Christopher G. Favilla

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.

Hemorrhagic Transformation of Childhood Arterial Ischemic Stroke

Background and Purpose— The objective of this study was to describe the occurrence of hemorrhagic transformation (HT) among children with arterial ischemic stroke within 30 days after symptom onset and to describe clinical factors associated with HT. Methods— Sixty-three children aged 1 month to 18 years with arterial ischemic stroke between January 2005 and November 2008 were identified from a single-center prospective pediatric stroke registry. All neuroimaging studies within 30 days of stroke were reviewed by a study neuroradiologist. Hemorrhage was classified according to the European Cooperative Acute Stroke Study-1 definitions. Association of HT with clinical factors, systemic anticoagulation, stroke volume, and outcome was analyzed. Results— HT occurred in 19 of 63 children (30%; 95% CI, 19% to 43%), only 2 (3%) of whom were symptomatic. Hemorrhage classification was hemorrhagic infarction (HI)1 in 14, HI2 in 2, parenchymal hematoma (PH)1 in 2, and PH2 in 1. HT was less common in children with vasculopathy (relative risk, 0.27; 95% CI, 0.07 to 1.06; P=0.04) than in those with other stroke mechanisms. HT was not significantly associated with anticoagulation versus antiplatelet therapy (relative risk, 0.6; 95% CI, 0.2 to 1.5; P=0.26) but was associated with larger infarct volumes (P=0.0084). In multivariable analysis, worse Pediatric Stroke Outcome Measure scores were associated with infarct volume ≥5% of total supratentorial brain volume (OR, 4.0; 95% CI, 1.1 to 15; P=0.04), and a trend existed toward association of worse Pediatric Stroke Outcome Measure scores with HT (OR, 4.0; 95% CI, 0.9 to 18; P=0.07). Conclusions— HT occurred in 30% of children with arterial ischemic stroke within 30 days. Most hemorrhages were petechial and asymptomatic. Infarct volume was associated with HT and worse outcome.

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.

Influence of probe pressure on the diffuse correlation spectroscopy blood flow signal: extra-cerebral contributions

A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.

Sulfonylurea Use Before Stroke Does Not Influence Outcome

Background and Purpose— Sulfonylureas block nonselective cation channels and lower serum glucose and are neuroprotective in animal models of ischemic stroke. Human data on sulfonylureas in acute stroke are sparse and conflicting. We aimed to measure the potential neuroprotective effect of prestroke sulfonylurea use in diabetic patients. Methods— We analyzed data from a prospective cohort of individuals with diabetes mellitus (DM) enrolled in nonreperfusion ischemic stroke trials within Virtual International Stroke Trials Archive (VISTA) comprising 1050 patients, 298 with sulfonylurea use before stroke onset. The primary outcome measures were baseline National Institutes of Health Stroke Scale score and 90-day modified Rankin Scale score. Results— Compared with patients on no DM medications, those with sulfonylurea use before stroke onset presented with less severe stroke (OR, 0.69; 95% CI, 0.53 to 0.89) but had similar modified Rankin Scale scores at 90 days (OR, 0.95; 95% CI, 0.74 to 1.23). Compared with those on other DM agents, there was no difference in initial stroke severity (OR, 1.04; 95% CI, 0.73 to 1.48) nor modified Rankin Scale score at 90 days (OR, 1.00; 95% CI, 0.71 to 1.40). Compared with those using any DM medication, patients not on any treatment experienced higher initial National Institutes of Health Stroke Scale scores (OR, 1.48; 95% CI, 1.18 to 1.86) and were marginally more likely to have poor outcomes (modified Rankin Scale score >2) at 90 days (OR, 1.31; 95% CI, 0.97 to 1.77). Conclusions— Sulfonylurea use before stroke onset did not affect stroke severity or long-term functional outcome compared with other DM treatments. This finding casts doubt on the use of sulfonylureas for prophylactic neuroprotection. Furthermore, patients not using any medication for DM appear to have more severe strokes and worse outcomes.

Modified Pediatric ASPECTS Correlates with Infarct Volume in Childhood Arterial Ischemic Stroke

Background and Purpose: Larger infarct volume as a percent of supratentorial brain volume (SBV) predicts poor outcome and hemorrhagic transformation in childhood arterial ischemic stroke (AIS). In perinatal AIS, higher scores on a modified pediatric version of the Alberta Stroke Program Early CT Score using acute MRI (modASPECTS) predict later seizure occurrence. The objectives were to establish the relationship of modASPECTS to infarct volume in perinatal and childhood AIS and to establish the interrater reliability of the score. Methods: We performed a cross sectional study of 31 neonates and 40 children identified from a tertiary care center stroke registry with supratentorial AIS and acute MRI with diffusion weighted imaging (DWI) and T2 axial sequences. Infarct volume was expressed as a percent of SBV using computer-assisted manual segmentation tracings. ModASPECTS was performed on DWI by three independent raters. The modASPECTS were compared among raters and to infarct volume as a percent of SBV. Results: ModASPECTS correlated well with infarct volume. Spearman rank correlation coefficients (ρ) for the perinatal and childhood groups were 0.76, p < 0.001 and 0.69, p < 0.001, respectively. Excluding one perinatal and two childhood subjects with multifocal punctate ischemia without large or medium sized vessel stroke, ρ for the perinatal and childhood groups were 0.87, p < 0.001 and 0.80, p < 0.001, respectively. The intraclass correlation coefficients for the three raters for the neonates and children were 0.93 [95% confidence interval (CI) 0.89–0.97, p < 0.001] and 0.94 (95% CI 0.91–0.97, p < 0.001), respectively. Conclusion: The modified pediatric ASPECTS on acute MRI can be used to estimate infarct volume as a percent of SBV with a high degree of validity and interrater reliability.

New Data Support Patent Foramen Ovale Closure After Stroke

Patent foramen ovale (PFO) can be found in ≈1 of 4 adults,1 and it has been implicated as a potential source of ischemic stroke, likely via paradoxical embolization.2 The association between stroke and PFO is particularly robust among younger patients with otherwise cryptogenic stroke.3 However, the merit of percutaneous PFO closure for secondary stroke prevention has been the focus of much debate. Although the first 3 randomized trials of PFO closure did not demonstrate benefit in their primary intention-to-treat analyses, newly available data will likely change practice for many clinicians. Percutaneous catheter-based PFO closure was introduced to clinical practice in 1992.4 Subsequently, randomized clinical trials were undertaken to demonstrate efficacy of closure for secondary stroke prevention, yet enrollment was slow because many clinicians and patients were pursuing PFO closure outside the trials. Eventually, in 2012, the CLOSURE I trial5 was published, comparing medical therapy with PFO closure with the NMT Medical STARFlex device in 909 patients with PFO and cryptogenic stroke or transient ischemic attack. Patients randomized to medical therapy were given aspirin, warfarin, or both at the discretion of the enrolling investigator. The 2-year recurrent stroke rate was 2.9% after closure and 3.1% with medical therapy (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.41–1.98; P =0.79). There was no heterogeneity in the results based on the presence of atrial septal aneurysm or large shunt. Major procedural complications, atrial fibrillation, and serious adverse event rates from this and other described trials are reported in the Table. View this table: Table. Safety of Patent Foramen Ovale Closure Across All Randomized Control Trials The PC trial6 (Randomized Clinical Trial Comparing the Efficacy …

Dynamic autoregulation of cerebral blood flow measured non-invasively with fast diffuse correlation spectroscopy:

Cerebral autoregulation (CA) maintains cerebral blood flow (CBF) in the presence of systemic blood pressure changes. Brain injury can cause loss of CA and resulting dysregulation of CBF, and the degree of CA impairment is a functional indicator of cerebral tissue health. Here, we demonstrate a new approach to noninvasively estimate cerebral autoregulation in healthy adult volunteers. The approach employs pulsatile CBF measurements obtained using high-speed diffuse correlation spectroscopy (DCS). Rapid thigh-cuff deflation initiates a chain of responses that permits estimation of rates of dynamic autoregulation in the cerebral microvasculature. The regulation rate estimated with DCS in the microvasculature (median: 0.26 s−1, inter quartile range: 0.19 s−1) agrees well (R = 0.81, slope = 0.9) with regulation rates measured by transcranial Doppler ultrasound (TCD) in the proximal vasculature (median: 0.28 s−1, inter quartile range: 0.10 s−1). We also obtained an index of systemic autoregulation in concurrently measured scalp microvasculature. Systemic autoregulation begins later than cerebral autoregulation and exhibited a different rate (0.55 s−1, inter quartile range: 0.72 s−1). Our work demonstrates the potential of diffuse correlation spectroscopy for bedside monitoring of cerebral autoregulation in the microvasculature of patients with brain injury.

Non-Invasive Respiratory Impedance Enhances Cerebral Perfusion in Healthy Adults

Optimization of cerebral blood flow (CBF) is the cornerstone of clinical management in a number of neurologic diseases, most notably ischemic stroke. Intrathoracic pressure influences cardiac output and has the potential to impact CBF. Here, we aim to quantify cerebral hemodynamic changes in response to increased respiratory impedance (RI) using a non-invasive respiratory device. We measured cerebral perfusion under varying levels of RI (6 cm H2O, 9 cm H2O, and 12 cm H2O) in 20 healthy volunteers. Simultaneous measurements of microvascular CBF and middle cerebral artery mean flow velocity (MFV), respectively, were performed with optical diffuse correlation spectroscopy and transcranial Doppler ultrasound. At a high level of RI, MFV increased by 6.4% compared to baseline (p = 0.004), but changes in cortical CBF were non-significant. In a multivariable linear regression model accounting for end-tidal CO2, RI was associated with increases in both MFV (coefficient: 0.49, p < 0.001) and cortical CBF (coefficient: 0.13, p < 0.001), although the magnitude of the effect was small. Manipulating intrathoracic pressure via non-invasive RI was well tolerated and produced a small but measurable increase in cerebral perfusion in healthy individuals. Future studies in acute ischemic stroke patients with impaired cerebral autoregulation are warranted in order to assess whether RI is feasible as a novel non-invasive therapy for stroke.

Diffuse Correlation Spectroscopy for Flow Assessment & Management of Acute Ischemic Stroke

We used diffuse correlation spectroscopy to assess cerebral autoregulation in acute ischemic stroke patients. Larger perfusion changes were observed in the infarcted hemisphere, and a novel relationship between perfusion and NIHSS was discovered.