Prospective Evaluation of a Modified Apnea Test in Brain Death Candidates that Does Not Require Disconnection from the Ventilator.

BACKGROUND: The apnea test (AT) is an important component in the determination of brain death/death by neurologic criteria (BD/DNC) and often entails disconnecting the patient from the ventilator followed by tracheal oxygen insufflation to ensure adequate oxygenation. To rate the test as positive, most international guidelines state that a lack of spontaneous breathing must be demonstrated when the arterial partial pressure of carbon dioxide (PaCO2) ≥ 60 mm Hg. However, the loss of positive end-expiratory pressure that is associated with disconnection from the ventilator may cause rapid desaturation. This, in turn, can lead to cardiopulmonary instability (especially in patients with pulmonary impairment and diseases such as acute respiratory distress syndrome), putting patients at increased risk. Therefore, this prospective study aimed to investigate whether a modified version of the AT (mAT), in which the patient remains connected to the ventilator, is a safer yet still valid alternative. METHODS: The mAT was performed in all 140 BD/DNC candidates registered between January 2019 and December 2022: after 10 min of preoxygenation, (1) positive end-expiratory pressure was increased by 2 mbar (1.5 mm Hg), (2) ventilation mode was switched to continuous positive airway pressure, and (3) apnea back-up mode was turned off (flow trigger 10 L/min). The mAT was considered positive when spontaneous breathing did not occur upon PaCO2 increase to ≥ 60 mm Hg (baseline 35-45 mm Hg). Clinical complications during/after mAT were documented. RESULTS: The mAT was possible in 139/140 patients and had a median duration of 15 min (interquartile range 13-19 min). Severe complications were not evident. In 51 patients, the post-mAT arterial partial pressure of oxygen (PaO2) was lower than the pre-mAT PaO2, whereas it was the same or higher in 88 cases. In patients with pulmonary impairment, apneic oxygenation during the mAT improved PaO2. In 123 cases, there was a transient drop in blood pressure at the end of or after the mAT, whereas in 12 cases, the mean arterial pressure dropped below 60 mm Hg. CONCLUSIONS: The mAT is a safe and protective means of identifying patients who no longer have an intact central respiratory drive, which is a critical factor in the diagnosis of BD/DNC. Clinical trial registration DRKS, DRKS00017803, retrospectively registered 23.11.2020, https://drks.de/search/de/trial/DRKS00017803.

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke.

BACKGROUND: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. METHODS: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. RESULTS: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P<0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; P<0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; P=0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P=0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy. CONCLUSIONS: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

[Prospective investigation of extracranial duplex sonography for the detection of cerebral circulatory arrest in patients with irreversible loss of brain function]. / Prospektive Untersuchung der extrakraniellen Duplexsonographie zum Nachweis des zerebralen Perfusionsstillstands bei Patienten mit irreversiblem Hirnfunktionsausfall.

BACKGROUND: A broader distribution of bedside color-coded duplex sonography (CCD) for detection of cerebral circulatory arrest (CCA) would be important to improve its use in the diagnosis of irreversible loss of brain function (ILBF-Dx). QUESTION: Is extracranial compared to the commonly applied transcranial CCD of the brain-supplying vessels (ECCD vs. TCCD) equivalent for the detection of CCA in ILBF-Dx regarding specificity and sensitivity? MATERIAL AND METHODS: Study period January 2019-June 2022, screening of 136 and inclusion of 114 patients with severe brain lesions > 24 h after onset of fixed and dilated pupils, apnea and completed ILBF-Dx. Exclusion of patients without brainstem areflexia and guideline-conform applicability of CCD. Complementary ECCD (and TCCD, if other method used for irreversibility detection). RESULTS: Detection of ILBF (ILBF+) in 86.8% (99/114), no ILBF (ILBF-) in 13.2% (15/114). ECCD was fully feasible in all patients; findings matching CCA were found in 94/99 ILBF+ cases (ECCD+) and not in 5 patients (ECCD-). All 15 patients with ILBF- showed ECCD- findings. Thus, the specificity of ECCD was 1.0, and the sensitivity was 0.949. TCCD showed CCA in 56 patients (TCCD+), and ECCD+ was also found in all of them. An inconclusive result of TCCD in ILBF+ was found in 38 cases, with parallel ECCD+ in all of these patients. In 20 cases, TCCD did not show CCA (TCCD-), these also showed ECCD-. Of these patients 15 were ILBF- and 5 were ILBF+. DISCUSSION: TCCD was not completely feasible or inconclusive in one third of the cases, whereas ECCD was always feasible. ECCD showed high validity with respect to the detection of CCA. Therefore, the possibility of using ECCD alone to detect CCA in ILBF-Dx should be discussed.

Hemodynamics of cerebral veins analyzed by 2d and 4d flow mri and ultrasound in healthy volunteers and patients with multiple sclerosis.

BACKGROUND: Hemodynamic alterations of extracranial veins are considered an etiologic factor in multiple sclerosis (MS). However, ultrasound and MRI studies could not confirm a pathophysiological link. Because of technical challenges using standard diagnostics, information about the involvement of superficial intracranial veins in proximity to the affected brain in MS is scarce. PURPOSE: To comprehensively investigate the hemodynamics of intracranial veins and of the venous outflow tract in MS patients and controls. STUDY TYPE: Prospective. POPULATION: Twenty-eight patients with relapsing-remitting MS (EDSS1.9 ± 1.1; range 0-3) and 41 healthy controls. FIELD STRENGTH/SEQUENCE: 3T/2D phase-contrast and time-resolved 4D flow MRI, extra- and transcranial sonography. ASSESSMENT: Hemodynamics within the superficial and deep intracranial venous system and outflow tract including the internal, basal, and great cerebral vein, straight, superior sagittal, and transverse sinuses, internal jugular and vertebral veins. Sonography adhered to the chronic cerebrospinal venous insufficiency (CCSVI) criteria. STATISTICAL TESTS: Multivariate repeated measure analysis of variance, Student's two-sample t-test, chi-square, Fisher's exact test; separate analysis of the entire cohort and 32 age- and sex-matched participants. RESULTS: Multi- and univariate main effects of the factor group (MS patient vs. control) and its interactions with the factor vessel position (lower flow within dorsal superior sagittal sinus in MS, 3 ± 1 ml/s vs. 3.8 ± 1 ml/s; P < 0.05) in the uncontrolled cohort were attributable to age-related differences. Age- and sex-matched pairs showed a different velocity gradient in a single segment within the deep cerebral veins (great cerebral vein, vena cerebri magna [VCM] 7.6 ± 1.7 cm/s; straight sinus [StS] 10.5 ± 2.2 cm/s vs. volunteers: VCM 9.2 ± 2.3 cm/s; StS 10.2 ± 2.3 cm/s; P = 0.01), reaching comparable velocities instantaneously downstream. Sonography was not statistically different between groups. DATA CONCLUSION: Consistent with previous studies focusing on extracranial hemodynamics, our comprehensive analysis of intracerebral venous blood flow did not reveal relevant differences between MS patients and controls. Level of Evidence 1. Technical Efficacy Stage 3. J. Magn. Reson. Imaging 2020;51:205-217.

Carotid geometry is an independent predictor of wall thickness - a 3D cardiovascular magnetic resonance study in patients with high cardiovascular risk.

BACKGROUND: The posterior wall of the proximal internal carotid artery (ICA) is the predilection site for the development of stenosis. To optimally prevent stroke, identification of new risk factors for plaque progression is of high interest. Therefore, we studied the impact of carotid geometry and wall shear stress on cardiovascular magnetic resonance (CMR)-depicted wall thickness in the ICA of patients with high cardiovascular disease risk. METHODS: One hundred twenty-one consecutive patients ≥50 years with hypertension, ≥1 additional cardiovascular risk factor and ICA plaque ≥1.5 mm thickness and < 50% stenosis were prospectively included. High-resolution 3D-multi-contrast (time of flight, T1, T2, proton density) and 4D flow CMR were performed for the assessment of morphological (bifurcation angle, ICA/common carotid artery (CCA) diameter ratio, tortuosity, and wall thickness) and hemodynamic parameters (absolute/systolic wall shear stress (WSS), oscillatory shear index (OSI)) in 242 carotid bifurcations. RESULTS: We found lower absolute/systolic WSS, higher OSI and increased wall thickness in the posterior compared to the anterior wall of the ICA bulb (p < 0.001), whereas this correlation disappeared in ≥10% stenosis. Higher carotid tortuosity (regression coefficient = 0.764; p < 0.001) and lower ICA/CCA diameter ratio (regression coefficient = - 0.302; p < 0.001) were independent predictors of increased wall thickness even after adjustment for cardiovascular risk factors. This association was not found for bifurcation angle, WSS or OSI in multivariate regression analysis. CONCLUSIONS: High carotid tortuosity and low ICA diameter were independent predictors for wall thickness of the ICA bulb in this cross-sectional study, whereas this association was not present for WSS or OSI. Thus, consideration of geometric parameters of the carotid bifurcation could be helpful to identify patients at increased risk of carotid plaque generation. However, this association and the potential benefit of WSS measurement need to be further explored in a longitudinal study.

Aortic atheroma as a source of stroke - assessment of embolization risk using 3D CMR in stroke patients and controls.

BACKGROUND: It was our purpose to identify vulnerable plaques in the thoracic aorta using 3D multi-contrast CMR and estimate the risk of cerebral embolization using 4D flow CMR in cryptogenic stroke patients and controls. METHODS: One hundred patients (40 with cryptogenic stroke, 60 ophthalmologic controls matched for age, sex and presence of hypertension) underwent a novel 3D multi-contrast (T1w, T2w, PDw) CMR protocol at 3 Tesla for plaque detection and characterization within the thoracic aorta, which was combined with 4D flow CMR for mapping potential embolization pathways. Plaque morphology was assessed in consensus reading by two investigators and classified according to the modified American-Heart-Association (AHA) classification of atherosclerotic plaques. RESULTS: In the thoracic aorta, plaques <4 mm thickness were found in a similar number of stroke patients and controls [23 (57.5%) versus 33 (55.0%); p = 0.81]. However, plaques ≥4 mm were more frequent in stroke patients [22 (55.0%) versus 10 (16.7%); p < 0.001]. Of those patients with plaques ≥4 mm, seven (17.5%) stroke patients and two (3.3%) controls (p < 0.001) had potentially vulnerable AHA type VI plaques. Six stroke patients with vulnerable AHA type VI plaques ≥4 mm had potential embolization pathways connecting the plaque, located in the aortic arch (n = 3) and proximal descending aorta (n = 3), with the individual territory of stroke, which made them the most likely source of stroke in those patients. CONCLUSIONS: Our findings underline the significance of ≥4 mm thick and vulnerable plaques in the aortic arch and descending aorta as a relevant etiology of stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: DRKS00006234 ; date of registration: 11/06/2014.

Prevalence of potential retrograde embolization pathways in the proximal descending aorta in stroke patients and controls.

BACKGROUND: Retrograde diastolic blood flow in the proximal descending aorta (DAo) connecting complex plaques (≥4 mm thick) with brain-supplying supra-aortic arteries may constitute a source of stroke. Yet, data only from high-risk populations (cryptogenic stroke patients with aortic atheroma≥3 mm) regarding the prevalence of this potential stroke mechanism are available. We aimed to quantify the frequency of this mechanism in unselected patients with cryptogenic stroke after routine diagnostics and controls without a history of stroke. METHODS: 88 patients (67 stroke patients, 21 cardiac controls) were prospectively included. 3D T1-weighted bright blood MRI of the aorta was applied for the detection of complex DAo atheroma. ECG-triggered and navigator-gated 4D flow MRI allowed measuring time-resolved 3D blood flow in vivo. Potential retrograde embolization pathways were defined as the co-occurrence of complex plaques and retrograde blood flow in the DAo reaching the outlet of (a) the left subclavian artery, (b) the left common carotid artery, or/and (c) the brachiocephalic trunk. The frequency of these pathways was analyzed by importing 2D plaque images into 3D blood flow visualization software. RESULTS: Complex DAo plaques were more frequent in stroke patients (44 in 31/67 patients (46.3%) vs. 5 in 4/21 controls (19.1%); p=0.039), especially in older patients (29/46 (63.04%) patients≥60 years of age with 41 plaques vs. 2/21 (9.14%) patients<60 years of age with 3 plaques; p<0.001). Contrary to our assumption, retrograde diastolic blood flow at the DAo occurred in every patient irrespective of the existence of plaques with a similar extent in both groups (26±14 vs. 32±18 mm; p=0.114). Therefore, only the higher prevalence of complex DAo plaques in stroke patients resulted in a three times higher frequency of potential retrograde embolization pathways compared to controls (22/67 (32.8%) vs. 2/21 (9.5%) controls; p=0.048). CONCLUSIONS: This study revealed that retrograde flow in the descending aorta is a common phenomenon not only in stroke patients. The existence of potential retrograde embolization pathways depends mainly on the occurrence of complex plaques in the area 0 to ∼30 mm behind the outlet of the left subclavian artery, which is exposed to flow reversal. In conclusion, we have shown that the frequency of potential retrograde embolization pathways was significantly higher in stroke patients suggesting that this mechanism may play a role in retrograde brain embolism.

Learning carotid vessel wall segmentation in black-blood MRI using sparsely sampled cross-sections from 3D data.

Purpose: Atherosclerosis of the carotid artery is a major risk factor for stroke. Quantitative assessment of the carotid vessel wall can be based on cross-sections of three-dimensional (3D) black-blood magnetic resonance imaging (MRI). To increase reproducibility, a reliable automatic segmentation in these cross-sections is essential. Approach: We propose an automatic segmentation of the carotid artery in cross-sections perpendicular to the centerline to make the segmentation invariant to the image plane orientation and allow a correct assessment of the vessel wall thickness (VWT). We trained a residual U-Net on eight sparsely sampled cross-sections per carotid artery and evaluated if the model can segment areas that are not represented in the training data. We used 218 MRI datasets of 121 subjects that show hypertension and plaque in the ICA or CCA measuring ≥ 1.5 mm in ultrasound. Results: The model achieves a high mean Dice coefficient of 0.948/0.859 for the vessel's lumen/wall, a low mean Hausdorff distance of 0.417 / 0.660 mm , and a low mean average contour distance of 0.094 / 0.119 mm on the test set. The model reaches similar results for regions of the carotid artery that are not incorporated in the training set and on MRI of young, healthy subjects. The model also achieves a low median Hausdorff distance of 0.437 / 0.552 mm on the 2021 Carotid Artery Vessel Wall Segmentation Challenge test set. Conclusions: The proposed method can reduce the effort for carotid artery vessel wall assessment. Together with human supervision, it can be used for clinical applications, as it allows a reliable measurement of the VWT for different patient demographics and MRI acquisition settings.

Carotid geometry is independently associated with complicated carotid artery plaques.

Introduction: Complicated carotid artery plaques (cCAPs) are associated with an increased risk of rupture and subsequent stroke. The geometry of the carotid bifurcation determines the distribution of local hemodynamics and could thus contribute to the development and composition of these plaques. Therefore, we studied the role of carotid bifurcation geometry in the presence of cCAPs. Methods: We investigated the association of individual vessel geometry with carotid artery plaque types in the Carotid Plaque Imaging in Acute Stroke (CAPIAS) study. After excluding arteries without plaque or with insufficient MRI quality, 354 carotid arteries from 182 patients were analyzed. Individual parameters of carotid geometry [i.e., internal carotid artery (ICA)/common carotid artery (CCA) ratio, bifurcation angle, and tortuosity) were derived from time-of-flight MR images. The lesion types of carotid artery plaques were determined according to the American Heart Association classification of lesions by multi-contrast 3T-MRI. The association between carotid geometry and a cCAP was studied using logistic regression after adjusting for age, sex, wall area, and cardiovascular risk factors. Results: Low ICA/CCA ratios (OR per SD increase 0.60 [95%CI: 0.42-0.85]; p = 0.004) and low bifurcation angles (OR 0.61 [95%CI: 0.42-0.90]; p = 0.012) were significantly associated with the presence of cCAPs after adjusting for age, sex, cardiovascular risk factors, and wall area. Tortuosity had no significant association with cCAPs. Only ICA/CCA ratio remained significant in a model containing all three geometric parameters (OR per SD increase 0.65 [95%CI: 0.45-0.94]; p = 0.023). Conclusions: A steep tapering of the ICA relative to the CCA and, to a lesser extent, a low angle of the carotid bifurcation were associated with the presence of cCAPs. Our findings highlight the contribution of bifurcation geometry to plaque vulnerability. Thus, assessment of carotid geometry could be helpful in identifying patients at risk of cCAPs.

Characterization of aortic aging using 3D multi-parametric MRI-long-term follow-up in a population study.

We comprehensively studied morphological and functional aortic aging in a population study using modern three-dimensional MR imaging to allow future comparison in patients with diseases of the aortic valve or aorta. We followed 80 of 126 subjects of a population study (20 to 80 years of age at baseline) using the identical methodology 6.0 ± 0.5 years later. All underwent 3 T MRI of the thoracic aorta including 3D T1 weighted MRI (spatial resolution 1 mm3) for measuring aortic diameter and plaque thickness and 4D flow MRI (spatial/temporal resolution = 2 mm3/20 ms) for calculating global and regional aortic pulse wave velocity (PWV) and helicity of aortic blood flow. Mean diameter of the ascending aorta (AAo) decreased and plaque thickness increased significantly in the aortic arch (AA) and descending aorta (DAo) in females. PWV of the thoracic aorta increased (6.4 ± 1.5 to 7.0 ± 1.7 m/s and 6.8 ± 1.5 to 7.3 ± 1.8 m/s in females and males, respectively) over time. Local normalized helicity volumes (LNHV) decreased significantly in the AAo and AA (0.33 to 0.31 and 0.34 to 0.32 in females and 0.34 to 0.32 and 0.32 to 0.28 in males). By contrast, helicity increased significantly in the DAo in both genders (0.28 to 0.29 and 0.29 to 0.30, respectively). 3D MRI was able to characterize changes in aortic diameter, plaque thickness, PWV and helicity during six years in our population. Aortic aging determined by 3D multi-parametric MRI is now available for future comparisons in patients with diseases of the aortic valve or aorta.

Flow-sensitive 4D MRI of the thoracic aorta: comparison of image quality, quantitative flow, and wall parameters at 1.5 T and 3 T.

PURPOSE: To evaluate the effect of field strength on flow-sensitive 4D magnetic resonance imaging (MRI) of the thoracic aorta. A volunteer study at 1.5 T and 3 T was conducted to compare phase-contrast MR angiography (MRA) and 3D flow visualization quality as well as quantification of aortic hemodynamics. MATERIALS AND METHODS: Ten healthy volunteers were examined by flow-sensitive 4D MRI at both 1.5 T and 3 T MRI with identical imaging parameters (TE/TR = 6/5.1 msec, spatial/temporal resolution ≈2 mm/40.8 msec). Analysis included assessment of image quality of derived aortic 3D phase contrast (PC) angiography and 3D flow visualization (semiquantitative grading on a 0-2 scale, two blinded observers) and quantification of blood flow velocities, net flow per cardiac cycle, wall shear stress (WSS), and velocity noise. RESULTS: Quality of 3D blood flow visualization (average grading = 1.8 ± 0.4 at 3 T vs. 1.1 ± 0.7 at 1.5 T) and the depiction of aortic lumen geometry by 3D PC-MRA (1.7 ± 0.5 vs. 1.2 ± 0.6) were significantly (P < 0.01) improved at 3 T while velocity noise was significantly higher (P < 0.01) at 1.5 T. Velocity quantification resulted in minimally altered (0.05 m/s, 3 mL/cycle and 0.01 N/m(2)) but not statistically different (P = 0.40, P = 0.39, and P = 0.82) systolic peak velocities, net flow, and WSS for 1.5 T compared to 3 T. CONCLUSION: Flow-sensitive 4D MRI at 3 T provided improved image quality without additional artifacts related to higher fields. Imaging at 1.5 T MRI, which is more widely available, was also feasible and provided information on aortic 3D hemodynamics of moderate quality with identical performance regarding quantitative analysis.

Analysis of pulse wave velocity in the thoracic aorta by flow-sensitive four-dimensional MRI: reproducibility and correlation with characteristics in patients with aortic atherosclerosis.

PURPOSE: To measure aortic pulse wave velocity (PWV) using flow-sensitive four-dimensional (4D) MRI and to evaluate test-retest reliability, inter- and intra-observer variability in volunteers and correlation with characteristics in patients with aortic atherosclerosis. MATERIALS AND METHODS: Flow-sensitive 4D MRI was performed in 12 volunteers (24 ± 3 years) and 86 acute stroke patients (68 ± 9 years) with aortic atherosclerosis. Retrospectively positioned 28 ± 4 analysis planes along the entire aorta (inter-slice-distance = 10 mm) and frame wise lumen segmentation yielded flow-time-curves for each plane. Global aortic PWV was calculated from time-shifts and distances between the upslope portions of all available flow-time curves. RESULTS: Inter- and intra-observer variability of PWV measurements in volunteers (7% and 8%) was low while test-retest reliability (22%) was moderate. PWV in patients was significantly higher compared with volunteers (5.8 ± 2.9 versus 3.8 ± 0.8 m/s; P = 0.02). Among 17 patient characteristics considered, statistical analysis revealed significant (P < 0.05) but low correlation of PWV with age (r = 0.25), aortic valve insufficiency (r = 0.29), and pulse pressure (r = 0.28). Multivariate modeling indicated that aortic valve insufficiency and elevated pulse pressure were significantly associated with higher PWV (adjusted R(2) = 0.13). CONCLUSION: Flow-sensitive 4D MRI allows for estimating aortic PWV with low observer dependence and moderate test-retest reliability. PWV in patients correlated with age, aortic valve insufficiency, and pulse pressure.

Exclusive color-coded duplex sonography of extracranial vessels reliably confirms brain death: A prospective study.

Background: Transcranial color-coded duplex sonography (TCCD) can be used as an ancillary test for determining irreversible loss of brain function (ILBF) when demonstration of cerebral circulatory arrest (CCA) is required. However, visualization of the intracranial vessels by TCCD is often difficult, or even impossible, in this patient cohort due to elevated intracranial pressure, an insufficient transtemporal bone window, or warped anatomical conditions. Since extracranial color-coded duplex sonography (ECCD) can be performed without restriction in the aforementioned situations, we investigated the feasibility of omitting TCCD altogether, such that the ILBF examination would be simplified, without compromising on its reliability. Methods: A total of 122 patients were prospectively examined by two experienced neurointensivists for the presence of ILBF from 01/2019-12/2021. Inclusion criteria were (i) the presence of a severe cerebral lesion on cranial CT or MRI, and (ii) brainstem areflexia. Upon standardized clinical examination, 9 patients were excluded due to incomplete brainstem areflexia, and a further 22 due to the presence of factors with a potentially confounding influence on apnea testing, EEG or sonography. A total of 91 patients were enrolled and underwent needle-EEG recording for >30 min (= gold standard), as well as ECCD and TCCD. The sonographer was blinded to the EEG result. Results: All patients whose ECCD result was consistent with ILBF had this diagnosis confirmed by EEG (n = 77; specificity: 1). Both ECCD and EEG were not consistent with ILBF in a further 12 patients. In the remaining two patients, ECCD detected reperfusion due to long-lasting cerebral hypoxia; however, ILBF was ultimately confirmed by EEG (sensitivity: 0.975). This yielded a positive predictive value (PPV) of one and a negative predictive value of 0.857 for the validity of ECCD in ILBF confirmation. TCCD was not possible/inconclusive in 31 patients (34%). Conclusions: The use of ECCD for the confirmation of ILBF is associated with high levels of specificity and a high positive predictive value when compared to needle-electrode EEG. This makes ECCD a potential alternative to the ancillary tests currently used in this setting, but confirmation in a multi-center trial is warranted. Trial registration: https://www.drks.de, DRKS00017803.

Basilar Artery Embolism Mimicking Transient Global Amnesia in a 61-Year-Old Female: A Case Report.

Transient global amnesia (TGA) is a self-limiting neurological condition that temporarily affects patients' ability to access and store memories. So far, its etiology is unknown; however, ischemic origin has been discussed in the past. We present the case of a 61-year-old female with clinical appearance of TGA. MRI and duplex scan revealed punctiform and patchy ischemic lesions in both temporal lobes and right vertebral artery dissection, suggesting basilar artery embolism as the underlying cause. Our case report shows that TGA can be a symptom of ischemic lesions in the hippocampus and patients with presentation of additional focal neurologic symptoms or atypical distribution or appearance of the diffusion-weighted image (multiple/patchy) lesions should get ischemic stroke diagnosis and treatment.

Influence of Pulse Wave Velocity on Atherosclerosis and Blood Flow Reversal in the Aorta: A 4-Dimensional Flow Magnetic Resonance Imaging Study in Acute Stroke Patients and Matched Controls.

BACKGROUND: Aortic stiffness is associated with a higher incidence of cardiovascular events including stroke. The primary aim of this study was to evaluate whether increased pulse wave velocity (PWV), a marker of stiffness, is an independent predictor of aortic atheroma. The secondary aim was to test whether increased PWV reinforces retrograde blood flow from the descending aorta (DAo), a mechanism of stroke. METHODS: We performed a cross-sectional case-control study with prospective data acquisition. In all, 40 stroke and 60 ophthalmic patients matched for age and cardiovascular risk factors were included. Multicontrast magnetic resonance imaging (MRI) protocol of the aorta tailored to allow a detailed plaque analysis using 3-dimensional (D) T1-weighted bright blood, T2-weighted and proton density-weighted black blood, and hemodynamic assessment using 4D flow MRI was applied. Individual PWV was calculated based on 4D flow MRI data using the time-to-foot of the blood flow waveform. The extent of maximum retrograde blood flow from the proximal DAo into the arch was quantified. RESULTS: PWV was higher in stroke patients compared with controls (7.62±2.59 vs. 5.96±2.49 m/s; P=0.005) and in patients with plaques (irrespective of thickness) compared with patients without plaques (7.47±2.89 vs. 5.62±1.89 m/s; P=0.002). Increased PWV was an independent predictor of plaque prevalence and contributed significantly to a predictor model explaining 36.5% (Nagelkerke R2) of the variance in plaque presence. Maximum retrograde flow extent from the proximal DAo was not correlated with PWV. CONCLUSIONS: Aortic stiffness was higher in stroke patients and associated with a higher prevalence of plaques. Increased PWV was an independent predictor of plaque presence. Accordingly, regional PWV seems to be a valuable biomarker for the assessment and management of aortic atherosclerosis. However, no association was found for increased retrograde flow extent from the DAo.

Bubble Test and Carotid Ultrasound to Guide Indication of Transesophageal Echocardiography in Young Patients With Stroke.

Background and Purpose: Indication of transesophageal echocardiography (TEE) in patients ≤60 years with brain ischemia is uncertain. Methods: This prospective double-blinded study included patients with cryptogenic acute ischemic stroke or transient ischemic attack (TIA) ≥18 and ≤60 years. After routine diagnostics, all patients underwent patent foramen ovale (PFO) screening by transcranial Doppler (TCD) bubble test, carotid ultrasound for atherosclerosis screening (intima-media-thickness >0.90 mm or plaques), and TEE. We calculated sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) of the combined non-invasive ultrasound to predict therapy-relevant TEE findings. Results: We included 240 consecutive patients (median 51 years, 39% women) of which 68 (28.3%) had both a negative bubble test and no carotid atherosclerosis. Of these, 66 (97.1%) had unremarkable TEE findings; in one patient a small PFO was found and closed subsequently, in another patient a 4.9 mm thick aortic atheroma was found, and double platelet inhibition initiated. Of the other 172 (71.7%) patients, 93 (54%) had PFO and 9 (5.2%) complex aortic plaques. No other therapy-relevant findings were present in both groups. Non-invasive ultrasound had a sensitivity of 98.0%, specificity of 47.8%, NPV of 97.1%, and PPV of 58.1% for therapy-relevant TEE findings. Conclusions: Bubble test and carotid ultrasound could be used for the individual decision for/against TEE in patients with cryptogenic stroke ≤60 years. If they are unremarkable, TEE can be omitted with high safety regarding secondary prevention. If bubble test is positive and/or carotid ultrasound shows atherosclerosis, TEE should be carried out if PFO or aortic atheroma are potentially relevant for further patient management.

Complicated Carotid Artery Plaques and Risk of Recurrent Ischemic Stroke or TIA.

BACKGROUND: Complicated nonstenosing carotid artery plaques (CAPs) are an under-recognized cause of stroke. OBJECTIVES: The purpose of this study was to determine whether complicated CAP ipsilateral to acute ischemic anterior circulation stroke (icCAP) are associated with recurrent ischemic stroke or transient ischemic attack (TIA). METHODS: The CAPIAS (Carotid Plaque Imaging in Acute Stroke) multicenter study prospectively recruited patients with ischemic stroke restricted to the territory of a single carotid artery. Complicated (AHA-lesion type VI) CAP were defined by multisequence, contrast-enhanced carotid magnetic resonance imaging obtained within 10 days from stroke onset. Recurrent events were assessed after 3, 12, 24, and 36 months. The primary outcome was recurrent ischemic stroke or TIA. RESULTS: Among 196 patients enrolled, 104 patients had cryptogenic stroke and nonstenosing CAP. During a mean follow-up of 30 months, recurrent ischemic stroke or TIA occurred in 21 patients. Recurrent events were significantly more frequent in patients with icCAP than in patients without icCAP, both in the overall cohort (incidence rate [3-year interval]: 9.50 vs 3.61 per 100 patient-years; P = 0.025, log-rank test) and in patients with cryptogenic stroke (10.92 vs 1.82 per 100 patient-years; P = 0.003). The results were driven by ipsilateral events. A ruptured fibrous cap (HR: 4.91; 95% CI: 1.31-18.45; P = 0.018) and intraplaque hemorrhage (HR: 4.37; 95% CI: 1.20-15.97; P = 0.026) were associated with a significantly increased risk of recurrent events in patients with cryptogenic stroke. CONCLUSIONS: Complicated CAP ipsilateral to acute ischemic anterior circulation stroke are associated with an increased risk of recurrent ischemic stroke or TIA. Carotid plaque imaging identifies high-risk patients who might be suited for inclusion into future secondary prevention trials. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933).

Carotid Geometry and Wall Shear Stress Independently Predict Increased Wall Thickness-A Longitudinal 3D MRI Study in High-Risk Patients.

Introduction: Carotid geometry and wall shear stress (WSS) have been proposed as independent risk factors for the progression of carotid atherosclerosis, but this has not yet been demonstrated in larger longitudinal studies. Therefore, we investigated the impact of these biomarkers on carotid wall thickness in patients with high cardiovascular risk. Methods: Ninety-seven consecutive patients with hypertension, at least one additional cardiovascular risk factor and internal carotid artery (ICA) plaques (wall thickness ≥ 1.5 mm and degree of stenosis ≤ 50%) were prospectively included. They underwent high-resolution 3D multi-contrast and 4D flow MRI at 3 Tesla both at baseline and follow-up. Geometry (ICA/common carotid artery (CCA)-diameter ratio, bifurcation angle, tortuosity and wall thickness) and hemodynamics [WSS, oscillatory shear index (OSI)] of both carotid bifurcations were measured at baseline. Their predictive value for changes of wall thickness 12 months later was calculated using linear regression analysis for the entire study cohort (group 1, 97 patients) and after excluding patients with ICA stenosis ≥10% to rule out relevant inward remodeling (group 2, 61 patients). Results: In group 1, only tortuosity at baseline was independently associated with carotid wall thickness at follow-up (regression coefficient = -0.52, p < 0.001). However, after excluding patients with ICA stenosis ≥10% in group 2, both ICA/CCA-ratio (0.49, p < 0.001), bifurcation angle (0.04, p = 0.001), tortuosity (-0.30, p = 0.040), and WSS (-0.03, p = 0.010) at baseline were independently associated with changes of carotid wall thickness at follow-up. Conclusions: A large ICA bulb and bifurcation angle and low WSS seem to be independent risk factors for the progression of carotid atherosclerosis in the absence of ICA stenosis. By contrast, a high carotid tortuosity seems to be protective both in patients without and with ICA stenosis. These biomarkers may be helpful for the identification of patients who are at particular risk of wall thickness progression and who may benefit from intensified monitoring and treatment.

Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model.

Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes.Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.

Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke.

BACKGROUND AND PURPOSE: To investigate the incidence of retrograde flow from complex plaques (> or =4-mm-thick, ulcerated, or superimposed thrombi) of the descending aorta (DAo) and its potential role in embolic stroke. METHODS: Ninety-four consecutive acute stroke patients with aortic plaques > or =3-mm-thick in transesophageal echocardiography were prospectively included. MRI was performed to localize complex plaques and to measure time-resolved 3-dimensional blood flow within the aorta. Three-dimensional visualization was used to evaluate if diastolic retrograde flow connected plaque location with the outlet of the left subclavian artery, left common carotid artery, or brachiocephalic trunk. Complex DAo plaques were considered an embolic source if retrograde flow reached a supra-aortic vessel that supplied the territory of visible acute and embolic retinal or cerebral infarction. RESULTS: Only decreasing heart rate was correlated (P<0.02) with increasing flow reversal to the aortic arch. Retrograde flow from complex DAo plaques reached the left subclavian artery in 55 (58.5%), the left common carotid artery in 23 (24.5%), and the brachiocephalic trunk in 13 patients (13.8%). Based on routine diagnostics and MRI of the ascending aorta/aortic arch, stroke etiology was determined in 57 and cryptogenic in 37 patients. Potential embolization from DAo plaques was then identified in 19 of 57 patients (33.3%) with determined and in 9 of 37 patients (24.3%) with cryptogenic stroke. CONCLUSIONS: Retrograde flow from complex DAo plaques was frequent in both determined and cryptogenic stroke and could explain embolism to all brain territories. These findings suggest that complex DAo plaques should be considered a new source of stroke.