Michael T. Mullen

CCR2+Ly6Chi Inflammatory Monocyte Recruitment Exacerbates Acute Disability Following Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating type of stroke that lacks a specific treatment. An intense immune response develops after ICH, which contributes to neuronal injury, disability, and death. However, the specific mediators of inflammation-induced injury remain unclear. The objective of the present study was to determine whether blood-derived CCR2+Ly6Chi inflammatory monocytes contribute to disability. ICH was induced in mice and the resulting inflammatory response was quantified using flow cytometry, confocal microscopy, and neurobehavioral testing. Importantly, blood-derived monocytes were distinguished from resident microglia by differential CD45 staining and by using bone marrow chimeras with fluorescent leukocytes. After ICH, blood-derived CCR2+Ly6Chi inflammatory monocytes trafficked into the brain, outnumbered other leukocytes, and produced tumor necrosis factor. Ccr2−/− mice, which have few circulating inflammatory monocytes, exhibited better motor function following ICH than control mice. Chimeric mice with wild-type CNS cells and Ccr2−/− hematopoietic cells also exhibited early improvement in motor function, as did wild-type mice after inflammatory monocyte depletion. These findings suggest that blood-derived inflammatory monocytes contribute to acute neurological disability. To determine the translational relevance of our experimental findings, we examined CCL2, the principle ligand for the CCR2 receptor, in ICH patients. Serum samples from 85 patients were collected prospectively at two hospitals. In patients, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 after adjusting for potential confounding variables. Together, these findings suggest that inflammatory monocytes worsen early disability after murine ICH and may represent a therapeutic target for patients.

Predictors of Finding Occult Atrial Fibrillation After Cryptogenic Stroke

Background and Purpose— Occult paroxysmal atrial fibrillation (AF) is found in a substantial minority of patients with cryptogenic stroke. Identifying reliable predictors of paroxysmal AF after cryptogenic stroke would allow clinicians to more effectively use outpatient cardiac monitoring and ultimately reduce secondary stroke burden. Methods— We analyzed a retrospective cohort of consecutive patients who underwent 28-day mobile cardiac outpatient telemetry after cryptogenic stroke or transient ischemic stroke. Univariate and multivariable analyses were performed to identify clinical, echocardiographic, and radiographic features associated with the detection of paroxysmal AF. Results— Of 227 patients with cryptogenic stroke (179) or transient ischemic stroke (48), 14% (95% confidence interval, 9%–18%) had AF detected on mobile cardiac outpatient telemetry, 58% of which was ≥30 seconds in duration. Age >60 years (odds ratio, 3.7; 95% confidence interval, 1.3–11) and prior cortical or cerebellar infarction seen on neuroimaging (odds ratio, 3.0; 95% confidence interval, 1.2–7.6) were independent predictors of AF. AF was detected in 33% of patients with both factors, but only 4% of patients with neither. No other clinical features (including demographics, CHA2DS2-VASc [combined stroke risk score: congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack, vascular disease, sex] score, or stroke symptoms), echocardiographic findings (including left atrial size or ejection fraction), or radiographic characteristics of the acute infarction (including location, topology, or number) were associated with AF detection. Conclusions— Mobile cardiac outpatient telemetry detects AF in a substantial proportion of cryptogenic stroke patients. Age >60 years and radiographic evidence of prior cortical or cerebellar infarction are robust indicators of occult AF. Patients with neither had a low prevalence of AF.

Systematic Review of Outcome After Ischemic Stroke Due to Anterior Circulation Occlusion Treated With Intravenous, Intra-Arterial, or Combined Intravenous+Intra-Arterial Thrombolysis

Background and Purpose— The optimal approach to recanalization in acute ischemic stroke is unknown. We performed a literature review and meta-analysis comparing the relative efficacy of 6 reperfusion strategies: (1) 0.9 mg/kg intravenous tissue-type plasminogen activator; (2) intra-arterial chemical thrombolysis; (3) intra-arterial mechanical thrombolysis; (4) intra-arterial combined chemical/mechanical thrombolysis; (5) 0.6 mg/kg intravenous tissue-type plasminogen activator and intra-arterial thrombolysis; and (6) 0.9 mg/kg intravenous tissue-type plasminogen activator and intra-arterial thrombolysis. Methods— A literature search in Medline, Embase, and the Cochrane database identified case series, observational studies, and treatment arms of randomized trials of anterior circulation arterial occlusion treated with thrombolytic therapy. Included studies had ≥10 subjects, mean time to treatment <6 hours, and treatment specific reporting of disability, death, and intracerebral hemorrhage. Multivariable metaregression evaluated the effects of treatment group on outcome at the same time as accounting for differences in baseline covariates. Results— A total of 2986 abstracts were identified from which 54 studies (5019 subjects) were included. There were significant differences across groups in age (P=0.0008), baseline National Institutes of Health Stroke Scale (P=0.0002), and time to treatment initiation (P<0.0001). There were also differences in mean modified Rankin Scale (P<0.0001), mortality (P=0.0024), and symptomatic intracerebral hemorrhage (P=0.0305). Differences in modified Rankin Scale were not significant in the metaregression and likely attributable to differences in baseline covariates between studies. Conclusions— This study found no evidence that one reperfusion strategy is superior with respect to efficacy or safety, supporting clinical equipoise between reperfusion strategies. Intravenous tissue-type plasminogen activator remains the standard of care for acute ischemic stroke. Randomized clinical trials are necessary to determine the efficacy of alternative reperfusion strategies. Participation in such trials is strongly recommended.

Cervical carotid artery dissection is associated with styloid process length

Objective: To investigate whether cervical carotid artery dissection (CCAD) is associated with anatomic characteristics of the styloid process of the temporal bone. Methods: CT angiograms from 38 case patients with CCAD and 38 age- and sex-matched control subjects without dissection were studied. Styloid process length, angulation in the axial and rostral-caudal planes, and proximity to the carotid artery were measured bilaterally by raters blinded to radiology reports and clinical information. Results: In control subjects, there was substantial variation in styloid process length (range 4.6–42.9 mm), medial angulation (range 16–89°), caudal angulation (range 31–80°), and proximity to the carotid (range 0.7–15.4 mm). Control subjects also demonstrated marked symmetry between sides (correlation coefficients 0.80 for length, 0.34 for proximity, 0.81 for medial angulation, and 0.87 for caudal angulation). In case patients, the mean styloid length on the side of the dissection was not significantly longer than that on the contralateral side (mean 30.3 vs 29.7 mm, p = 0.30). The styloid process was significantly longer ipsilateral to the dissection in case patients compared with the side-matched process in control subjects (mean 30.3 vs 26.6 mm, p = 0.03). Carotid dissection was associated with increasing styloid process length (OR [OR] 1.08/mm, 95% confidence interval [CI] 1.002–1.17, p = 0.04). The OR of dissection in the highest quartile of length compared with that in the lower 3 quartiles was 4.0 (95% CI 1.3–14.2, p = 0.03). Conclusions: CCAD is associated with a longer styloid process, suggesting that mechanical injury from the styloid may contribute to the pathogenesis of CCAD.

Joint Commission Primary Stroke Centers Utilize More rt-PA in the Nationwide Inpatient Sample

Background The Joint Commission began certifying primary stroke centers (PSCs) in December 2003 and provides a standardized definition of stroke center care. It is unknown if PSCs outperform noncertified hospitals. We hypothesized that PSCs would use more recombinant tissue plasminogen activator (rt‐PA) for ischemic stroke than would non‐PSCs. Methods and Results Data were obtained from the Nationwide Inpatient Sample from 2004 to 2009. The analysis was limited to states that publicly reported hospital identity. All patients ≥18 years with a primary diagnosis of acute ischemic stroke were included. Subjects were excluded if the treating hospital was not identified, if it was not possible to determine the temporal relationship between certification and admission, and/or if admitted as a transfer. Rt‐PA was defined by ICD9 procedure code 99.10. All eligibility criteria were met by 323 228 discharges from 26 states. There were 63 145 (19.5%) at certified PSCs. Intravenous rt‐PA was administered to 3.1% overall: 2.2% at non‐PSCs and 6.7% at PSCs. Between 2004 and 2009, rt‐PA administration increased from 1.4% to 3.3% at non‐PSCs and from 6.0% to 7.6% at PSCs. In a multivariable model incorporating year, age, sex, race, insurance, income, comorbidities, DRG‐based disease severity, and hospital characteristics, evaluation at a PSC was significantly associated with rt‐PA utilization (OR, 1.87; 95% CI, 1.61 to 2.16). Conclusions Subjects evaluated at PSCs were more likely to receive rt‐PA than those evaluated at non‐PSCs. This association was significant after adjustment for patient and hospital‐level variables. Systems of care are necessary to ensure stroke patients have rapid access to PSCs throughout the United States.

Extinction, Renewal, and Spontaneous Recovery of a Spatial Preference in the Water Maze

Four experiments with C57BL/6 mice investigated extinction of a spatial preference in the Morris water maze. In Experiment 1, a spatial preference was extinguished by exposing mice to the water maze in the absence of a platform but in the presence of the distal spatial cues. In Experiment 2, extinction occurred when the platform was removed from the pool, when it was presented in random locations, or when it was presented consistently in the opposite location. Contextual renewal (Experiment 3) and spontaneous recovery (Experiment 4) of spatial preferences argue against an interpretation of extinction in terms of unlearning and instead suggest that extinction in the water maze, like extinction in Pavlovian conditioning, suppresses the original association. Implications of these findings for theories of spatial learning and hippocampal function are discussed.

Racial and Gender Differences in Stroke Severity, Outcomes and Treatment in Patients with Acute Ischemic Stroke

BACKGROUND Previous research has indicated that women and blacks have worse outcomes after acute ischemic stroke (AIS). Little research has been done to investigate the combined influence of race and gender in the presentation, treatment, and outcome of patients with AIS. We sought to determine the association of race and gender on initial stroke severity, thrombolysis, and functional outcome after AIS. METHODS AIS patients who presented to 2 academic medical centers in the United States (2004-2011) were identified through prospective registries. In-hospital strokes were excluded. Stroke severity, measured by admission National Institutes of Health Stroke Scale (NIHSS) scores, treatment with tissue plasminogen activator (tPA), neurologic deterioration (defined by a ≥2-point increase in NIHSS score), and functional outcome at discharge, measured by the modified Rankin Scale, were investigated. These outcomes were compared across race/gender groups. A subanalysis was conducted to assess race/gender differences in exclusion criteria for tPA. RESULTS Of the 4925 patients included in this study, 2346 (47.6%) were women and 2310 (46.9%) were black. White women had the highest median NIHSS score on admission (8), whereas white men had the lowest median NIHSS score on admission (6). There were no differences in outcomes between black men and white men. A smaller percentage of black women than white women were treated with tPA (27.6% versus 36.6%, P < .0001), partially because of a greater proportion of white women presenting within 3 hours (51% versus 45.5%, P = .0005). Black women had decreased odds of poor functional outcome relative to white women (odds ratio [OR] = .85, 95% confidence interval [CI] .72-1.00), but after adjustment for baseline differences in age, NIHSS, and tPA use, this association was no longer significant (OR = 1.2, 95% CI .92-1.46, P = .22). Black women with an NIHSS score less than 7 on admission were at lower odds of receiving tPA than the other race/gender groups, even after adjusting for arriving within 3 hours and admission glucose (OR = .66, 95% CI .44-.99, P = .0433). CONCLUSION Race and gender were not significantly associated with short-term outcome, although black women were significantly less likely to be treated with tPA. Black women had more tPA exclusions than any other group. The primary reason for tPA exclusion in this study was not arriving within 3 hours of stroke symptom onset. Given the growth in incident strokes projected in minority groups in the next 4 decades, identifying factors that contribute to black women not arriving to the emergency department in time are of great importance.

Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients During Head-of-Bed Manipulation

Background and Purpose— A primary goal of acute ischemic stroke (AIS) management is to maximize perfusion in the affected region and surrounding ischemic penumbra. However, interventions to maximize perfusion, such as flat head-of-bed (HOB) positioning, are currently prescribed empirically. Bedside monitoring of cerebral blood flow (CBF) allows the effects of interventions such as flat HOB to be monitored and may ultimately be used to guide clinical management. Methods— Cerebral perfusion was measured during HOB manipulations in 17 patients with unilateral AIS affecting large cortical territories in the anterior circulation. Simultaneous measurements of frontal CBF and arterial flow velocity were performed with diffuse correlation spectroscopy and transcranial Doppler ultrasound, respectively. Results were analyzed in the context of available clinical data and a previous study. Results— Frontal CBF, averaged over the patient cohort, decreased by 17% (P=0.034) and 15% (P=0.011) in the ipsilesional and contralesional hemispheres, respectively, when HOB was changed from flat to 30°. Significant (cohort-averaged) changes in blood velocity were not observed. Individually, varying responses to HOB manipulation were observed, including paradoxical increases in CBF with increasing HOB angle. Clinical features, stroke volume, and distance to the optical probe could not explain this paradoxical response. Conclusions— A lower HOB angle results in an increase in cortical CBF without a significant change in arterial flow velocity in AIS, but there is variability across patients in this response. Bedside CBF monitoring with diffuse correlation spectroscopy provides a potential means to individualize interventions designed to optimize CBF in AIS.

The treatment of spinal cord ischemia following thoracic endovascular aortic repair.

IntroductionThoracic endovascular aortic repair (TEVAR) is a promising alternative to the traditional open surgical approach, though spinal cord ischemia remains a challenging complication. Spinal cord ischemia has been treated using lumbar cerebral spinal fluid (CSF) drainage.MethodsWe report a case of delayed spinal cord ischemia that was successfully treated with vasopressor therapy alone, supporting aggressive blood pressure augmentation as a primary intervention to increase spinal cord perfusion.ResuldsThe pathophysiology of spinal cord ischemia after TEVAR is presented along with our treatment protocol.

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from the rupture of a blood vessel in the brain, leading to a mass of blood within the brain parenchyma. The injury causes a rapid inflammatory reaction that includes activation of the tissue-resident microglia and recruitment of blood-derived macrophages and other leukocytes. In this work, we investigated the specific responses of microglia following ICH with the aim of identifying pathways that may aid in recovery after brain injury. We used longitudinal transcriptional profiling of microglia in a murine model to determine the phenotype of microglia during the acute and resolution phases of ICH in vivo and found increases in TGF-&bgr;1 pathway activation during the resolution phase. We then confirmed that TGF-&bgr;1 treatment modulated inflammatory profiles of microglia in vitro. Moreover, TGF-&bgr;1 treatment following ICH decreased microglial Il6 gene expression in vivo and improved functional outcomes in the murine model. Finally, we observed that patients with early increases in plasma TGF-&bgr;1 concentrations had better outcomes 90 days after ICH, confirming the role of TGF-&bgr;1 in functional recovery from ICH. Taken together, our data show that TGF-&bgr;1 modulates microglia-mediated neuroinflammation after ICH and promotes functional recovery, suggesting that TGF-&bgr;1 may be a therapeutic target for acute brain injury.