Brian Mac Grory

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.

The effect of pro-inflammatory cytokines on the discharge rate of vagal nerve paraganglia in the rat.

Vagal paraganglia resemble the carotid body and are chemosensitive to reduction in the partial pressure of oxygen (PO2) (O’Leary et al., 2004). We hypothesised that they may also mediate communication between the immune system and the central nervous system and more specifically respond to the pro-inflammatory cytokines: interleukin-1 beta (IL-1β) and tumour necrosis factor-α (TNF-α). We recorded axonal firing rate of isolated superfused rat glomus cells – located at the bifurcation of the superior laryngeal nerve – to IL-1β or TNF-α at concentrations of 0.5 ng/ml, 5 ng/ml and 50 ng/ml. Twenty-three successful single fibre recordings were obtained from 10 animals. IL-1β and TNF-α had no statistically significant effect on the frequency of action potentials observed (p = 0.39 and 0.42, respectively, repeated measures ANOVA). The activity of both cytokines was tested by observing translocation of P65-NFκB from cytoplasm to nucleus in cultured HELA cells. In conclusion, an immune role for SLN paraganglia has not been established.

Cerebral Microhemorrhages and Meningeal Siderosis in Infective Endocarditis

Objective: Patients with infective endocarditis (IE) frequently experience cerebral insults, and neurological involvement in IE has been reported to herald a worse prognosis. In this manuscript, we describe a distinctive pattern of findings on susceptibility-weighted imaging (SWI) sequences in subjects with IE. Methods: Patients with IE who underwent SWI MRI at an academic hospital from 2009 to 2014 were retrospectively analyzed. The pattern of findings was compared to SWI findings in groups of subjects with cerebral amyloid angiopathy (CAA) or severe hypertension. Results: Sixty-six subjects with IE were included; 64 (94%) had microhemorrhages and the average number per patient was 21.5. In 11 (17%) patients, microhemorrhages were the only neuroimaging abnormality. The majority of microhemorrhages were between 1 and 3 mm. In a direct comparison of gradient-echo T2* (GRE-T2*) and SWI, many microhemorrhages in this size range were not detected by GRE-T2*. Microhemorrhages in IE involved every part of the brain with a significant predilection for the cerebellum. This pattern was distinct from that seen in hypertension or CAA. Small subarachnoid hemorrhage or meningeal siderosis were also frequently detected in IE, but were not associated with mycotic aneurysms. Interpretation: SWI is a sensitive diagnostic technique for detecting infectious cerebral angiopathy in subjects with IE, producing a pattern of microhemorrhages that were distinct from other common microangiopathies.

A Simple Score That Predicts Paroxysmal Atrial Fibrillation on Outpatient Cardiac Monitoring after Embolic Stroke of Unknown Source

BACKGROUND Occult paroxysmal atrial fibrillation (AF) is detected in 16%-30% of patients with embolic stroke of unknown source (ESUS). The identification of AF predictors on outpatient cardiac monitoring can help guide clinicians decide on a duration or method of cardiac monitoring after ESUS. METHODS We included all patients with ESUS who underwent an inpatient diagnostic evaluation and outpatient cardiac monitoring between January 1, 2013, and December 31, 2016. Patients were divided into 2 groups based on detection of AF or atrial flutter during monitoring. We compared demographic data, clinical risk factors, and cardiac biomarkers between the 2 groups. Multivariable logistic regression was used to determine predictors of AF. RESULTS We identified 296 consecutive patients during the study period; 38 (12.8%) patients had AF detected on outpatient cardiac monitoring. In a multivariable regression analysis, advanced age (ages 65-74: odds ratio [OR] 2.36, 95% confidence interval [CI] .85-6.52; ages 75 or older: OR 4.08, 95% CI 1.58-10.52) and moderate-to-severe left atrial enlargement (OR 4.66, 95% CI 1.79-12.12) were predictors of AF on outpatient monitoring. We developed the Brown ESUS-AF score: age (65-74 years: 1 point, 75 years or older: 2 points) and left atrial enlargement (moderate or severe: 2 points) with good prediction of AF (area under the curve .725) and was internally validated using bootstrapping. The percentage of patients with AF detected in each score category were as follows: 0: 4.2%; 1: 14.8%; 2: 20.8%; 3: 22.2%; 4: 55.6%. CONCLUSIONS The Brown ESUS-AF score predicts AF on prolonged outpatient monitoring after ESUS. More studies are needed to externally validate our findings.

Predictors of symptomatic intracranial haemorrhage in patients with an ischaemic stroke with neurological deterioration after intravenous thrombolysis

Objectives Early neurological deterioration prompting urgent brain imaging occurs in nearly 15% of patients with ischaemic stroke receiving intravenous tissue plasminogen activator (tPA). We aim to determine risk factors associated with symptomatic intracranial haemorrhage (sICH) in patients with ischaemic stroke undergoing emergent brain imaging for early neurological deterioration after receiving tPA. Methods We abstracted data from our prospective stroke database and included all patients receiving tPA for ischaemic stroke between 1 March 2015 and 1 March 2017. We then identified patients with neurological deterioration who underwent urgent brain imaging prior to their per-protocol surveillance imaging and divided patients into two groups: those with and without sICH. We compared baseline demographics, clinical variables, in-hospital treatments and functional outcomes at 90 days between the two groups. Results We identified 511 patients who received tPA, of whom 108 (21.1%) had an emergent brain CT. Of these patients, 17.5% (19/108) had sICH; 21.3% (23/108) of emergent scans occurred while tPA was infusing, though only 4.3% of these scans (1/23) revealed sICH. On multivariable analyses, the only predictor of sICH was a change in level of consciousness (OR 6.62, 95% CI 1.64 to 26.70, P=0.008). Conclusion Change in level of consciousness is associated with sICH among patients undergoing emergent brain imaging after receiving tPA. In this group of patients, preparation of tPA reversal agents while awaiting brain imaging may reduce reversal times. Future studies are needed to study the cost-effectiveness of this approach.

Early Elevated Troponin Levels After Ischemic Stroke Suggests a Cardioembolic Source

Background and Purpose— Elevated cardiac troponin is a marker of cardiac disease and has been recently shown to be associated with embolic stroke risk. We hypothesize that early elevated troponin levels in the acute stroke setting are more prevalent in patients with embolic stroke subtypes (cardioembolic and embolic stroke of unknown source) as opposed to noncardioembolic subtypes (large-vessel disease, small-vessel disease, and other). Methods— We abstracted data from our prospective ischemic stroke database and included all patients with ischemic stroke during an 18-month period. Per our laboratory, we defined positive troponin as ≥0.1 ng/mL and intermediate as ≥0.06 ng/mL and <0.1 ng/mL. Unadjusted and adjusted regression models were built to determine the association between stroke subtype (embolic stroke of unknown source and cardioembolic subtypes) and positive and intermediate troponin levels, adjusting for key confounders, including demographics (age and sex), clinical characteristics (hypertension, hyperlipidemia, diabetes mellitus, renal function, coronary heart disease, congestive heart failure, current smoking, and National Institutes of Health Stroke Scale score), cardiac variables (left atrial diameter, wall-motion abnormalities, ejection fraction, and PR interval on ECG), and insular involvement of infarct. Results— We identified 1234 patients, of whom 1129 had admission troponin levels available; 10.0% (113/1129) of these had a positive troponin. In fully adjusted models, there was an association between troponin positivity and embolic stroke of unknown source subtype (adjusted odds ratio, 4.46; 95% confidence interval, 1.03–7.97; P=0.003) and cardioembolic stroke subtype (odds ratio, 5.00; 95% confidence interval, 1.83–13.63; P=0.002). Conclusions— We found that early positive troponin after ischemic stroke may be independently associated with a cardiac embolic source. Future studies are needed to confirm our findings using high-sensitivity troponin assays and to test optimal secondary prevention strategies in patients with embolic stroke of unknown source and positive troponin.

Level of consciousness at discharge and associations with outcome after ischemic stroke

BACKGROUND Many factors may potentially complicate the stroke recovery process, including persistently impaired level of consciousness (LOC)-whether from residual stroke effects or from superimposed delirium. We aimed to determine the degree to which impaired LOC at hospital discharge is associated with outcomes after ischemic stroke. METHODS We conducted a single-center retrospective cohort study using prospectively-collected data from 2015 to 2017, collecting total NIHSS-LOC score at discharge as well as subscores for responsiveness (LOC-R), orientation questions (LOC-Q), and command-following (LOC-C). We determined associations between LOC scores and 3-month outcome using logistic regression, with discharge location (skilled nursing facility [SNF] vs. inpatient rehabilitation) representing a pre-specified secondary outcome. RESULTS We identified 1003 consecutive patients with ischemic stroke who survived to discharge, of whom 32% had any LOC score > 0. Total LOC score at discharge was associated with unfavorable 3-month outcome (OR 4.9 [95% CI 2.4-9.8] for LOC = 1; OR 8.0 [2.7-23.9] for LOC = 2-3; OR 6.3 [2.1-18.5] for LOC = 4-5; all patients with LOC = 6-7 had poor outcomes), as were subscores for LOC-R (OR 5.3 [1.3-21.2] for LOC-R = 1; all patients with LOC-R = 2-3 had poor outcomes) and LOC-Q (OR 4.1 [2.1-8.3] for LOC-Q = 1; OR 4.9 [1.8-13.5] for LOC-Q = 2). Total LOC score (OR 2.6 [1.3-5.3] for LOC = 1; OR 3.1 [1.2-8.2] for LOC = 2-3) and LOC-Q (OR 3.3 [1.6-6.6] for LOC-Q = 1; OR 3.4 [1.3-9.0] for LOC-Q = 2) were also associated with discharge to SNF rather than to inpatient rehabilitation. CONCLUSIONS The presence of impaired consciousness or disorientation at discharge is associated with markedly worse outcomes after ischemic stroke. Further studies are necessary to determine the separate effects of residual stroke-related LOC changes and those caused by superimposed delirium.

Left Atrial Appendage Morphology and Embolic Stroke of Undetermined Source: A Cross-Sectional Multicenter Pilot Study

BACKGROUND The left atrial appendage (LAA) is the main source of thrombus in atrial fibrillation, and there is an association between non-chicken wing (NCW) LAA morphology and stroke. We hypothesized that the prevalence of NCW LAA morphology would be higher among patients with cardioembolic (CE) stroke and embolic stroke of undetermined source (ESUS) than among those with noncardioembolic stroke (NCS). METHODS This multicenter retrospective pilot study included consecutive patients with ischemic stroke from 3 comprehensive stroke centers who previously underwent a qualifying chest computed tomography (CT) to assess LAA morphology. Patients underwent inpatient diagnostic evaluation for ischemic stroke, and stroke subtype was determined based on ESUS criteria. LAA morphology was determined using clinically performed contrast enhanced thin-slice chest CT by investigators blinded to stroke subtype. The primary predictor was NCW LAA morphology and the outcome was stroke subtype (CE, ESUS, NCS). RESULTS We identified 172 patients with ischemic stroke who had a clinical chest CT performed. Mean age was 70.1 ± 14.3 years and 51.7% were male. Compared with patients with NCS, the prevalence of NCW LAA morphology was higher in patients with CE stroke (58.7% versus 46.3%, P = .1) and ESUS (58.8% versus 46.3%, P = .2), but this difference did not achieve statistical significance. CONCLUSION The prevalence of NCW LAA morphology may be similar in patients with ESUS and CE, and may be higher than that in those with NCS. Larger studies are needed to confirm these associations.

Association between age and outcomes following thrombectomy for anterior circulation emergent large vessel occlusion is determined by degree of recanalisation

Background Older patients undergoing thrombectomy for emergent large vessel occlusion have worse outcomes. However, complete or near-complete reperfusion (modified Thrombolysis in Cerebral Ischemia (mTICI) score of 2 c/3) is associated with improved outcomes compared with partial recanalisation (mTICI 2b). Objective To examine the relationship between outcomes and age separately for the mTICI 2c/3, 2b and 0-2a groups in patients undergoing thrombectomy for anterior circulation emergent large vessel occlusion. Methods Retrospective review of 157 consecutive patients undergoing thrombectomy at a single centre with an occlusion of the internal carotid artery (ICA), M1 or proximal M2 segments of the middle cerebral artery (MCA). Angiograms were graded in a blinded fashion. Patients were divided into three groups: mTICI 0-2a, mTICI 2b, and mTICI 2c/3. Demographics and workflow parameters were compared. Outcomes at 90 days were compared as a function of age, using both the conventional modified Rankin scale (mRs) and utility weighted mRs (UWmRs). Results There were 72, 61 and 24 patients in the mTICI 2c/3, 2b and 0-2a groups, respectively. Outcomes were significantly worse with increasing age for the mTICI 2b group, but not for the mTICI 0-2a and 2c/3 groups (P=0.0002). With increasing age, outcomes of the mTICI 2b group approached those of the mTICI 0-2a group. However, outcomes of the mTICI 2c/3 groups were similar for all ages. This association was present for both the original mRs and UWmRs. Conclusion Increasing age was associated with worse outcomes for those with partial (mTICI 2b) recanalisation, not in patients with complete (mTICI 2c/3) recanalisation.

Baseline NIH Stroke Scale is an inferior predictor of functional outcome in the era of acute stroke intervention

Background and aims Baseline National Institutes of Health Stroke Scale (NIHSS) scores have frequently been used for prognostication after ischemic stroke. With the increasing utilization of acute stroke interventions, we aimed to determine whether baseline NIHSS scores are still able to reliably predict post-stroke functional outcome. Methods We retrospectively analyzed prospectively collected data from a high-volume tertiary-care center. We tested strength of association between NIHSS scores at baseline and 24 h with discharge NIHSS using Spearman correlation, and diagnostic accuracy of NIHSS scores in predicting favorable outcome at three months (defined as modified Rankin Scale 0–2) using receiver operating characteristic curve analysis with area under the curve. Results There were 1183 patients in our cohort, with median baseline NIHSS 8 (IQR 3–17), 24-h NIHSS 4 (IQR 1–11), and discharge NIHSS 2 (IQR 1–8). Correlation with discharge NIHSS was r = 0.60 for baseline NIHSS and r = 0.88 for 24-h NIHSS. Of all patients with follow-up data, 425/1037 (41%) had favorable functional outcome at three months. Receiver operating characteristic curve analysis for predicting favorable outcome showed area under the curve 0.698 (95% CI 0.664–0.732) for baseline NIHSS, 0.800 (95% CI 0.772–0.827) for 24-h NIHSS, and 0.819 (95% CI 0.793–0.845) for discharge NIHSS; 24 h and discharge NIHSS maintained robust predictive accuracy for patients receiving mechanical thrombectomy (AUC 0.846, 95% CI 0.798–0.895; AUC 0.873, 95% CI 0.832–0.914, respectively), while accuracy for baseline NIHSS decreased (AUC 0.635, 95% CI 0.566–0.704). Conclusion Baseline NIHSS scores are inferior to 24 h and discharge scores in predicting post-stroke functional outcomes, especially in patients receiving mechanical thrombectomy.