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Background and Purpose— Many patients with acute ischemic stroke are not eligible for thrombolysis or mechanical reperfusion therapies due to contraindications, inaccessible vascular occlusions, late presentation, or large infarct core. Sphenopalatine ganglion (SPG) stimulation to enhance collateral flow and stabilize the blood-brain barrier offers an alternative, potentially more widely deliverable, therapy. Methods— In a randomized, sham-controlled, double-masked trial at 41 centers in 7 countries, patients with anterior circulation ischemic stroke not treated with reperfusion therapies within 24 hours of onset were randomly allocated to active SPG stimulation or sham control. The primary efficacy outcome was improvement beyond expectations on the modified Rankin Scale of global disability at 90 days (sliding dichotomy), assessed in the modified intention-to-treat population. The initial planned sample size was 660 patients, but the trial was stopped early when technical improvements in device placement occurred, so that analysis of accumulated experience could be conducted to inform a successor trial. Results— Among 303 enrolled patients, 253 received at least one active SPG or sham stimulation, constituting the modified intention-to-treat population (153 SPG stimulation and 100 sham control). Age was median 73 years (interquartile range, 64–79), 52.6% were female, deficit severity on the National Institutes of Health Stroke Scale was median 11 (interquartile range, 9–15), and time from last known well median 18.6 hours (interquartile range, 14.5–22.5). For the primary outcome, improved 3-month disability beyond expectations, rates in the SPG versus sham treatment groups were 49.7% versus 40.0%; odds ratio, 1.48 (95% CI, 0.89–2.47); P =0.13. A significant treatment interaction with stroke location (cortical versus noncortical) was noted, P =0.04. In the 87 patients with confirmed cortical involvement, rates of improvement beyond expectations were 50.0% versus 27.0%; odds ratio, 2.70 (95% CI, 1.08–6.73); P =0.03. Similar response patterns were observed for all prespecified secondary efficacy outcomes. No differences in mortality or serious adverse event safety end points were observed. Conclusions— SPG stimulation within 24 hours of onset is safe in acute ischemic stroke. SPG stimulation was not shown to statistically significantly improve 3-month disability above expectations, though favorable outcomes were nominally higher with SPG stimulation. Beneficial effects may distinctively be conferred in patients with confirmed cortical involvement. The results of this study need to be confirmed in a larger pivotal study. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03767192.

Introduction: Identifying factors associated with short term outcome following carotid endarterectomy (CEA) is important to improve patient selection. There are limited data assessing 30-day major adverse cardiac and cerebrovascular events (MACCE: stroke, myocardial infarction (MI) and death) in clinical practice. Hypothesis: We hypothesized that patients fulfilling SAPPHIRE high risk (SHR) or exclusion (SEC) criteria contribute to worse outcomes in a real-life cohort. Methods: Patients undergoing CEA at 2 centers between 1998 and 2010 were prospectively entered into a database. Baseline characteristics, comorbidities, SHR and SEC were assessed using Cox regression to determine predictors for the MACCE 30-day endpoint. Results: The analysis included 748 operations, 262 (35%) asymptomatic , 211 (28%) with previous strokes, and 278 (37%) with transient ischemic attacks (TIA). The overall MACCE rate was 6.7%, 5.0% of asymptomatic and 7.6% in symptomatic patients. SEC patients (n=137) had a MACCE rate of 14.7%; after exclusion, the MACCE rate of the remainder dropped to 4.9% (3.5% in asymptomatic and 5.4% in symptomatic patients). Hazard ratio (HR) for SEC was 3.605 (p=0.0001) after adjustment for symptomatic status. SHR patients did not show a significantly increased event rate (HR 1.714, p=0.16). In multivariate analysis diabetes (HR 2.019, p=0.02), symptomatic status (HR 2.015, p=0.049) and prior MI (HR 1.957, p=0.03) showed an independent influence on MACCE. Conclusion: High risk clinical characteristics, as defined by the SAPPHIRE study were not independently associated with 30-day increased risk of MACCE, although exclusion criteria from that study, diabetes, symptomatic status and prior MI were associated with outcomes.

The controversy as to whether Doppler ultrasonic methods should play a role in clinical decision-making in the prevention of stroke is attributable to reported disagreement between angiographic and ultrasonic results and the lack of internationally accepted ultrasound criteria for describing the degree of stenosis. Foremost among the explanations for both is the broad scatter of peak systolic velocities in the stenosis, the criterion that has so far received most attention. Grading based on a set of main and additional criteria can overcome diagnostic errors. Morphological measurements (B-mode images and color flow imaging) are the main criteria for low and moderate degrees of stenosis. Increased velocities in the stenosis indicate narrowing, but the appearance of collateral flow and decreased poststenotic flow velocity prove a high degree stenosis (≥70%), additionally allowing the estimation of the hemodynamic effect in the category of high-degree stenosis. Additional criteria refer to the effect of a stenosis on prestenotic flow (common carotid artery), the extent of poststenotic flow disturbances, and derived velocity criteria (diastolic peak velocity and the carotid ratio). This multiparametric approach is intended to increase the reliability and the standard of reporting of ultrasonic results for arteriosclerotic disease of the carotid artery.

Background and Purpose— We hypothesized that for the prediction or exclusion of aortic thrombi or plaques ≥4 mm, the combination of intima-media thickness (IMT) and distensibility (DC) of the common carotid arteries would be superior to the measurement of IMT alone. Methods— We prospectively included 208 stroke patients (mean age, 60 years) undergoing transesophageal echocardiography for screening of aortic plaques. IMT and DC were determined by ultrasound, and DC was quantified by measuring blood pressure and the common carotid arteries diameter change on M-mode ultrasound during the cardiac cycle. Results— Negative predictive values of IMT −3 /kPa for the exclusion of aortic atheroma ≥4 mm were similar (92.0% and 91.7%, respectively). However, negative predictive values increased to 98.2% and to 100.0% for the exclusion of aortic thrombi when both parameters were combined. Positive predictive values of IMT ≥0.9 mm and DC Conclusions— Our findings suggest that IMT and DC represent different vessel wall properties and that measuring both parameters provides optimized characterization of carotid atherosclerosis. Combining IMT and DC increases the predictive power of carotid ultrasound, making transesophageal echocardiography dispensable for assessment of the aorta for those with normal carotid arteries and indispensable for those patients with carotid atherosclerosis.

Background and Purpose— This study investigates dynamic cerebral autoregulation assessed from spontaneous blood pressure (ABP) and cerebral blood flow velocity (CBFV) fluctuations and its time course in acute ischemic stroke. Methods— Forty patients admitted with acute ischemic stroke in the territory of the middle cerebral artery (MCA) were enrolled. Admission National Institutes of Health Stroke score was 6±4. Study 1 was performed within 22 (±11) hours and study 2 was performed within 134 (±25) hours of ictus. The final analysis comprised 33 and 29 patients for study 1 and study 2, respectively. Twenty-five age- and sex-matched controls were studied. ABP (Finapres method) and CBFV in both MCAs (transcranial Doppler) were recorded over 10 minutes. Correlations between diastolic and mean ABP and CBFV fluctuations were averaged, yielding the correlation coefficient indices (Dx, Mx). Transfer function analysis was applied to obtain phase shift and gain between ABP and CBFV oscillations. Results— No disturbance of autoregulation was indicated by all parameters at study 1. Separate analyses for clinical severity, stroke side, and size did not reveal significant differences for the various autoregulatory indices at study 1 and 2. At study 2, MCA flow velocity was significantly increased on both sides, the autoregulation index Mx was slightly but significantly ( P Conclusions— Dynamic cerebral autoregulation assessed from spontaneous blood pressure fluctuations does not seem to be relevantly disturbed in early minor MCA stroke. At the subacute stage, slight autoregulatory disturbance may be present.

Background and Purpose— Analysis of dynamic cerebral autoregulation (DCA) from spontaneous blood pressure fluctuations might contribute to prognosis of severe internal carotid artery stenosis, but its response to carotid recanalization has not been investigated so far. This study investigates the effect of carotid endarterectomy or stenting on various DCA parameters. Methods— In 58 patients with severe unilateral stenosis undergoing carotid endarterectomy (n=41) or stenting (n=17), cerebral blood flow velocity (CBFV, transcranial Doppler) and arterial blood pressure (ABP, Finapres method) were recorded over 10 minutes before and on average 3 days after carotid recanalization. Nineteen patients were additionally examined after 7 months. Correlations between diastolic and mean ABP and CBFV fluctuations were averaged to form the correlation coefficient indices (diastolic [Dx] and mean values [Mx]). Transfer function parameters (low-frequency phase and high-frequency gain between ABP and CBFV oscillations) were calculated over the same 10 minutes. CO 2 reactivity was assessed via inhalation of 7% CO 2 . Results— Before recanalization, all DCA parameters were clearly impaired ipsilaterally compared with contralateral sides. Phase, Dx, and Mx indicated early normalization of DCA after both endarterectomy and stenting. By multiple regression, the degree of DCA improvement was highly significantly related to the extent of impairment before recanalization. No significant change in DCA was found at follow-up. Ipsilateral gain and CO 2 reactivity increased significantly less after endarterectomy than after stenting ( P Conclusions— Dynamic cerebral dysautoregulation in patients with severe carotid obstruction is readily and completely remedied by carotid recanalization.

Background and Purpose— Estimation of dynamic cerebral autoregulation from spontaneous fluctuations of arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) is an attractive monitoring option for cerebral hemodynamic impairment. We evaluated the correlation coefficient index method in patients with severe obstructive carotid disease and compared it with transfer function analysis (frequency domain approach to cerebral autoregulation) and CO 2 vasomotor reactivity. Methods— In 139 patients with severe unilateral carotid stenosis (≥70%) or occlusion, CBFV (transcranial Doppler) and ABP (Finapres method) were recorded over 10 minutes. Correlations between systolic pressure, diastolic pressure, and mean ABP and CBFV oscillations over 1-minute epochs were averaged over 10 minutes to form the correlation coefficient indexes (Sx, Dx, Mx, respectively). Transfer function parameters (phase shift and gain between ABP and CBFV oscillations) were determined from the entire 10-minute period. CO 2 reactivity was assessed by inhalation of 7% CO 2 . Results— The correlation indexes Dx and Mx were significantly higher ipsilateral to stenosis and increased with degree of stenosis, indicating increasing dependence of CBFV on ABP and thus impairment of cerebral autoregulation. Dx and Mx correlated moderately but highly significantly with transfer function parameters and CO 2 reactivity and showed a good level of agreement in detecting pathological values. Patients with a small variance of the 1-minute source correlations of Dx and Mx showed clearly better correlation values. Transfer function parameters and CO 2 reactivity but not Dx and Mx were significantly poorer in patients with symptomatic stenosis or occlusion. Conclusions— The potential of the correlation coefficient indexes Dx and Mx in detecting hemodynamic impairment in patients with carotid stenosis is comparable to that of transfer function analysis and CO 2 reactivity testing. In future, a combination of various hemodynamic tests might help to identify patients at risk for ischemic events.

Background and Purpose —Responsiveness to CO 2 is an established test of cerebrovascular reserve capacity. Arterial partial pressure of CO 2 (P co 2 ) and arterial blood pressure (BP) are key parameters for cerebral blood flow. To investigate the interaction between P co 2 and BP, we performed a study with simultaneous measurement of CO 2 and BP during CO 2 reactivity testing with transcranial Doppler sonography. Methods —Eighty-one healthy volunteers, aged 19 to 74 years, underwent examination defined by a protocol with multimodality monitoring of BP, heart rate (HR), P co 2 , and Doppler frequencies (DFs) of the left middle cerebral artery (MCA). Reproducibility was tested in a subgroup of 14 volunteers ≥65 years of age by CO 2 reactivity testing on different days. Results —Increase of P co 2 was accompanied by a parallel increase of mean±SD time values of DF (3.6±1.6%/mm Hg CO 2 ). BP levels were significantly elevated after 60-second hypercapnia (mean values, 0.5±0.55 mm Hg/mm Hg CO 2 ). A significant decrease over time was seen only for pulsatility in DF but not in BP. Analysis of variance and covariance with repeated measures revealed a highly significant effect of CO 2 on MCA Doppler shift. A less-pronounced effect on DF was seen for BP. Correlation analysis showed no significance for CO 2 reactivity, but a significant correlation between test and retest was seen in BP-related CO 2 reactivity. Conclusions —The CO 2 response curve showed the known linear increase of DF. The parallel significant increase in BP most likely results from activation of the central sympathetic nervous system. The poor reproducibility for Doppler CO 2 reactivity is to some extent explainable by variability of BP. CO 2 -induced increases in BP can have relevant influence on MCA Doppler shift and lead to misinterpretation of Doppler CO 2 test results.

Background and Purpose— A recent study showed a dramatic increase in cerebral hemorrhage comprising atypical locations with low-frequency ultrasound–mediated recombinant tissue plasminogen activator–thrombolysis in humans. Here, we provide a possible explanation for this phenomenon by a side effect observed in a study using the similar ultrasound device. Methods— The study was originally undertaken to investigate by transcranial Doppler sonography, positron emission tomography and perfusion MRI whether transcranial application of wide-field low-frequency ultrasound (300 kHz) improves cerebral hemodynamics in patients with cerebral small vessel disease. Results— Showing no clear positive effect on cerebral hemodynamics in 4 patients and on cerebral perfusion (positron emission tomography) in 2 patients, the study has been terminated early because of a remarkable side effect in the first patient (a 62 year-old man) undergoing perfusion-MRI: detection of frontoparietal extravasation of Gadolinium contrast agent (applied during MRI perfusion imaging preinsonation) on MRI immediately postinsonation. Conclusions— Abnormal permeability of the human blood-brain barrier can be induced by wide-field low-frequency insonation. The observed excessive bleeding rate with low-frequency sonothrombolysis might thus be attributable to primary blood-brain barrier disruption by ultrasound.

Background and Purpose— Transesophageal echocardiography (TEE) is the gold standard in detecting high-risk (ie, aortic thrombi) and potential sources (ie, patent foramen ovale [PFO]) of cerebral embolism. We sought to evaluate the additional information and therapeutic impact provided by TEE in stroke patients and to characterize patients in whom TEE is indispensable. Methods— We included 503 consecutive patients (mean age 62.2 years) with acute brain ischemia. Each patient received TEE and the following routine diagnostics: ultrasound of brain supplying arteries, ECG or Holter-ECG, transthoracic echocardiography, and brain imaging (computed tomography or MRI). Stroke etiology was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. High-risk sources in TEE were: aortic thrombi or plaques ≥4 mm, thrombi in left atrial cavity/left atrial appendage, spontaneous echo contrast, and left atrial flow velocity Results— Stroke etiology was determined by routine diagnostics in 276 of 503 patients (54.9%). Of the remaining 227 patients (undetermined etiology), 212 (93.4%) were candidates for oral anticoagulation (OA). TEE revealed a high-risk source, with indication for OA in 17 of them (8.0%). A potential source leading to OA was found in an additional 48 patients (22.6%). The remaining 147 patients (69.3%) were treated by platelet inhibitors or statins. Conclusions— TEE strongly influenced secondary prevention and led to OA in one third of our patients with stroke of undetermined etiology. TEE is indispensable in all patients being candidates for OA when routine diagnostics cannot clarify stroke etiology.

Background and Purpose— Impaired cerebrovascular reserve capacity (CVC) is a risk factor for ischemic events in patients with high-grade carotid stenosis and occlusion. In this study, the CVC in response to a CO 2 challenge was evaluated with blood oxygen level–dependent (BOLD) MRI and the results compared with those of a transcranial Doppler CO 2 tests. Methods— A T 2 *-weighted single-shot multigradient echo-planar imaging sequence was used to determine cerebral CO 2 reactivity. T 2 * values were calculated for each pixel at rest and during a challenge with 7% CO 2 , and a reference function was fitted to the T 2 * time courses. Whole-brain color-coded ΔT 2 * parameter maps were calculated and visually evaluated for regional differences. Additionally, a region-of-interest analysis was undertaken. Average values for ΔT 2 * normalized to changes in end-tidal P co 2 were calculated. Results were correlated with a transcranial Doppler CO 2 tests in 20 patients with high-grade stenosis or occlusion of the carotid artery. Results— Color parameter maps showed areas of decreased BOLD effect within the internal carotid artery territory in 12 of 13 hemispheres with impaired CVC in transcranial Doppler CO 2 test. Regional normalized ΔT 2 * was highly correlated with changes of middle cerebral artery blood flow velocity in transcranial Doppler CO 2 test. Normalized ΔT 2 * was significantly reduced in hemispheres with impaired CVC in transcranial Doppler ( P Conclusions— BOLD MRI can easily be included in routine MRI exams. The technique is robust and yields diagnostic information concerning the cerebrovascular reserve.

Response: We greatly appreciate the thoughtful comments by Dr Gerriets and coworkers. Our finding of blood-brain barrier disruption after 300 kHz insonation in a 62-year-old man with cerebral small-vessel disease1 is substantiated by their remarkable animal study demonstrating vasogenic edema on MRI after 20 kHz insonation.2 Mechanical …

Blood flow velocity of the middle cerebral artery was monitored during cardiopulmonary bypass procedures by means of transcranial Doppler ultrasonography. Our investigation was carried out in a group of 16 patients with severe carotid stenosis or occlusion and in a control group of 42 patients with no or stenosis of less than 50% local diameter reduction. After onset of cardiopulmonary bypass, both groups showed a short unstable phase followed by increased blood flow velocity (10% increase ipsilateral to the obstruction, 27% increase in the control group). Just before rewarming, blood flow velocity was still comparable to (control group -3%) or higher than (ipsilateral to obstructions +14%) prebypass values. Analysis of three patients with postoperative diffuse encephalopathy did not reveal reduced blood flow during cardiopulmonary bypass as a relevant factor. Two of the three showed luxury perfusion. Reduced perfusion due to carotid obstruction was not observed during cardiopulmonary bypass and therefore cannot be considered a significant risk factor for the development of intraoperative stroke.