thick clot on initial computed tomography is associated with an increased risk of vasospasm and delayed cerebral ischemia. In this post hoc analysis, we hypothesized that use of clazosentan in this subpopulation would provide stronger benefit.

Methods—
We analyzed SAH patients enrolled in the CONSCIOUS-2 and CONSCIOUS-3 studies (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) and compared the effects of clazosentan 5 mg/h, 15 mg/h, and placebo starting the day after aneurysm repair. The analysis was performed separately based on the presence or absence of thick (≥4 mm) and diffuse (≥3 cisterns) SAH on admission computed tomography. The primary composite end point was all-cause mortality and vasospasm-related morbidity at 6 weeks, and the main secondary end point was the extended Glasgow Outcome Scale at 3 months, adjusted for admission clinical grade.

Results—
Of 1718 randomized patients, 919 (53%) had thick and diffuse SAH. The primary composite end point in this group occurred in 36% of placebo-treated patients (n=294), 30% patients treated with clazosentan 5 mg/h (n=514; relative risk, 0.82; 95% CI, 0.67–0.99), and 19% patients treated with clazosentan 15 mg/h (n=111; relative risk, 0.54; 95% CI, 0.36–0.80). Despite this, death or poor functional outcome (Glasgow Outcome Scale ≤4) occurred in 33% of placebo-treated patients, 34% of patients treated with clazosentan 5 mg/h (relative risk 1.02; 95% CI, 0.84–1.23), and 35% of patients treated with clazosentan 15 mg/h (relative risk 1.14; 95% CI, 0.88–1.48).

Conclusions—
In an enriched population with thick and diffuse SAH, clazosentan at a dose of 5 and 15 mg/h was able to significantly reduce vasospasm-related morbidity in a dose-dependent manner. The absence of an effect on long-term functional status likely reflects the complexity and multiplicity of factors that contribute to poor outcome after SAH.

Clinical Trial Registration—
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00558311; NCT00940095.

Stereotactic Radiosurgery for Unruptured Versus Ruptured Pediatric Brain Arteriovenous Malformations

Ching-Jen Chen,
Cheng-Chia Lee,
Dale Ding,
Shih-Wei Tzeng,
Kathryn N. Kearns,
Hideyuki Kano,
Ahmet Atik,
Natasha Ironside,
Krishna Joshi,
Paul P. Huang,
Douglas Kondziolka,
David Mathieu,
Christian Iorio-Morin,
Inga S. Grills,
Thomas J. Quinn,
Zaid Siddiqui,
Kim Marvin,
Caleb Feliciano,
Andrew Faramand,
Robert M. Starke,
Gene Barnett,
L. Dade Lunsford,
Jason P. Sheehan and
on behalf of the International Radiosurgery Research Foundation

Stroke. 2019 | Volume 50, Issue 10: 2745–2751,

originally publishedAugust 7, 2019,

https://doi.org/10.1161/STROKEAHA.119.026211

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Background and Purpose—
The effects of prior hemorrhage on stereotactic radiosurgery (SRS) outcomes for pediatric arteriovenous malformations (AVMs) are not well defined. The aim of this multicenter, retrospective cohort study is to compare the SRS outcomes for unruptured versus ruptured pediatric AVMs.

Methods—
The International Radiosurgery Research Foundation pediatric AVM database from 1987 to 2018 was reviewed retrospectively. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. Associations between prior hemorrhage and outcomes were adjusted for baseline differences, inverse probability weights, and competing risks.

Results—
The study cohort comprised 153 unruptured and 386 ruptured AVMs. Favorable outcome was achieved in 48.4% and 60.4% of unruptured and ruptured AVMs, respectively (adjusted odds ratio, 1.353; P=0.190). Cumulative AVM obliteration probabilities were 51.2%, 59.4%, 64.2%, and 70.0% for unruptured and 61.0%, 69.3%, 74.0%, and 79.3% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.311; P=0.020). Cumulative post-SRS hemorrhage probabilities were 4.5%, 5.6%, 5.6%, and 9.8% for unruptured and 4.7%, 6.1%, 6.1%, and 10.6% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.086; P=0.825). Probabilities of AVM obliteration (adjusted subhazard ratio, 0.968; P=0.850) and post-SRS hemorrhage (adjusted subhazard ratio, 1.663; P=0.251) were comparable between the 2 cohorts after inverse probability weight adjustments. Symptomatic (15.8% versus 8.1%; adjusted odds ratio, 0.400; P=0.008) and permanent (9.2% versus 5.0%; adjusted odds ratio, 0.441; P=0.045) radiation-induced change were more common in unruptured AVMs.

Conclusions—
The overall outcomes after SRS for unruptured versus ruptured pediatric AVMs are comparable. However, symptomatic and permanent radiation-induced change occur more frequently in pediatric patients with unruptured AVMs.

Associated Factors and Long-Term Prognosis of 24-Hour Worsening of Arterial Patency After Ischemic Stroke

Stroke. 2019 | Volume 50, Issue 10: 2752–2760,

originally publishedAugust 15, 2019,

https://doi.org/10.1161/STROKEAHA.119.025787

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Background and Purpose—
Early arterial recanalization in acute ischemic stroke is strongly associated with better outcomes. However, early worsening of arterial patency was seldom studied. We investigated potential predictors and long-term prognosis of worsening of arterial patency at 24 hours after stroke onset.

Methods—
Patients from the Acute Stroke Registry and Analysis of Lausanne registry including admission and 24-hour vascular imaging (computed tomography or magnetic resonance angiography) were included. Worsening of arterial patency was defined as a new occlusion and significant stenosis in any extracranial or intracranial artery, comparing 24 hours with admission imaging. Variables associated with worsening of arterial patency were assessed by stepwise multiple logistic regression. The impact of arterial worsening on 3-month outcome was investigated with an adjusted modified Rankin Scale shift analysis.

Results—
Among 2152 included patients, 1387 (64.5%) received intravenous thrombolysis and endovascular treatment, and 65 (3.0%) experienced 24-hour worsening of arterial patency. In multivariable analysis, history of hypertension seemed protective (adjusted odds ratio [aOR], 0.45; 95% CI, 0.27–0.75) while higher admission National Institutes of Health Stroke Scale (aOR, 1.06; 95% CI, 1.02–1.10), intracranial (aOR, 4.78; 95% CI, 2.03–11.25) and extracranial stenosis (aOR, 3.67; 95% CI, 1.95–6.93), and good collaterals (aOR, 3.71; 95% CI, 1.54–8.95) were independent predictors of worsening of arterial patency. Its occurrence was associated with a major unfavorable shift in the distribution of the modified Rankin Scale at 3 months (aOR, 5.97; 95% CI, 3.64–9.79).

Conclusions—
Stroke severity and admission vascular imaging findings may help to identify patients at a higher risk of developing worsening of arterial patency at 24 hours. The impact of worsening of arterial patency on long-term outcome warrants better methods to detect and prevent this early complication.

Brain Connectivity Measures Improve Modeling of Functional Outcome After Acute Ischemic Stroke

Stroke. 2019 | Volume 50, Issue 10: 2761–2767,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.025738

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Background and Purpose—
The ability to model long-term functional outcomes after acute ischemic stroke represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain’s connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club organization, a high capacity backbone system of brain function.

Methods—
In a hospital-based cohort of 41 acute ischemic stroke patients, we investigated the effect of acute infarcts on the brain’s prestroke rich club backbone and poststroke functional connectomes with respect to poststroke outcome. Functional connectomes were created using 3 anatomic atlases, and characteristic path-length (L) was calculated for each connectome. The number of rich club regions affected were manually determined using each patient’s diffusion weighted image. We investigated differences in L with respect to outcome (modified Rankin Scale score; 90 days) and the National Institutes of Health Stroke Scale (NIHSS; early: 2–5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including number of rich club regions and L in outcome models, using linear regression and assessing the explained variance (R²).

Results—
Of 41 patients (mean age [range]: 70 [45–89] years), 61% were male. Lower L was generally associated with better outcome. Including number of rich club regions in the backward selection models of outcome, R² increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and modified Rankin Scale score.

Conclusions—
In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of poststroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.

Extent to Which Network Hubs Are Affected by Ischemic Stroke Predicts Cognitive Recovery

Hugo P. Aben,
Geert Jan Biessels,
Nick A. Weaver,
Jacoba M. Spikman,
Johanna M.A. Visser-Meily,
Paul L.M. de Kort,
Yael D. Reijmer,
on behalf of the PROCRAS Study Group and
The PROCRAS Study Group

Stroke. 2019 | Volume 50, Issue 10: 2768–2774,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.025637

This article is commented on by the following:

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Background and Purpose—
It is uncertain what determines the potential for cognitive recovery after ischemic stroke. The extent to which strategic areas of the brain network, so-called hubs, are affected by the infarct could be a key factor. We developed a lesion impact score, which estimates the damage to network hubs by integrating information on infarct size with healthy brain network topology. We verified whether the lesion impact score indeed reflects global network disturbances in patients and assessed if it could predict cognitive recovery.

Methods—
Seventy-five ischemic stroke patients without signs of a prestroke cognitive disorder were included, all with evidence of a cognitive disorder during hospitalization. A brain magnetic resonance imaging and neuropsychological assessment were performed 5 weeks (±1 week) after stroke. Neuropsychological testing was repeated after 1 year to assess cognitive recovery. Brain networks were reconstructed from diffusion-weighted data and consisted of 90 gray matter regions (ie, network nodes). A standard brain network map, indicating the hub-score of each node, was obtained from network data of 44 cognitively healthy adults. For each patient, we calculated the lesion impact score by multiplying the percentage of node volume affected by the infarct with the node’s corresponding hub-score. The patients’ maximum lesion impact score was used as outcome predictor.

Results—
A higher lesion impact score in patients, indicating an increasing infarct size in nodes with a higher hub-score, was related to lower global brain network efficiency (β=−0.528 [−0.776 to −0.277]; P<0.001), independent of age, brain volume, infarct volume, and white matter hyperintensity severity. A lower lesion impact score, however, was an independent predictor of cognitive recovery 1 year after stroke (odds ratio=0.434 [0.193–0.978]; P=0.044).

Conclusions—
We introduced a lesion impact score that combines information on infarct size and network topology to predict long-term recovery after stroke. This score can potentially be used in a clinical setting, also without availability of high-resolution diffusion-weighted magnetic resonance imaging.

Predicting Dementia in Cerebral Small Vessel Disease Using an Automatic Diffusion Tensor Image Segmentation Technique

Stroke. 2019 | Volume 50, Issue 10: 2775–2782,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.025843

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Background and Purpose—
Cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment, with a significant proportion of cases going on to develop dementia. We explore the extent to which diffusion tensor image segmentation technique (DSEG; which characterizes microstructural damage across the cerebrum) predicts both degree of cognitive decline and conversion to dementia, and hence may provide a useful prognostic procedure.

Methods—
Ninety-nine SVD patients (aged 43–89 years) underwent annual magnetic resonance imaging scanning (for 3 years) and cognitive assessment (for 5 years). DSEG-θ was used as a whole-cerebrum measure of SVD severity. Dementia diagnosis was based Diagnostic and Statistical Manual of Mental Disorders V criteria. Cox regression identified which DSEG measures and vascular risk factors were related to increased risk of dementia. Linear discriminant analysis was used to classify groups of stable versus subsequent dementia diagnosis individuals.

Results—
DSEG-θ was significantly related to decline in executive function and global cognition (P<0.001). Eighteen (18.2%) patients converted to dementia. Baseline DSEG-θ predicted dementia with a balanced classification rate=75.95% and area under the receiver operating characteristic curve=0.839. The best classification model included baseline DSEG-θ, change in DSEG-θ, age, sex, and premorbid intelligence quotient (balanced classification rate of 79.65%; area under the receiver operating characteristic curve=0.903).

Conclusions—
DSEG is a fully automatic technique that provides an accurate method for assessing brain microstructural damage in SVD from a single imaging modality (diffusion tensor imaging). DSEG-θ is an important tool in identifying SVD patients at increased risk of developing dementia and has potential as a clinical marker of SVD severity.

Cerebral Blood Flow Predicts the Infarct Core

New Insights From Contemporaneous Diffusion and Perfusion Imaging

Stroke. 2019 | Volume 50, Issue 10: 2783–2789,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.026640

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Background and Purpose—
The aim of this study is to determine the spatial and volumetric accuracy of infarct core estimates from relative cerebral blood flow (rCBF) by comparison with near-contemporaneous diffusion-weighted imaging (DWI), and evaluate whether it is sufficient for patient triage to reperfusion therapies.

Methods—
One hundred ninety-three patients enrolled in the DEFUSE 2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) and SENSE 3 (Sensitivity Encoding) stroke studies were screened, and 119 who underwent acute magnetic resonance imaging with DWI and perfusion imaging within 24 hours of onset were included. Infarct core was estimated using reduced rCBF at 12 thresholds (<0.20–<0.44) and compared against DWI (apparent diffusion coefficient <620 10⁻⁶mm2/s). For each threshold, volumetric agreement between the rCBF and DWI core estimates was assessed using Bland-Altman, correlation, and linear regression analyses; spatial agreement was assessed using receiver operating characteristic analysis.

Results—
An rCBF threshold of 0.32 yielded the smallest mean absolute volume difference (14.7 mL), best linear regression fit (R²=0.84), and best spatial agreement (Youden index, 0.38; 95% CI, 0.34–0.41) between rCBF and DWI, with high correlation (r=0.91, P<0.05), a small mean volume difference (1.3 mL) and no fixed bias (P<0.05). At this threshold, 110 of 119 (92.4%) patients were correctly triaged when applying 70 mL as the volume limit for thrombectomy. Spatial agreement was better for prediction of large infarcts (>70 mL) than small infarcts (≤70 mL), with Youden indices of 0.53 (95% CI, 0.49–0.56) and 0.34 (95% CI, 0.30–0.37), respectively.

Conclusions—
Strong correlation and agreement with near-contemporaneous DWI indicate that infarct core estimates obtained using rCBF are sufficiently accurate for patient triage to reperfusion therapies. The identified optimal rCBF threshold of 0.32 closely approximates the threshold currently used in clinical practice.

Automated Detection of Intracranial Large Vessel Occlusions on Computed Tomography Angiography

A Single Center Experience

Stroke. 2019 | Volume 50, Issue 10: 2790–2798,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.026259

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Background and Purpose—
Endovascular thrombectomy is highly effective in acute ischemic stroke patients with an anterior circulation large vessel occlusion (LVO), decreasing morbidity and mortality. Accurate and prompt identification of LVOs is imperative because these patients have large volumes of tissue that are at risk of infarction without timely reperfusion, and the treatment window is limited to 24 hours. We assessed the accuracy and speed of a commercially available fully automated LVO-detection tool in a cohort of patients presenting to a regional hospital with suspected stroke.

Methods—
Consecutive patients who underwent multimodal computed tomography with thin-slice computed tomography angiography between January 1, 2017 and December 31, 2018 for suspected acute ischemic stroke within 24 hours of onset were retrospectively identified. The multimodal computed tomographies were assessed by 2 neuroradiologists in consensus for the presence of an intracranial anterior circulation LVO or M2-segment middle cerebral artery occlusion (the reference standard). The patients’ computed tomography angiographies were then processed using an automated LVO-detection algorithm (RAPID CTA). Receiver-operating characteristic analysis was used to determine sensitivity, specificity, and negative predictive value of the algorithm for detection of (1) an LVO and (2) either an LVO or M2-segment middle cerebral artery occlusion.

Results—
CTAs from 477 patients were analyzed (271 men and 206 women; median age, 71; IQR, 60–80). Median processing time was 158 seconds (IQR, 150–167 seconds). Seventy-eight patients had an anterior circulation LVO, and 28 had an isolated M2-segment middle cerebral artery occlusion. The sensitivity, negative predictive value, and specificity were 0.94, 0.98, and 0.76, respectively for detection of an intracranial LVO and 0.92, 0.97, and 0.81, respectively for detection of either an intracranial LVO or M2-segment middle cerebral artery occlusion.

Conclusions—
The fully automated algorithm had very high sensitivity and negative predictive value for LVO detection with fast processing times, suggesting that it can be used in the emergent setting as a screening tool to alert radiologists and expedite formal diagnosis.

Clinical and Imaging Parameters Associated With Hyperacute Infarction Growth in Large Vessel Occlusion Stroke

Stroke. 2019 | Volume 50, Issue 10: 2799–2804,

originally publishedAugust 20, 2019,

https://doi.org/10.1161/STROKEAHA.119.025809

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Background and Purpose—
Large vessel occlusion stroke leads to highly variable hyperacute infarction growth. Our aim was to identify clinical and imaging parameters associated with hyperacute infarction growth in patients with an large vessel occlusion stroke of the anterior circulation.

Methods—
Seven hundred twenty-two consecutive patients with acute stroke were prospectively included in our monocentric stroke registry between 2009 and 2017. We selected all patients with a large vessel occlusion stroke of the anterior circulation, documented times from symptom onset, and CT perfusion on admission for our analysis (N=178). Ischemic core volume was determined with CT perfusion using automated thresholds. Hyperacute infarction growth was defined as ischemic core volume divided by times from symptom onset, assuming linear progression during times from symptom onset to imaging on admission. For collateral assessment, the regional leptomeningeal collateral score (rLMC) was used. Clinical data included the National Institutes of Health Stroke Scale score on admission and cardiovascular risk factors. Regression analysis was performed to adjust for confounders.

Results—
Median ischemic core volume was 34.4 mL, and median hyperacute infarction growth was 0.27 mL/min. In regression analysis including age, sex, National Institutes of Health Stroke Scale, clot burden score, diabetes mellitus, smoking, hypercholesteremia, hypertension, Alberta Stroke Program Early CT Score, and rLMC scores, only the rLMC score had a significant, independent association with hyperacute infarction growth (adjusted β=−0.35; P<0.001). Trichotomizing patients by rLMC scores yielded 65 patients with good (rLMC >15), 67 with intermediate (rLMC 11–15) and 46 with poor collaterals (rLMC <11) with an infarction growth of 0.17 mL/min, 0.26 mL/min, and 0.41 mL/min, respectively.

Conclusions—
Hyperacute infarction growth strongly depends on collaterals. In primary stroke centers, hyperacute infarction growth may be extrapolated to estimate the stroke progression during transfer times to thrombectomy centers and to support decisions on which patients to transfer.

Association of Blood Pressure During Thrombectomy for Acute Ischemic Stroke With Functional Outcome

A Systematic Review

Stroke. 2019 | Volume 50, Issue 10: 2805–2812,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.024915

This article is commented on by the following:

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Background and Purpose—
Optimal blood pressure (BP) targets during mechanical thrombectomy (MT) for acute ischemic stroke (AIS) are unknown, and randomized controlled trials addressing this issue are lacking. We aimed to perform a systematic review of studies evaluating the influence of periprocedural BP on functional outcome after MT.

Methods—
Studies assessing periprocedural BP effect on functional outcome published after January 1st, 2012 were included in the systematic review. The PRISMA checklist and flow diagram were followed for the design and reporting of this work.

Results—
Nine studies were included, for a total of 1037 patients. The heterogeneity in findings with respect to BP monitoring and studied parameters precluded a meta-analysis. Mean arterial pressure was the most frequently reported parameter to describe BP variability during MT, and systolic BP was the main parameter used to define periprocedural BP targets. Five studies suggested an association between 3 types of BP drops as predictors of poor functional outcome at 3 months: >40% drop in mean arterial pressure compared with baseline (odds ratio=2.8; [1.09–7.19]; P=0.032), lowest mean arterial pressure before recanalization (odds ratio=1.28; [1.01–1.62] per 10 mm Hg drop below 100 mm Hg; P=0.04), and MAP drops (odds ratio=4.38; [1.53–12.6] for drops >10%). Four studies did not show an association between BP during MT and functional outcome, including 3 studies with strict periprocedural systolic BP targets (within a 140–180 mm Hg).

Conclusions—
BP drops during MT may be associated with a worse functional outcome. When strict systolic BP targets are achieved, no association between BP and functional outcome was also noted. Both conclusions require further evaluation in randomized studies.

Intravenous Thrombolysis for Acute Ischemic Stroke After Recent Myocardial Infarction

Case Series and Systematic Review

Stroke. 2019 | Volume 50, Issue 10: 2813–2818,

originally publishedAugust 22, 2019,

https://doi.org/10.1161/STROKEAHA.119.025630

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Background and Purpose—
The safety of IV r-tPA (intravenous tissue-type plasminogen activator) for acute ischemic stroke (AIS) treatment after recent myocardial infarction (MI) is still a matter of debate. We studied the safety of delivering IV r-tPA to AIS patients with a MI within the preceding 3 months.

Methods—
Retrospective review of consecutive AIS admitted to 2 tertiary university hospitals’ and systematic literature review for AIS patients with history of MI in the previous 3 months. Patients were divided into 2 groups: treated or not treated with standard IV r-tPA dose for AIS. Cardiac complications (cardiac rupture/tamponade, intracardiac thrombus embolization, or life-threatening arrhythmias) were compared between groups and assessed by type of MI (non–ST-segment–elevation myocardial infarction [STEMI], or STEMI) and time elapsed between vascular events.

Results—
One hundred and two patients were included; 46 (45.1%) were derived from literature review. Median age (interquartile range) was 64 (53–75) years old, and 69 (67.6%) were men. Forty-seven (46.1%) received IV r-tPA. In the treated group, 25 (53.2%) and 23 (48.9%) patients had, respectively, concurrent AIS and MI and STEMI, in comparison with 12 (21.8%; P=0.002) and 36 (65.5%; P=0.110) patients in the nontreated. Four (8.5%) IV r-tPA–treated patients died from confirmed or presumed cardiac rupture/ tamponade, all with a STEMI in the week preceding stroke. This complication occurred in 1 (1.8%) patients in the nontreated group (P=0.178). There were no differences in thrombus embolization (1 [2.1%) versus 2 [3.6]; P=1.000) and life-threatening arrhythmias (3 [6.4%) versus 7 [12.7]; P=0.335). No non-STEMI patients receiving IV r-tPA had cardiac complications.

Conclusions—
In patients with AIS and recent or concurrent MI, MI type and the time elapsed between the 2 events should be taken into consideration when deciding to deliver IV r-tPA. Although recent non-STEMI or concurrent events seem safe, STEMI in the week preceding stroke should prompt caution. The low number of events and publication bias may have influenced our conclusions.

Non–Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Asians With Atrial Fibrillation

Meta-Analysis of Randomized Trials and Real-World Studies

Zhengbiao Xue and
Hao Zhang

Stroke. 2019 | Volume 50, Issue 10: 2819–2828,

originally publishedAugust 19, 2019,

https://doi.org/10.1161/STROKEAHA.119.026054

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Background and Purpose—
Several randomized trials and real-world studies have reported the efficacy and safety of non–vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with atrial fibrillation; and therefore, this meta-analysis was aimed to compare the effects of NOACs with warfarin for atrial fibrillation stroke prevention in Asians.

Methods—
The PubMed and Embase databases were searched from January 2009 to February 2019 for studies on comparisons of NOACs versus warfarin in Asians. Risk ratios (RRs) with 95% CIs were pooled using a random-effects model.

Results—
Five NOAC trials and 21 observational cohorts were included. For the NOAC trials, compared with warfarin, NOACs was associated with reduced risks of stroke or systemic embolism (RR, 0.73; 95% CI, 0.59–0.90), all-cause death (RR, 0.83; 95% CI, 0.73–0.95), major bleeding (RR, 0.59; 95% CI, 0.48–0.72), and intracranial bleeding (RR, 0.36; 95% CI, 0.26–0.49). For the real-world data, compared with warfarin, NOACs was associated with decreased rates of stroke or systemic embolism (RR, 0.75; 95% CI, 0.68–0.82), ischemic stroke (RR, 0.70; 95% CI, 0.59–0.83), myocardial infarction (RR, 0.74; 95% CI, 0.58–0.93), all-cause death (RR, 0.67; 95% CI, 0.59–0.77), major bleeding (RR, 0.63; 95% CI, 0.55–0.73), intracranial bleeding (RR, 0.50; 95% CI, 0.43–0.59), and gastrointestinal bleeding (RR, 0.65; 95% CI, 0.51–0.84). The results did not change in the subgroup analyses based on the type and dose of NOACs.

Conclusions—
Based on published NOAC trials and real-world studies, the use of NOACs is noninferior to warfarin in Asians with atrial fibrillation irrespective of the NOAC type and dose.

Door-in-Door-Out Time of 60 Minutes for Stroke With Emergent Large Vessel Occlusion at a Primary Stroke Center

Stroke. 2019 | Volume 50, Issue 10: 2829–2834,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.025838

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Background and Purpose—
Rapid reperfusion with mechanical thrombectomy in ischemic strokes with emergent large vessel occlusions leads to significant reduction in morbidity and mortality. The door-in-door-out (DIDO) time is an important metric for stroke centers without an on-site mechanical thrombectomy service. We report the outcome of a continuous quality improvement program to improve the DIDO time since 2015.

Methods—
Retrospective analysis of consecutive patients transferred out from a metropolitan primary stroke center for consideration of mechanical thrombectomy between January 1, 2015, and October 31, 2018. Clinical records were interrogated for eligible patients with DIDO times and reasons for treatment delays extracted.

Results—
One hundred thirty-three patients were transferred over the 46-month period. Median DIDO time reduced by 14% per year, from 111 minutes interquartile range (IQR, 98– 142) in 2015 to 67 minutes (IQR, 55–94) in 2018. A median DIDO time of 59 minutes (IQR, 51–80) was achieved in 2018 during working hours (0800–1700 hours). Overall, 65 patients had no documented delays (49%) with a median DIDO time of 75 minutes (IQR, 54–93) and 103 minutes (IQR, 75–143) in those with at least one delay factor documented.

Conclusions—
A median DIDO time of <60 minutes can be achieved in a primary stroke center.

Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke

Stroke. 2019 | Volume 50, Issue 10: 2835–2841,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.026318

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Background and Purpose—
Stroke is a leading cause of long-term disability. Limited treatment options exist for patients with chronic stroke and substantial functional deficits. The current study examined safety and preliminary efficacy estimates of intravenous allogeneic mesenchymal stem cells in this population.

Methods—
Entry criteria included ischemic stroke >6 months prior and substantial impairment (National Institutes of Health Stroke Scale score ≥6) and disability. Enrollees received a single intravenous dose of allogeneic ischemia-tolerant mesenchymal stem cells. Phase 1 used a dose-escalation design (3 tiers, n=5 each). Phase 2 was an expanded safety cohort. The primary end point was safety over 1-year. Secondary end points examined behavioral change.

Results—
In phase 1 (n=15), each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects (n=21) received 1.5 million cells/kg. At baseline, subjects (n=36) averaged 4.2±4.6 years poststroke, age 61.1±10.8 years, National Institutes of Health Stroke Scale score 8 (6.5–10), and Barthel Index 65±29. Two were lost to follow-up, one was withdrawn and 2 died (unrelated to study treatment). Of 15 serious adverse events, none was possibly or probably related to study treatment. Two mild adverse events were possibly related to study treatment, a urinary tract infection and intravenous site irritation. Treatment was safe based on serial exams, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis. All behavioral end points showed significant gains over the 12-months of follow-up. For example, Barthel Index scores increased by 6.8±11.4 points (mean±SD) at 6-months (P=0.002) and by 10.8±15.5 points at 12-months (P<0.001) post-infusion; the proportion of patients achieving excellent functional outcome (Barthel score ≥95) increased from 11.4% at baseline to 27.3% at 6-months and to 35.5% at 12-months.

Conclusions—
Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains. These data support proceeding to a randomized, placebo-controlled study of this therapy in this population.

Clinical Trial Registration—
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01297413.

Workflow Intervals of Endovascular Acute Stroke Therapy During On- Versus Off-Hours

The MR CLEAN Registry

Wouter H. Hinsenveld,
Inger R. de Ridder,
Robert J. van Oostenbrugge,
Jan A. Vos,
Adrien E. Groot,
Jonathan M. Coutinho,
Geert J. Lycklama à Nijeholt,
Jelis Boiten,
Wouter J. Schonewille,
on behalf of the MR CLEAN Registry Investigators and
MR CLEAN Registry Investigators

Stroke. 2019 | Volume 50, Issue 10: 2842–2850,

originally publishedAugust 7, 2019,

https://doi.org/10.1161/STROKEAHA.119.025381

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Background and Purpose—
Endovascular treatment (EVT) of patients with acute ischemic stroke because of large vessel occlusion involves complicated logistics, which may cause a delay in treatment initiation during off-hours. This might lead to a worse functional outcome. We compared workflow intervals between endovascular treatment–treated patients presenting during off- and on-hours.

Methods—
We retrospectively analyzed data from the MR CLEAN Registry, a prospective, multicenter, observational study in the Netherlands and included patients with an anterior circulation large vessel occlusion who presented between March 2014 and June 2016. Off-hours were defined as presentation on Monday to Friday between 17:00 and 08:00 hours, weekends (Friday 17:00 to Monday 8:00) and national holidays. Primary end point was first door to groin time. Secondary end points were functional outcome at 90 days (modified Rankin Scale) and workflow time intervals. We stratified for transfer status, adjusted for prognostic factors, and used linear and ordinal regression models.

Results—
We included 1488 patients of which 936 (62.9%) presented during off-hours. Median first door to groin time was 140 minutes (95% CI, 110–182) during off-hours and 121 minutes (95% CI, 85–157) during on-hours. Adjusted first door to groin time was 14.6 minutes (95% CI, 9.3–20.0) longer during off-hours. Door to needle times for intravenous therapy were slightly longer (3.5 minutes, 95% CI, 0.7–6.3) during off-hours. Groin puncture to reperfusion times did not differ between groups. For transferred patients, the delay within the intervention center was 5.0 minutes (95% CI, 0.5–9.6) longer. There was no significant difference in functional outcome between patients presenting during off- and on-hours (adjusted odds ratio, 0.92; 95% CI, 0.74–1.14). Reperfusion rates and complication rates were similar.

Conclusions—
Presentation during off-hours is associated with a slight delay in start of endovascular treatment in patients with acute ischemic stroke. This treatment delay did not translate into worse functional outcome or increased complication rates.

Pathophysiology of Central Poststroke Pain

Motor Cortex Disinhibition and Its Clinical and Sensory Correlates

Stroke. 2019 | Volume 50, Issue 10: 2851–2857,

originally publishedSeptember 10, 2019,

https://doi.org/10.1161/STROKEAHA.119.025692

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Background and Purpose—
Central poststroke pain (CPSP) is a disabling condition in stroke patients, and evidence suggests that altered corticospinal and motor intracortical excitability occurs in neuropathic pain. The objective of this study was to investigate changes in motor cortex excitability and sensorimotor interaction and their correlates with clinical manifestations and alterations in somatosensory systems in CPSP patients.

Methods—
Fourteen patients with CPSP but no motor weakness were compared with age- and sex-matched healthy controls for motor cortex excitability and sensorimotor interaction assessed by transcranial magnetic stimulation to measure resting motor thresholds, short-interval intracortical inhibition, intracortical facilitation, and afferent inhibitions. The sensory pathway was evaluated by quantitative sensory testing, contact heat evoked potential, and somatosensory evoked potentials. Clinical pain and quality of life were assessed with validated tools.

Results—
The duration of CPSP was 3.3±3.0 years (ranging 0.5–10 years), and pain significantly impaired quality of life. Compared with the unaffected hemisphere, the stroke hemisphere had higher thermal thresholds, lower contact heat evoked potential amplitudes, and prolonged cortical somatosensory evoked potential latencies. There was no difference in resting motor thresholds between the stroke and unaffected hemisphere or between patients and controls. CPSP patients had a reduction in short-interval intracortical inhibition in the stroke hemisphere compared with that in the unaffected hemispheres of patients and controls. No changes were noted in afferent inhibitions between the stroke and unaffected hemispheres. The short-interval intracortical inhibition of the stroke hemisphere was negatively correlated with self-rated health on a visual analog scale and positively correlated with cortical somatosensory evoked potential latencies.

Conclusions—
CPSP patients with intact corticospinal tracts showed reduced motor intracortical inhibition in the stroke hemisphere, suggesting defective gamma-aminobutyric acid-ergic inhibition. This disinhibition was associated with impaired quality of life and was related to dorsal column–medial lemniscus pathway dysfunction.

Systematic Review of Malpractice Litigation in the Diagnosis and Treatment of Acute Stroke

Stroke. 2019 | Volume 50, Issue 10: 2858–2864,

originally publishedAugust 19, 2019,

https://doi.org/10.1161/STROKEAHA.119.025352

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Background and Purpose—
The emergency management of stroke is complex and highly time-sensitive. Recent landmark trials demonstrating the strong benefit of thrombectomy have led to rapid change in stroke management. This article reviews a large number of medical malpractice lawsuits related to the emergency management of stroke to characterize factors involved in these lawsuits.

Methods—
Three large legal databases were used to search for jury verdicts and settlements in cases related to the acute care of stroke patients in the United States. Search terms included “stroke” and “medical malpractice.” Cases were screened to include only cases in which the allegation involved negligence in the acute care of a patient suffering a stroke.

Results—
We found 246 medical malpractice cases related to the acute management of ischemic stroke and 26 related to intracranial hemorrhage. Seventy-one cases specifically alleged a failure to treat with tPA (tissue-type plasminogen activator) and 7 cases alleged a failure to treat, or to timely treat, with thrombectomy. Overall there were 151 cases (56%) which ended with no payout, 74 cases (27%) were settled out of court, and 47 cases (17%) went to court and resulted in a verdict for the plaintiff. The average payout in settlements was $1 802 693, and the average payout in plaintiff verdicts was $9 705 099.

Conclusions—
Malpractice litigation is a risk in acute stroke care and can lead to significant financial consequences. The majority of malpractice lawsuits related to the emergency management of stroke allege a failure to diagnose and failure to treat. Allegations of a failure to treat acute ischemic stroke with tPA were frequently found and are common in lawsuits. Allegations of a failure to treat a large vessel occlusion with thrombectomy were less frequently found. Given recent changes in practice guidelines and the demonstrated strong treatment effect of thrombectomy, it is likely that such litigation will increase in the coming years.

MiR-126 Mediates Brain Endothelial Cell Exosome Treatment–Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice

Stroke. 2019 | Volume 50, Issue 10: 2865–2874,

originally publishedAugust 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.025371

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Background and Purpose—
Stroke patients with type 2 diabetes mellitus (T2DM) exhibit increased vascular and white matter damage and have worse prognosis compared with nondiabetic stroke patients. We investigated the neurorestorative effects of exosomes derived from mouse brain endothelial cells (EC-Exo) as treatment for stroke in T2DM mice and investigated the role of miR-126 in mediating EC-Exo–derived therapeutic benefits in T2DM-stroke mice.

Methods—
Adult, male BKS.Cg-m+/+Lepr^db/J (T2DM) mice were subjected to photothrombotic stroke model. T2DM mice were intravenously injected at 3 days after stroke with (1) PBS; (2) liposome mimic (vehicle control, 3×10¹⁰); (3) EC-Exo (3×10¹⁰); (4) knockdown of miR-126 in EC-Exo (miR-126⁻^/− EC-Exo, 3×10¹⁰). Behavioral and cognitive tests were performed, and mice were sacrificed at 28 days after stroke.

Results—
Compared with non-DM stroke mice, T2DM-stroke mice exhibit significantly decreased serum and brain tissue miR-126 expression. Endothelial cells and EC-Exo contain high levels of miR-126 compared with other cell types or exosomes derived from other types of cells, respectively (smooth muscle cells, astrocytes, and marrow stromal cells). Compared with PBS or liposome mimic treatment, EC-Exo treatment of T2DM-stroke mice significantly improves neurological and cognitive function, increases axon density, myelin density, vascular density, arterial diameter, as well as induces M2 macrophage polarization in the ischemic boundary zone. MiR-126^−/− EC-Exo treatment significantly decreases miR-126 expression in serum and brain, as well as attentuates EC-Exo treatment–induced functional improvement and does not significantly increase axon and myelin density, vascular density, arterial diameter or induce M2 macrophage polarization in T2DM-stroke mice. In vitro, EC-Exo treatment significantly increases primary cortical neuron axonal outgrowth and increases endothelial capillary tube formation whereas miR-126^−/− EC-Exo attentuates EC-Exo induced capillary tube formation and axonal outgrowth.

Conclusions—
EC-Exo treatment of stroke promotes neurorestorative effects in T2DM mice. MiR-126 may mediate EC-Exo–induced neurorestorative effects in T2DM mice.

Visual Overview—
An online visual overview is available for this article.

Validity and Reliability of Neurological Scores in Mice Exposed to Middle Cerebral Artery Occlusion

Stroke. 2019 | Volume 50, Issue 10: 2875–2882,

originally publishedAugust 15, 2019,

https://doi.org/10.1161/STROKEAHA.119.026652

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Background and Purpose—
The selection of appropriate neurological scores and tests is crucial for the evaluation of stroke consequences. The validity and reliability of neurological deficit scores and tests has repeatedly been questioned in ischemic stroke models in the past.

Methods—
In 198 male mice exposed to transient intraluminal middle cerebral artery occlusion, we examined the validity and reliability of 11 neurological scores (Bederson score 0–3, Bederson score 0–4, Bederson score 0–5, modified neurological severity [0–14], subjective overall impression [0–10], or simple neurological tests: grip test, latency to move body length test, pole test, wire hanging test, negative geotaxis test, and elevated body swing test) in the acute stroke phase, that is, after 24 hours. Combinations of neurological scores or tests for predicting infarct volume were statistically analyzed.

Results—
Infarct volume was left skewed (median [Q1–Q3], 78.4 [54.8–101.3] mm³). Among all tests, the Bederson (0–5; r=0.63, P<0.001), modified neurological severity (r=0.80, P<0.001), and subjective overall impression (r=−0.63, P<0.001) scores had the highest test validities, using infarct volume as external reference. Subjective overall impression had the best agreement between 5 raters (Kendall W=0.11, P<0.001). The Bederson (0–5) score discriminated infarct volume in mice with small (≤50 mm³; r=0.33, P=0.027) and large (>50 mm³; r=0.48, P<0.001) brain infarcts, all other tests only in mice with large infarcts. Combining subjective overall impression with Bederson (0–5) score explained 47.6% of the variance of infarct volume.

Conclusions—
Despite their simplicity, the Bederson (0–5) score, modified neurological severity score, and subjective overall impression have reasonable validity and reliability in the acute stroke phase. The Bederson (0–5) score equally distinguishes infarct volume in small and large infarcts.

Visual Overview—
An online visual overview is available for this article.

Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke

Stroke. 2019 | Volume 50, Issue 10: 2883–2891,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.026669

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Background and Purpose—
The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies.

Methods—
To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used.

Results—
We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation.

Conclusions—
Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants.

Visual Overview—
An online visual overview is available for this article.

Central Nervous System Electrical Stimulation for Neuroprotection in Acute Cerebral Ischemia

Meta-Analysis of Preclinical Studies

Stroke. 2019 | Volume 50, Issue 10: 2892–2901,

originally publishedSeptember 4, 2019,

https://doi.org/10.1161/STROKEAHA.119.025364

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Background and Purpose—
Brain electrical stimulation, widely studied to facilitate recovery from stroke, has also been reported to confer direct neuroprotection in preclinical models of acute cerebral ischemia. Systematic review of controlled preclinical acute cerebral ischemia studies would aid in planning for initial human clinical trials.

Methods—
A systematic Medline search identified controlled, preclinical studies of central nervous system electrical stimulation in acute cerebral ischemia. Studies were categorized among 6 stimulation strategies. Three strategies applied different stimulation types to tissues within the ischemic zone (cathodal hemispheric stimulation [CHS], anodal hemispheric stimulation, and pulsed hemispheric stimulation), and 3 strategies applied deep brain stimulation to different neuronal targets remote from the ischemic zone (fastigial nucleus stimulation, subthalamic vasodilator area stimulation, and dorsal periaqueductal gray stimulation). Random-effects meta-analysis assessed electrical stimulation modification of final infarct volume. Study-level risk of bias and intervention-level readiness-for-translation were assessed using formal rating scales.

Results—
Systematic search identified 28 experiments in 21 studies, including a total of 350 animals, of electrical stimulation in preclinical acute cerebral ischemia. Overall, in animals undergoing electrical stimulation, final infarct volumes were reduced by 37% (95% CI, 34%–40%; P<0.001), compared with control. There was evidence of heterogeneity of efficacy among stimulation strategies (I²=93.1%, P_{heterogeneity}<0.001). Among the within-ischemic zone stimulation strategies, only CHS significantly reduced the infarct volume (27 %; 95% CI, 22%–33%; P<0.001); among the remote-from ischemic zone approaches, all (fastigial nucleus stimulation, subthalamic vasodilator area stimulation, and dorsal periaqueductal gray stimulation) reduced infarct volumes by approximately half. On formal rating scales, CHS studies had the lowest risk of bias, and CHS had the highest overall quality of intervention-level evidence supporting readiness to proceed to clinical testing.

Conclusions—
Electrical stimulation reduces final infarct volume across preclinical studies. CHS shows the most robust evidence and is potentially appropriate for progression to early-stage human clinical trial testing as a promising neuroprotective intervention.

β-Estradiol Protects Against Acidosis-Mediated and Ischemic Neuronal Injury by Promoting ASIC1a (Acid-Sensing Ion Channel 1a) Protein Degradation

Stroke. 2019 | Volume 50, Issue 10: 2902–2911,

originally publishedAugust 15, 2019,

https://doi.org/10.1161/STROKEAHA.119.025940

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Background and Purpose—
Sex differences in the incidence and outcome of stroke have been well documented. The severity of stroke in women is, in general, significantly lower than that in men, which is mediated, at least in part, by the protective effects of β-estradiol. However, the detailed mechanisms underlying the neuroprotection by β-estradiol are still elusive. Recent studies have demonstrated that activation of ASIC1a (acid-sensing ion channel 1a) by tissue acidosis, a common feature of brain ischemia, plays an important role in ischemic brain injury. In the present study, we assessed the effects of β-estradiol on acidosis-mediated and ischemic neuronal injury both in vitro and in vivo and explored the involvement of ASIC1a and underlying mechanism.

Methods—
Cultured neurons and NS20Y cells were subjected to acidosis-mediated injury in vitro. Cell viability and cytotoxicity were measured by methylthiazolyldiphenyl-tetrazolium bromide and lactate dehydrogenase assays, respectively. Transient (60 minutes) focal ischemia in mice was induced by suture occlusion of the middle cerebral artery in vivo. ASIC currents were recorded using whole-cell patch-clamp technique while intracellular Ca²⁺ concentration was measured with fluorescence imaging using Fura-2. ASIC1a expression was detected by Western blotting and quantitative real-time polymerase chain reaction.

Results—
Treatment of neuronal cells with β-estradiol decreased acidosis-induced cytotoxicity. ASIC currents and acid-induced elevation of intracellular Ca²⁺ were all attenuated by β-estradiol treatment. In addition, we showed that β-estradiol treatment reduced ASIC1a protein expression, which was mediated by increased protein degradation, and that estrogen receptor α was involved. Finally, we showed that the level of ASIC1a protein expression in brain tissues and the degree of neuroprotection by ASIC1a blockade were lower in female mice, which could be attenuated by ovariectomy.

Conclusions—
β-estradiol can protect neurons against acidosis-mediated neurotoxicity and ischemic brain injury by suppressing ASIC1a protein expression and channel function.

Visual Overview—
An online visual overview is available for this article.

Transient Focal Ischemia Significantly Alters the m⁶A Epitranscriptomic Tagging of RNAs in the Brain

Stroke. 2019 | Volume 50, Issue 10: 2912–2921,

originally publishedAugust 22, 2019,

https://doi.org/10.1161/STROKEAHA.119.026433

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Background and Purpose—
Adenosine in many types of RNAs can be converted to m⁶A (N⁶-methyladenosine) which is a highly dynamic epitranscriptomic modification that regulates RNA metabolism and function. Of all organs, the brain shows the highest abundance of m⁶A methylation of RNAs. As recent studies showed that m⁶A modification promotes cell survival after adverse conditions, we currently evaluated the effect of stroke on cerebral m⁶A methylation in mRNAs and lncRNAs.

Methods—
Adult C57BL/6J mice were subjected to transient middle cerebral artery occlusion. In the peri-infarct cortex, m⁶A levels were measured by dot blot analysis, and transcriptome-wide m⁶A changes were profiled using immunoprecipitated methylated RNAs with microarrays (44 122 mRNAs and 12 496 lncRNAs). Gene ontology analysis was conducted to understand the functional implications of m⁶A changes after stroke. Expression of m⁶A writers, readers, and erasers was also estimated in the ischemic brain.

Results—
Global m⁶A levels increased significantly at 12 hours and 24 hours of reperfusion compared with sham. While 139 transcripts (122 mRNAs and 17 lncRNAs) were hypermethylated, 8 transcripts (5 mRNAs and 3 lncRNAs) were hypomethylated (>5-fold compared with sham) in the ischemic brain at 12 hours reperfusion. Inflammation, apoptosis, and transcriptional regulation are the major biological processes modulated by the poststroke differentially m⁶A methylated mRNAs. The m⁶A writers were unaltered, but the m⁶A eraser (fat mass and obesity-associated protein) decreased significantly after stroke compared with sham.

Conclusions—
This is the first study to show that stroke alters the cerebral m⁶A epitranscriptome, which might have functional implications in poststroke pathophysiology.

Visual Overview—
An online visual overview is available for this article.

Role of TLR4 (Toll-Like Receptor 4) in N1/N2 Neutrophil Programming After Stroke

Stroke. 2019 | Volume 50, Issue 10: 2922–2932,

originally publishedAugust 27, 2019,

https://doi.org/10.1161/STROKEAHA.119.025085

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Background and Purpose—
After stroke, the population of infiltrated neutrophils in the brain is heterogeneous, including a population of alternative neutrophils (N2) that express M2 phenotype markers. We explored the role of TLR4 (toll-like receptor 4) on neutrophil infiltration and polarization in this setting.

Methods—
Focal cerebral ischemia was induced by occlusion of the middle cerebral artery occlusion in TLR4-KO and WT (wild type) mice. Infarct size was measured by Nissl staining and magnetic resonance imaging. Leukocyte infiltration was quantified 48 hours after middle cerebral artery occlusion by immunofluorescence and flow cytometry. To elucidate mechanisms underlying TLR4-mediated N2 phenotype, a cDNA microarray analysis was performed in neutrophils isolated from blood 48 hours after stroke in WT and TLR4-KO mice.

Results—
As demonstrated previously, TLR4-deficient mice presented lesser infarct volumes than WT mice. TLR4-deficient mice showed higher density of infiltrated neutrophils 48 hours after stroke compared with WT mice, concomitantly to neuroprotection. Furthermore, cytometric and stereological analyses revealed an increased number of N2 neutrophils (YM1⁺ cells) into the ischemic core in TLR4-deficient mice, suggesting a protective effect of this neutrophil subset that was corroborated by depleting peripheral neutrophils or using mice with TLR4 genetically ablated in the myeloid lineage. Finally, cDNA microarray analysis in neutrophils, confirmed by quantitative polymerase chain reaction, showed that TLR4 modulates several pathways associated with ischemia-induced inflammation, migration of neutrophils into the parenchyma, and their functional priming, which might explain the opposite effect on outcome of the different neutrophil subsets.

Conclusions—
TLR4 deficiency increased the levels of alternative neutrophils (N2)—an effect associated with neuroprotection after stroke—supporting that modulation of neutrophil polarization is a major target of TLR4 and highlighting the crucial role of TLR4 at the peripheral level after stroke.

Visual Overview—
An online visual overview is available for this article.

Assessment of the Most Optimal Control Tissue for Intracranial Aneurysm Gene Expression Studies

Stroke. 2019 | Volume 50, Issue 10: 2933–2936,

originally publishedAugust 20, 2019,

https://doi.org/10.1161/STROKEAHA.119.024881

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Background and Purpose—
Finding adequate control tissue for intracranial aneurysm (IA) pathophysiological studies, including gene expression studies, can be challenging. We compared gene expression profiles of superficial temporal, cortical, and circle of Willis (CoW) arteries and IA in search of the most optimal control tissue for future experiments.

Methods—
We compared RNA-sequencing data of IA samples and of superficial temporal, cortical, and CoW artery samples using Pearson correlation, Euclidean distance, and principal component analysis. We used the Mann-Whitney U test for comparison of Pearson correlation coefficients and Euclidean distances, to assess which control tissue is most similar to IA in terms of gene expression. Other unrelated tissues were used as negative controls.

Results—
The cortical and the CoW arteries were more similar to IA in terms of gene expression than the superficial temporal artery. This was based on Pearson correlation (+0.023 [90% CI, 0.017/0.029; P=1.9E-09] for the cortical artery and +0.034 [90% CI, 0.028/0.040; P=6.0E-15] for the CoW artery compared with the superficial temporal artery), Euclidean distance (−25.71 [90% CI, −31.54/−20.02; P=1.9E-11] for the cortical artery and −38.09 [90% CI, −44.08/−32.19; P<2.2E-16] for the CoW artery compared with the superficial temporal artery) and principal component analysis. In all analyses, the unrelated tissues formed separate groups compared with IA and the 3 control arteries.

Conclusions—
The cortical arteries and the CoW arteries are better controls for gene expression studies on IA than the superficial temporal artery. This probably relates to differences in anatomy of these tissues, such as the presence of an external elastic lamina in the extracranial vasculature and absence in the intracranial vasculature, because IAs, cortical arteries, and CoW arteries are all intracranial while the superficial temporal artery is extracranial. Since CoW arteries can only be obtained postmortem, cortical arteries are preferred over CoW arteries.

Incidence and Etiologies of Stroke Mimics After Incident Stroke or Transient Ischemic Attack

Stroke. 2019 | Volume 50, Issue 10: 2937–2940,

originally publishedAugust 26, 2019,

https://doi.org/10.1161/STROKEAHA.119.026573

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Background and Purpose—
Stroke mimics (SM) pose a common clinical challenge, but the burden of SM in patients with previous ischemic stroke (IS) or transient ischemic attack is unknown. The objective of this study was to calculate the incidence of SM in IS survivors, compare it with the incidence of recurrent stroke in the same population, and explore the time-dependent patterns of SM etiologies.

Methods—
This prospective cohort study registered SM events and etiologies among 1872 IS and transient ischemic attack survivors diagnosed with index stroke at Haukeland University Hospital stroke unit from 2007 to 2013 by review of medical records. Cumulative incidences of SM were estimated with a competing risks Cox model and compared with incidence of recurrent stroke in the same population.

Results—
During 8172 person-years of follow-up, 339 patients had 480 SM events. The cumulative incidence rate of SM during follow-up was 58.7 per 1.000 person-years (95% CI, 53.7–64.2) compared with 34.0 per 1.000 person-years (95% CI, 30.2–38.2) for recurrent stroke in the same time period. The risks of SM and recurrent stroke were highest the first year after index IS or transient ischemic attack. The most frequent SM diagnoses were sequelae of cerebral infarction (19.8%), medical observation, and evaluation for suspected cerebrovascular disease (15.6%) and infections (14.0%). The 2 most frequent and unspecific diagnoses (sequelae of cerebral infarction and medical observation) were clustered in the first months after index stroke.

Conclusions—
SM after IS or transient ischemic attack are more frequent than recurrent stroke and the risk is especially high in the early period. SMs are multietiological and unspecific diagnoses are most frequent early after index stroke.

Educating Paramedics on the Finger-to-Nose Test Improves Recognition of Posterior Stroke

Stroke. 2019 | Volume 50, Issue 10: 2941–2943,

originally publishedAugust 6, 2019,

https://doi.org/10.1161/STROKEAHA.119.026221

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Background and Purpose—
Emergency medical services (EMS) stroke recognition facilitates rapid care, however, prehospital stroke screening tools rely on signs that are often absent in posterior circulation strokes. We hypothesized that addition of the finger-to-nose (FTN) test to the Cincinnati Prehospital Stroke Scale would improve EMS posterior stroke recognition.

Methods—
In this controlled before and after study of consecutive EMS transported posterior ischemic strokes, paramedics in a single EMS agency received in-person training in the use of the FTN test. Paramedics at 2 other local EMS agencies served as controls. We compared the change in posterior stroke recognition, door-to-CT times, and alteplase delivery between the FTN (intervention) and control agencies.

Results—
Over 21 months, 51 posterior circulation strokes were transported by the FTN agency and 88 in the control agencies. Following training, posterior stroke recognition improved from 46% to 74% (P=0.039) in the FTN agency, whereas there was no change in the control agencies (32% before versus 39% after, P=0.467). Mean door-to-CT time in the FTN agency also improved following training (62–41 minutes, P=0.037) but not in the control agencies (58–61 minutes, P=0.771). There was no difference in alteplase delivery.

Conclusions—
Paramedics trained in the FTN test were more likely to identify posterior stroke. If future studies confirm these findings, such training may expedite the care of posterior stroke patients transported by EMS.

Circulating DNAs, a Marker of Neutrophil Extracellular Traposis and Cancer-Related Stroke

The OASIS-Cancer Study

Stroke. 2019 | Volume 50, Issue 10: 2944–2947,

originally publishedAugust 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.026373

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Background and Purpose—
The role of circulating neutrophil extracellular traps (NETs) in cancer-related stroke is unknown.

Methods—
We conducted a prospective cohort study to test whether NETs are increased in cancer-related stroke and whether elevated NETs levels are associated with coagulopathy, assessed using D-dimer levels (≥2 μg/mL). Plasma DNA and nucleosome were assessed as NET-specific biomarkers.

Results—
In total, 138 patients were recruited; 38 patients had cancer-related stroke (active cancer and acute cryptogenic embolic stroke), 33 patients were healthy-controls, 27 patients were cancer-controls (active cancer but no stroke), and 40 patients were stroke-controls (acute ischemic stroke but no cancer). Plasma DNA and nucleosome levels were significantly elevated in cancer-related stroke patients than in healthy-controls (P<0.05). These levels were correlated with the D-dimer levels (P<0.01). In multiple regression analyses, increased plasma DNA levels were associated with cancer-related stroke (odds ratio=11.65 for highest quartile; 95% CI, 3.199–42.46) and D-dimer levels of ≥2 μg/mL (odds ratio=19.09 for highest quartile; 95% CI, 4.143–87.95) after adjusting for possible confounders.

Conclusions—
Increased circulating DNA levels were associated with cancer-related stroke, suggesting that NETosis is one of the molecular mechanisms of cancer-related stroke. Further long-term follow-up studies in large cohorts are needed to confirm the role of NET-specific biomarkers.

Multiple Soluble Components of the Glycocalyx Are Increased in Patient Plasma After Ischemic Stroke

Stroke. 2019 | Volume 50, Issue 10: 2948–2951,

originally publishedAugust 14, 2019,

https://doi.org/10.1161/STROKEAHA.119.025953

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Background and Purpose—
The GLX (glycocalyx) is a protein/polysaccharide meshwork at the cellular surface. Consisting largely of glycosaminoglycans and proteoglycans, the GLX can shed in response to stress. In this study, we assay 11 components of the GLX in plasma from patients with ischemic stroke from a longitudinal cohort.

Methods—
Plasma samples from healthy individuals (N=8), and patients with ischemic stroke day ≥3, day 7, and day 90 (N=9–14) were immunoassayed for diverse components of the GLX.

Results—
Median stroke severity was mild (National Institutes of Health Stroke Scale 2.0 (range, 0–6) at day ≤3). Three (keratan-chondroitin-heparan-sulfate) of 4 glycosaminoglycans and CD44 (proteoglycan) were increased at day 7 and returned to baseline at day 90. Proteoglycan syndecan (Syn)-3 increased and Syn-2 levels decreased, significantly.

Conclusions—
Individual GLX components are often assayed as stand-alone biomarkers for endothelial health. This study suggests a full assessment of GLX components is more indicative of the endothelial health of an individual and represents a complex GLX signature that may be valuable as a composite biomarker of disease.

Risk Factors for Unruptured Intracranial Aneurysms and Subarachnoid Hemorrhage in a Prospective Population-Based Study

Stroke. 2019 | Volume 50, Issue 10: 2952–2955,

originally publishedAugust 2, 2019,

https://doi.org/10.1161/STROKEAHA.119.025951

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Background and Purpose—
We wanted to evaluate potential risk factors for unruptured intracranial aneurysms (UIAs) and aneurysmal subarachnoid hemorrhage (aSAH) in a large, prospective study of the general population with risk factors collected before the detection of UIA or aSAH.

Methods—
All residents ≥20 years were invited to the HUNT (The Nord-Trøndelag Health Study). In this study, 89 951 participants were included. The study included standardized measurements of blood pressure and self-administered questionnaires. Cases of UIA and aSAH from 1999 to 2014 were identified using hospital records and the Norwegian Cause of Death Register. Hazard ratios with CIs were estimated using Cox regression analysis.

Results—
The detection rate of UIA was 8.2 per 100 000 person-years (97 patients). Current smoking (hazard ratio, 4.1; 95% CI, 2.4–7.1) and female sex (hazard ratio, 2.8; 95% CI, 1.7–4.5) were associated with markedly increased risk of UIA, but we found no association with systolic blood pressure (P for trend 0.62). The incidence of aSAH was 9.9 per 100 000 person-years (117 patients). The most important risk factors for aSAH were current smoking, female sex and increasing blood pressure (P for trend 0.006 for systolic blood pressure).

Conclusions—
In contrast to previous studies on risk factors of UIA, we found no association with systolic blood pressure. However, there was a strong association between systolic blood pressure and aSAH in the same population. Current smoking and female sex were associated with both diseases.

Differences in Brain Areas Affecting Language Function After Stroke

Stroke. 2019 | Volume 50, Issue 10: 2956–2959,

originally publishedAugust 6, 2019,

https://doi.org/10.1161/STROKEAHA.119.026222

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Background and Purpose—
Brain areas associated with functional improvement differ between acute and chronic phases after stroke. This study investigated brain areas associated with language function, according to time after stroke.

Methods—
Patients with aphasia after stroke were divided into subacute (≤3 months after stroke, 17 patients) and chronic groups (>12 months after stroke, 23 patients). Voxel-wise linear regression analyses in each group were conducted by using fractional anisotropy mapping in diffusion tensor images as a dependent variable, while scores of spontaneous speech, comprehension, repetition, and naming were used as independent variables.

Results—
Structural connectivity in the left dorsal pathway (eg, superior temporal gyrus, inferior parietal lobule, and superior longitudinal fasciculus) was positively associated with spontaneous speech, repetition, and naming, whereas structural connectivity in the corona radiata, internal capsule, and corpus callosum of the right hemisphere was negatively associated with language function in the subacute phase. Comprehension was associated with the left superior temporal gyrus and the right corona radiata in the subacute phase and the right corpus callosum in the chronic phase (P_FWE<0.05).

Conclusions—
More lateralized language function related to the dorsal pathway was influenced in the bilateral brain areas in the subacute phase but not in the chronic phase. Less lateralized language function related to the ventral pathway was influenced in the bilateral brain areas during both subacute and chronic phases after stroke.

Twenty-Four–Hour Reocclusion After Successful Mechanical Thrombectomy

Associated Factors and Long-Term Prognosis

Stroke. 2019 | Volume 50, Issue 10: 2960–2963,

originally publishedAugust 6, 2019,

https://doi.org/10.1161/STROKEAHA.119.026228

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Background and Purpose—
Early arterial recanalization is a strong determinant of prognosis in acute ischemic stroke. Nevertheless, reocclusion can occur after initial recanalization. We assessed associated factors and long-term prognosis of reocclusion after successful mechanical thrombectomy (MT).

Methods—
From the prospectively constructed Acute Stroke Registry and Analysis of Lausanne cohort, we included consecutive patients with anterior and posterior circulation strokes treated by successful MT (modified treatment in cerebral infarction 2b-3) and with 24-hour vascular imaging available. Reocclusion at this time-point was defined as new intracranial occlusion within an arterial segment recanalized at the end of MT. Through multivariate logistic regression, we investigated associated factors and 3-months outcome. In a 4:1 matched-cohort, we also assessed the role of residual thrombus or stenosis on post-recanalization angiographic images as potential predictor of reocclusion.

Results—
Among 473 patients with successful recanalization, 423 (89%) were included. Of these, 28 (6.6%) had 24-hour reocclusion. Preadmission statin therapy (aOR [adjusted odds ratio], 0.27; 95% CI, 0.08–0.94), intracranial internal carotid artery occlusion (aOR, 3.53; 95% CI, 1.50–8.32), number of passes (aOR, 1.31; 95% CI, 1.06–1.62), transient reocclusion during MT (aOR, 8.55; 95% CI, 2.14–34.09), and atherosclerotic cause (aOR, 3.14; 95% CI, 1.34–7.37) were independently associated with reocclusion. In the matched-cohort analysis, residual thrombus or stenosis was associated with reocclusion (aOR, 15.6; 95% CI, 4.6–52.8). Patients experiencing reocclusion had worse outcome (aOR, 5.0; 95% CI, 1.2–20.0).

Conclusions—
Reocclusion within 24-hours of successful MT was independently associated with statin pretreatment, occlusion site, more complex procedures, atherosclerotic cause, and residual thrombus or stenosis after recanalization. Reocclusion impact on long-term outcome highlights the need to monitor and prevent this early complication.

Outcomes of Surgery for Brainstem Cavernous Malformations

A Systematic Review

Stroke. 2019 | Volume 50, Issue 10: 2964–2966,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.026120

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Background and Purpose—
The goal of this study was to systematically review the outcomes and complications after surgical resection of brain stem cavernous malformations (BCMs).

Methods—
A systematic literature review was performed using the PubMed database for studies published between 1986 and 2018. All studies comprising ≥2 patients with surgically resected BCMs and available follow-up data were included. Data extracted from studies included patient demographics, BCM location, and surgical outcomes.

Results—
Eighty-six studies comprising 2493 patients (adult and pediatric) were included for final analysis. Complete resection was achieved in 92.3% (fixed-effects pooled estimate [FE], 92.9% [91.7%–94.0%]; random-effects pooled estimate [RE], 89.4% [86.5%–92.0%]) of patients, and rehemorrhage of residual BCMs occurred in 58.6% (FE, 58.8% [49.7%–67.6%]; RE, 57.2% [43.5%–70.2%]). Postoperative morbidity occurred in 34.8% (FE, 30.9% [29.0%–32.8%]; RE, 31.1% [25.8%–36.6%]) of patients. Postoperative morbidities included motor deficit in 11.0% (FE, 9.9% [8.1%–11.7%]; RE, 11.1% [7.0%–16.0%]), sensory deficit in 6.7% (FE, 6.3% [4.8%–7.9%]; RE, 7.6% [4.5%–11.5%]), tracheostomy/gastrostomy in 6.0% (FE, 5.2% [4.3%–6.1%]; RE, 3.8% [2.6%–5.3%]), and other cranial nerve deficits in 29.4% (FE, 27.6% [25.3%–29.9%]; RE, 33.9% [25.7%–42.6%]) of patients. At final follow-up, 57.9% (FE, 57.6% [55.6%–59.6%]; RE, 57.2% [52.1%–62.3%]) and 25.9% (FE, 24.1% [22.4%–25.9%]; RE, 18.5% [14.6%–22.8%]) of patients had improvement and stability of preoperative symptoms, respectively. Mortality rate was 1.6% (FE, 1.9% [1.4%–2.5%]; RE, 1.8% [1.4%–2.5%]).

Conclusions—
High cure rates and low rates of postoperative morbidity can be achieved with surgery in patients with BCMs. Most patients had improved preoperative symptoms at final follow-up. To avoid rehemorrhage, complete resection should be the goal of surgery.

Intracranial Artery Stenosis and Its Association With Conventional Risk Factors in a General Population of Japanese Men

Stroke. 2019 | Volume 50, Issue 10: 2967–2969,

originally publishedJuly 22, 2019,

https://doi.org/10.1161/STROKEAHA.119.025964

This article corrects the following:
- Correction to: Intracranial Artery Stenosis and Its Association With Conventional Risk Factors in a General Population of Japanese Men
  - Volume 50Issue 11Stroke
  - 28 October 2019

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Background and Purpose—
Few community-based studies have reported the prevalence of intracranial artery stenosis (ICAS) assessed with magnetic resonance angiography. The aim was to determine the prevalence of ICAS using magnetic resonance angiography in a general population of Japanese men and to investigate the associations between ICAS and conventional cardiovascular risk factors.

Methods—
The Shiga Epidemiological Study of Subclinical Atherosclerosis randomly recruited and examined participants from Kusatsu City, Shiga, Japan, in 2006 to 2008 (baseline); 740 men returned for follow-up and underwent 1.5 T brain magnetic resonance angiography in 2012 to 2015. Participants were categorized as having no-ICAS, mild-ICAS (1 to <50%), or severe-ICAS (≥50%) in any of the arteries examined. After excluding the men with a history of stroke, 709 men were analyzed using multivariable logistic regression to assess independent associations of conventional cardiovascular risk factors with reference to the no-ICAS group.

Results—
The participants’ mean age was 68.0 years. The age-standardized prevalences of mild and severe-ICAS were 20.7% and 4.5%, respectively (with the population of the 2010 Japanese vital statistics as the reference). Age, hypertension, diabetes mellitus, and dyslipidemia were associated with a higher prevalence of severe-ICAS after simultaneous adjustment for conventional cardiovascular risk factors.

Conclusions—
In a community-based sample of Japanese men, ICAS was estimated to be present in 25.2%, and related to metabolic risk factors, in addition to hypertension and age. These results support the importance of comprehensive management of conventional cardiovascular risk factors for stroke prevention.

Intracranial Vessel Wall Magnetic Resonance Imaging Does Not Allow for Accurate and Precise Wall Thickness Measurements

An Ex Vivo Study

Stroke. 2019 | Volume 50, Issue 10: e283–e284,

originally publishedAugust 26, 2019,

https://doi.org/10.1161/STROKEAHA.119.026497

Atrial Fibrillation Ablation and Reduction of Stroke Events

Understanding the Paradoxical Lack of Evidence

Stroke. 2019 | Volume 50, Issue 10: 2970–2976,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.026890

This article corrects the following:
- Correction to: Atrial Fibrillation Ablation and Reduction of Stroke Events: Understanding the Paradoxical Lack of Evidence
  - Volume 50Issue 12Stroke
  - 25 November 2019

Advances and Innovations in Aphasia Treatment Trials

Shauna Berube and
Argye E. Hillis

Stroke. 2019 | Volume 50, Issue 10: 2977–2984,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.025290

Pericytes

A Novel Target to Improve Success of Recanalization Therapies

Turgay Dalkara

Stroke. 2019 | Volume 50, Issue 10: 2985–2991,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.118.023590

Prehospital Stroke Scales as Screening Tools for Early Identification of Stroke and Transient Ischemic Attack

Stroke. 2019 | Volume 50, Issue 10: e285–e286,

originally publishedAugust 14, 2019,

https://doi.org/10.1161/STROKEAHA.119.026527

Building a Career as a Pediatric Stroke Neurologist

Stroke. 2019 | Volume 50, Issue 10: e287–e289,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.026187

Acute Lateral Medullary Infarct due to Giant Cell Arteritis

A Case Study

Stroke. 2019 | Volume 50, Issue 10: e290–e293,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.026566

Letter by Diplomatico and Barbi Regarding Article, “Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association”

Mario Diplomatico and
Egidio Barbi

Stroke. 2019 | Volume 50, Issue 10: e294,

originally publishedAugust 19, 2019,

https://doi.org/10.1161/STROKEAHA.119.025698

Letter by Bourcier et al Regarding Article, “Per-Pass Analysis of Thrombus Composition in Patients With Acute Ischemic Stroke Undergoing Mechanical Thrombectomy”

Stroke. 2019 | Volume 50, Issue 10: e295,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026485

Response by Duffy et al to Letter Regarding Article, “Per-Pass Analysis of Thrombus Composition in Patients With Acute Ischemic Stroke Undergoing Mechanical Thrombectomy”

Stroke. 2019 | Volume 50, Issue 10: e296,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026621

Letter by Semerano et al Regarding Article, “Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source”

Stroke. 2019 | Volume 50, Issue 10: e297,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026662

Response by Fitzgerald and Brinjikji to Letter Regarding Article, “Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source”

Seán Fitzgerald and
Waleed Brinjikji

Stroke. 2019 | Volume 50, Issue 10: e298,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026856

Letter by Liu and Zhang Regarding Article, “Relationship Between Impaired Consciousness and Injury of Ascending Reticular Activating System in Patients With Intracerebral Hemorrhage”

Wei Liu and
Jian-Guo Zhang

Stroke. 2019 | Volume 50, Issue 10: e299,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.026689

Response by Ho Jang and Kwon to Letter Regarding Article, “Relationship Between Impaired Consciousness and Injury of Ascending Reticular Activating System in Patients With Intracerebral Hemorrhage”

Sung Ho Jang and
Young Hyeon Kwon

Stroke. 2019 | Volume 50, Issue 10: e300,

originally publishedSeptember 9, 2019,

https://doi.org/10.1161/STROKEAHA.119.027289

Letter by Wu et al Regarding Article, “Detrimental Effect of Chronic Hypertension on Leptomeningeal Collateral Flow in Acute Ischemic Stroke”

Stroke. 2019 | Volume 50, Issue 10: e301,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026682

Response by Fujita et al to Letter Regarding Article, “Detrimental Effect of Chronic Hypertension on Leptomeningeal Collateral Flow in Acute Ischemic Stroke”

Stroke. 2019 | Volume 50, Issue 10: e302,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026855

Letter by Wu et al Regarding Article, “Intracranial Cerebrospinal Fluid Volume as a Predictor of Malignant Middle Cerebral Artery Infarction”

Stroke. 2019 | Volume 50, Issue 10: e303,

originally publishedAugust 27, 2019,

https://doi.org/10.1161/STROKEAHA.119.026615

Response by Kauw et al to Letter Regarding Article, “Intracranial Cerebrospinal Fluid Volume as a Predictor of Malignant Middle Cerebral Artery Infarction”

Stroke. 2019 | Volume 50, Issue 10: e304,

originally publishedAugust 27, 2019,

https://doi.org/10.1161/STROKEAHA.119.026853

Letter by Wen et al Regarding Article, “Validation of Wall Enhancement as a New Imaging Biomarker of Unruptured Cerebral Aneurysm”

Stroke. 2019 | Volume 50, Issue 10: e305,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.026830

Response by Quan et al to Letter Regarding Article, “Validation of Wall Enhancement as a New Imaging Biomarker of Unruptured Cerebral Aneurysm”

Stroke. 2019 | Volume 50, Issue 10: e306,

originally publishedAugust 29, 2019,

https://doi.org/10.1161/STROKEAHA.119.027038

Letter by Sugiyama Regarding Article, “Screening and Treatment for Osteoporosis After Stroke: Results From the Ontario Stroke Registry”

Toshihiro Sugiyama

Stroke. 2019 | Volume 50, Issue 10: e307,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026863

Response by Cheung and Kapral to Letter Regarding Article, “Screening and Treatment for Osteoporosis After Stroke: Results From the Ontario Stroke Registry”

Angela M. Cheung and
Moira K. Kapral

Stroke. 2019 | Volume 50, Issue 10: e308,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026949

Letter by Ross Regarding Article, “Circulating Multiple Metals and Incident Stroke in Chinese Adults: The Dongfeng-Tongji Cohort”

Celia M. Ross

Stroke. 2019 | Volume 50, Issue 10: e309,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.026984

Response by Xiao et al to Letter Regarding Article, “Circulating Multiple Metals and Incident Stroke in Chinese Adults: The Dongfeng-Tongji Cohort”

Stroke. 2019 | Volume 50, Issue 10: e310,

originally publishedSeptember 13, 2019,

https://doi.org/10.1161/STROKEAHA.119.027042

Letter by Renú et al Regarding Article, “Frequency of Blood-Brain Barrier Disruption Postendovascular Therapy and Multiple Thrombectomy Passes in Acute Ischemic Stroke Patients”

Stroke. 2019 | Volume 50, Issue 10: e311,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.027122

Response by Luby et al to Letter Regarding Article, “Frequency of Blood-Brain Barrier Disruption Postendovascular Therapy and Multiple Thrombectomy Passes in Acute Ischemic Stroke Patients”

Stroke. 2019 | Volume 50, Issue 10: e312,

originally publishedSeptember 12, 2019,

https://doi.org/10.1161/STROKEAHA.119.027214

Correction to: Brief Educational Intervention Improves Emergency Medical Services Stroke Recognition

Stroke. 2019 | Volume 50, Issue 10: e313,

originally publishedSeptember 23, 2019,

https://doi.org/10.1161/STR.0000000000000208

Correction(s) for this article
- Brief Educational Intervention Improves Emergency Medical Services Stroke Recognition
  - J. Adam Oostema
  - Todd Chassee
  - William Baer
  - Allison Edberg
  - Mathew J. Reeves
  - Volume 50Issue 5Stroke
  - 28 March 2019

Table of Contents

Editorials

Poststroke Cognitive Recovery Prediction

Optimal Blood Pressure for Stroke Thrombectomy

High Time for Prospective Data!

Stroke: Highlights of Selected Articles

Stroke: Highlights of Selected Articles

Original Contributions

Clinical Sciences

The Atherosclerosis Risk Variant rs2107595 Mediates Allele-Specific Transcriptional Regulation of HDAC9 via E2F3 and Rb1

Background and Purpose—

Methods—

Results—

Conclusions—

Stroke Incidence and Case Fatality According to Rural or Urban Residence

Results From the French Brest Stroke Registry

Background and Purpose—

Methods—

Results—

Conclusions—

Brain Activity and Cerebral Oxygenation After Perinatal Arterial Ischemic Stroke Are Associated With Neurodevelopment

Background and Purpose—

Methods—

Results—

Conclusions—

Blood Pressure Drop and Penumbral Tissue Loss in Nonrecanalized Emergent Large Vessel Occlusion

Background and Purpose—

Methods—

Results—

Conclusions—

Infection During Delivery Hospitalization and Risk of Readmission for Postpartum Stroke

Background and Purpose—

Methods—

Results—

Conclusions—

Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Disease

Classification and Clinical Implications

Background and Purpose—

Methods—

Results—

Conclusions—

Degeneration of the Inferior Cerebellar Peduncle After Middle Cerebral Artery Stroke

Another Perspective on Crossed Cerebellar Diaschisis

Background and Purpose—

Methods—

Results—

Conclusions—

Collateral Circulation in Moyamoya Disease

A New Grading System

Background and Purpose—

Methods—

Results—

Conclusions—

Early Fibrinogen Depletion and Symptomatic Intracranial Hemorrhage After Reperfusion Therapy

Background and Purpose—

Methods—

Results—

Conclusions—

Clinical Trial Registration—

Impact of Cerebral Small Vessel Disease on Functional Recovery After Intracerebral Hemorrhage

Background and Purpose—

Methods—

Results—

Conclusions—

Deviation From Personalized Blood Pressure Targets Is Associated With Worse Outcome After Subarachnoid Hemorrhage

Background and Purpose—

Methods—

Results—

Conclusions—

Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage

Background and Purpose—

Methods—

Results—

Conclusions—

Clinical Trial Registration—

Stereotactic Radiosurgery for Unruptured Versus Ruptured Pediatric Brain Arteriovenous Malformations

Background and Purpose—

Methods—

Results—

Conclusions—