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Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background Oral Factor Xa inhibitors for the prevention of stroke in atrial fibrillation require dose adjustment based on certain clinical criteria, but the off-label use of the reduced doses is common. Methods Data from an observational registry including patients admitted with acute cerebral ischemia while taking oral Factor Xa inhibitors for atrial fibrillation between April 2016 and December 2018 were investigated. The dose regimen of the Xa inhibitor was classified as “appropriate”, “underdosed” and “overdosed” in conformity with the European Medicines Agency labelling. The effect of underdosing on the functional factor Xa plasma level on admission, the clinical stroke severity and the functional outcome after 3 months were investigated. Results 254 patients with cerebral ischemia while on Factor Xa inhibitors were included. The dose regimen of the Factor Xa inhibitor was appropriate in 166 patients (65%), underdosed in 67 patients (26%) and overdosed in 21 patients (8%). Underdosing was associated with female sex, diabetes mellitus and higher CHA2DS2–Vasc scores. Underdosing independently predicted lower anti-Xa plasma levels on admission [median 69.4 ng/ml (IQR 0.0–121.6) vs. 129.2 ng/ml (65.5–207.2); p p = 0.041] and worse functional outcome after 3 months (favorable outcome 26.9% vs. 46.9%; p = 0.025). Conclusion One in three patients with ischemic stroke during treatment with oral Xa inhibitors used inappropriate dose regimens. Underdosing was associated with lower functional plasma levels, higher clinical stroke severity and worse functional outcome.

To investigate A-delta fiber pathways in patients with large, mixed, and small fiber neuropathies using pain-related evoked potentials (PREP).We prospectively examined consecutive and unselected 108 patients with neuropathies using PREP. Patients were stratified according to impaired fiber types in those with large fiber neuropathy (LFN, n = 23), mixed fiber neuropathy (MFN, n = 80), and small fiber neuropathy (SFN, n = 5). Additionally, medical history, nerve conduction studies, quantitative sensory testing (QST), and skin punch biopsy were applied. Data was compared with those of 49 healthy controls.Patients with MFN showed a distal loss of PREP (16/80, 20%) and prolonged PREP latencies after stimulation at the foot (MFN: 225.8 [135-293.6] ms, controls: 218 [135-394] ms, p 0.05). Patients with demyelinating neuropathies had prolonged PREP latencies after stimulation at the hand (p 0.05 each). QST showed an impairment of small and large fiber function in patients with MFN. PREP were mostly absent in patients at advanced stages of neuropathies: in 10/31 (30%) patients with no recordable sural nerve action potential (SNAP, preserved SNAP: 8/76, 10% missing) and in 4/17 (24%) patients with loss of distal epidermal innervation (preserved epidermal innervation: 7/60, 24%) PREP was not recordable. PREP peak-to-peak amplitude after stimulation at the face was lowered in patients with reduced proximal intraepidermal nerve fiber density (p 0.02).PREP is a useful screening method for A-delta fiber pathology also in patients with simultaneous large fiber pathology. Loss of PREP indicates advance stages of nerve fiber damage.PREP may be useful as a complementary method for detection of small fiber impairment also in patients with mixed fiber neuropathy and in advanced stages.

Atrial fibrillation (AF) in stroke patients can be classified as either "known AF" (KAF), defined as AF confirmed before stroke onset, or "AF detected after stroke" (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke-triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype.Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3-month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention.A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre-stroke anticoagulation. OAC for secondary prevention was associated with favorable 3-month functional outcome (odds ratio 7.60, 95% confidence interval 3.42-16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly.Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype.

Patients with atrial fibrillation have a relevant risk for ischemic stroke despite the recommended use of direct oral anticoagulants (DOAC). The risk correlates with the functional DOAC plasma levels in clinical trials, but the value of their measurement in community use remains undetermined.We aim to investigate the clinical implications and the prognostic value of DOAC plasma level measurement during steady state.In this observational clinical cohort study among patients with ischemic stroke and atrial fibrillation, 397 individuals on oral anticoagulants for secondary stroke prevention were included between 2016 and 2020. The functional DOAC plasma levels were measured during steady state. Early stroke recurrence within 3 months was recorded as the main outcome parameter.Three hundred ninety-seven patients (201 female, mean age 78 [±9] years, median CHAMonitoring of DOAC plasma levels could help to identify patients with increased risk for stroke recurrence and should be considered for certain subgroups, including patients with high GFR.

IntroductionMyocardial injury related to acute ischaemic stroke is common even without primary cardiac disease. We intended to determine associations between values of left ventricular ejection fraction (LVEF) and ischaemic stroke lesion sites.MethodsOf a local database, patients with acute first-ever ischaemic stroke confirmed by brain imaging but without pre-existing heart disease were included. The cardiac morphology and LVEF were obtained from transthoracic or transesophageal echocardiography, and impaired LVEF was categorised as mild (35%–50%), moderate (34%–25%) and severe (0.1 ng/mL), atrial fibrillation and cardiac wall motion abnormalities were assessed and compared between patients with and without impaired LVEF after stroke (significance: pResultsOf 1209 patients who had a stroke, 231 (mean age 66.3±14.0 years) met the inclusion criteria; 40 patients (17.3%) had an impaired LVEF after stroke. Patients with impaired LVEF had higher infarct volumes (53.8 mL vs 30.0 mL, p=0.042), a higher prevalence of troponin increase (17.5% vs 4.2%, p=0.006), cardiac wall motion abnormalities (42.5% vs 5.2%, p50%. The multivariate voxelwise lesion analysis yielded associations between decreased LVEF and damaged voxels in the insula, amygdala and operculum of the right hemisphere.ConclusionOur imaging analysis unveils a prominent role of the right hemispheric central autonomic network, especially of the insular cortex, in the brain–heart axis. Our results support preliminary evidence that acute ischaemic stroke in distinct brain regions of the central autonomic network may directly impair cardiac function and thus further supports the concept of a distinct stroke-heart syndrome.

Purpose Endovascular therapy (EVT) of large-vessel occlusion in acute ischemic stroke (AIS) may be performed in general anesthesia (GA) or conscious sedation (CS). We intended to determine the contribution of ischemic cerebral lesion sites on the physician’s decision between GA and CS using voxel-based lesion symptom mapping (VLSM). Methods In a prospective local database, we sought patients with documented AIS and EVT. Age, stroke severity, lesion volume, vigilance, and aphasia scores were compared between EVT patients with GA and CS. The ischemic lesions were analyzed on CT or MRI scans and transformed into stereotaxic space. We determined the lesion overlap and assessed whether GA or CS is associated with specific cerebral lesion sites using the voxel-wise Liebermeister test. Results One hundred seventy-nine patients with AIS and EVT were included in the analysis. The VLSM analysis yielded associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas. Stroke severity and lesion volume were significantly higher in the GA group. The prevalence of aphasia and aphasia severity was significantly higher and parameters of vigilance lower in the GA group. Conclusions The VLSM analysis showed associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas including the thalamus that are known to cause neurologic deficits, such as aphasia or compromised vigilance, in AIS-patients with EVT. Our data suggest that higher disability, clinical impairment due to neurological deficits like aphasia, or reduced alertness of affected patients may influence the physician’s decision on using GA in EVT.

Background: rt-PA for ischemic stroke in the unknown or extended time window beyond the first 4. 5 h after symptom onset is safe and effective for certain patients after selection by multimodal neuroimaging. However, the evidence for this approach comes mainly from patients with anterior circulation stroke (ACS), while the data on posterior circulation stroke (PCS) are scarce.Methods: Ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window between January 2011 and May 2019 were identified from an institutional registry. The patients were categorized into PCS or ACS based on clinico-radiological findings. We analyzed the hemorrhagic complications, clinical and imaging efficacy outcomes, and mortality rates by comparing the PCS and ACS patient groups. Adjusted outcome analyses were performed after propensity score matching for the relevant factors.Results: Of the 182 patients included, 38 (20.9%) had PCS and 144 (79.1%) had ACS. Symptomatic acute large vessel occlusion (LVO) was present in 123 patients on admission [27 (22.0%) PCS and 96 (78.0%) ACS]. The score on the National Institutes of Health Stroke Scale (NIHSS), the time from last seen normal, and the door-to-needle times were similar in PCS and ACS. In patients with LVO, the NIHSS score was lower [8 (5–15) vs. 14 (9–18), p = 0.005], and infarction visible on follow-up imaging was less common [70.4 vs. 87.5%; aRD, −18.9% (−39.8 to −2.2%)] in the PCS patient group. There was a trend toward a lower risk for intracranial hemorrhage (ICH) following intravenous thrombolysis in PCS vs. ACS, without reaching a statistical significance [5.3 vs. 16.9%; aRD, −10.4% (−20.4 to 4.0%)]. The incidence of symptomatic ICH [according to the ECASS III criteria: 2.6 vs. 3.5%; aRD, −2.9% (−10.3 to 9.2%)], efficacy outcomes, and mortality rates were similar in PCS and ACS patients.Conclusions: In this real-world clinical cohort, the safety and the efficacy of rt-PA for ischemic stroke in the unknown or extended time window did not show relevant differences between PCS and ACS, with a trend toward less hemorrhagic complications in PCS. The findings reconfirm the clinician in the usage of rt-PA beyond the first 4.5 h also in selected patients with PCS.

Performing a diagnostic lumbar puncture is an essential clinical skill for the clinician. The procedure is of high importance for both, the emergency care for patients with suspected infection of the cerebral nervous system or subarachnoidal hemorrhage, as well as the elective diagnostic work up of chronic disease including multiple sclerosis and dementia. Furthermore the technique’s principles are applied for spinal anesthesia or the intrathecal administration of drugs. This article describes a Standard Operating Procedure for the lumbar puncture step by step. Based on the latest evidence, it particularly focusses on clinically relevant questions and practical aspects.

Background and Purpose— In patients with ischemic stroke on therapy with vitamin K antagonists, stroke severity and clinical course are affected by the quality of anticoagulation at the time of stroke onset, but clinical data for patients using direct oral anticoagulants (DOACs) are limited. Methods— Data from our registry including all patients admitted with acute cerebral ischemia while taking oral anticoagulants for atrial fibrillation between November 2014 and October 2017 were investigated. The activity of vitamin K antagonists was assessed using the international normalized ratio on admission and categorized according to a threshold of 1.7. DOAC plasma levels were measured using the calibrated Xa-activity (apixaban, rivaroxaban, and edoxaban) or the Hemoclot-assay (dabigatran) and categorized into low (100 ng/mL). Primary objective was the association between anticoagulant activity and clinical and imaging characteristics. Results— Four hundred sixty patients were included (49% on vitamin K antagonists and 51% on DOAC). Patients on vitamin K antagonists with low international normalized ratio values had higher scores on the National Institutes of Health Stroke Scale and a higher risk of large vessel occlusion on admission. For patients on DOAC, plasma levels were available in 75.6% and found to be low in 49 (27.7%), intermediate in 41 (23.2%), and high in 87 patients (49.2%). Low plasma levels were associated with higher National Institutes of Health Stroke Scale scores on admission (low: 8 [interquartile range, 3–15] versus intermediate: 4 [1–11] versus high: 3 [0–8]; P P P =0.001). Conclusions— The activity of anticoagulation measured by specific DOAC plasma levels on admission is associated with stroke severity and presence of large vessel occlusion.

Moyamoya vasculopathy (MMV) is characterized by a progressive, usually bilateral narrowing of the terminal segment of the internal carotid artery or the initial segments of the anterior/middle cerebral artery leading to occlusion and formation of a fragile network of abundant collateral vessels with a high risk of stroke.

ObjectiveTo investigate differences in procedure times, safety, and efficacy outcomes comparing 2 different protocols to enable thrombolysis in the extended or unknown time window after stroke onset with either multimodal CT or MRI.MethodsPatients with ischemic stroke in the extended or unknown time window who received IV thrombolysis between January 2011 and May 2019 were identified from an institutional registry. Imaging-based selection was done by multimodal CT or MRI according to institutional treatment algorithms.ResultsIV thrombolysis was performed in 100 patients (54.3%) based on multimodal CT imaging and in 84 patients (45.7%) based on MRI. Baseline clinical data, including stroke severity and time from last seen normal to hospital admission, were similar in patients with CT and MRI. Door-to-needle times were shorter in patients with CT-based selection (median [interquartile range] 45 [37–62] minutes vs 75 [59–90] minutes; mean difference [95% confidence interval (CI)] −28 minutes [−35 to −21]). No differences were detected regarding the incidence of symptomatic intracranial hemorrhage (2 [2.0%] vs 4 [4.8%]; adjusted odds ratio [aOR] [95% CI] 0.47 [0.08–2.83]) and favorable outcome at day 90 (25 [33.8%] vs 33 [42.9%]; aOR 0.95 [0.45–2.02]).ConclusionIV thrombolysis in ischemic stroke in the unknown or extended time window appeared safe in CT- and MRI-selected patients, while the use of CT imaging led to faster door-to-needle times.Classification of evidenceThis study provides Class IV evidence that for patients with ischemic stroke in the extended or unknown time window, imaging-based selection for IV thrombolysis by multimodal CT compared to MRI led to shorter door-to-needle times.

Background and Purpose— Heart failure (HF) in patients with acute ischemic stroke constitutes the source of various detrimental pathophysiologic mechanisms including prothrombotic and proinflammatory states, worsening of cerebral tissue oxygenation, and hemodynamic impairment. In addition, HF might affect the safety and efficacy of the acute recanalization stroke therapies. Methods— Patients treated with intravenous recombinant tissue-type plasminogen activator or mechanical recanalization at a universitary stroke center were included into a prospective registry. Patients received cardiological evaluation, including echocardiography, during acute care. Functional outcome was assessed after 90 days by structured telephone interviews. Safety and efficacy of intravenous thrombolysis and mechanical thrombectomy were investigated among patients with HF and compared with patients with normal cardiac function after propensity score matching. Results— One thousand two hundred nine patients were included. HF was present in 378 patients (31%) and an independent predictor of unfavorable functional outcome. Recanalization rates were equal among patients with HF after intravenous thrombolysis and after mechanical recanalization or combined treatment. The rate of secondary intracranial hemorrhage was not different (7% versus 8%; P =0.909 after thrombolysis and 15% versus 20%, P =0.364 after mechanical recanalization or combined therapy). Early mortality within 48 hours after admission was equal ( Conclusions— In this real-world cohort of patients with stroke, HF was an independent predictor of unfavorable functional long-term outcome, while the safety and efficacy of intravenous thrombolysis and mechanical recanalization appeared unaffected.

Background and Purpose- In patients with ischemic stroke on therapy with vitamin K antagonists, stroke severity and clinical course are affected by the quality of anticoagulation at the time of stroke onset, but clinical data for patients using direct oral anticoagulants (DOACs) are limited. Methods- Data from our registry including all patients admitted with acute cerebral ischemia while taking oral anticoagulants for atrial fibrillation between November 2014 and October 2017 were investigated. The activity of vitamin K antagonists was assessed using the international normalized ratio on admission and categorized according to a threshold of 1.7. DOAC plasma levels were measured using the calibrated Xa-activity (apixaban, rivaroxaban, and edoxaban) or the Hemoclot-assay (dabigatran) and categorized into low (50 ng/mL), intermediate (50-100 ng/mL), or high (100 ng/mL). Primary objective was the association between anticoagulant activity and clinical and imaging characteristics. Results- Four hundred sixty patients were included (49% on vitamin K antagonists and 51% on DOAC). Patients on vitamin K antagonists with low international normalized ratio values had higher scores on the National Institutes of Health Stroke Scale and a higher risk of large vessel occlusion on admission. For patients on DOAC, plasma levels were available in 75.6% and found to be low in 49 (27.7%), intermediate in 41 (23.2%), and high in 87 patients (49.2%). Low plasma levels were associated with higher National Institutes of Health Stroke Scale scores on admission (low: 8 [interquartile range, 3-15] versus intermediate: 4 [1-11] versus high: 3 [0-8]; P0.001) and higher risk of persisting neurological deficits or cerebral infarction on imaging (85.7% versus 75.6% versus 54.0%; P0.001). Low DOAC plasma levels were an independent predictor of large vessel occlusion (odds ratio, 3.84 [95% CI, 1.80-8.20]; P=0.001). Conclusions- The activity of anticoagulation measured by specific DOAC plasma levels on admission is associated with stroke severity and presence of large vessel occlusion.

To investigate A-delta fiber conduction in mild to moderate Fabry disease (FD) patients using pain-related evoked potentials (PREP).In this case-control study we prospectively investigated 58 patients with mild to moderate FD and compared data with those of healthy controls. Small fiber function (quantitative sensory testing, QST and sympathetic skin response, SSR), morphology (intraepidermal nerve fiber density, IENFD), and electrical conduction (PREP) were assessed and correlated with sweating as major autonomic function disturbed in FD. Patients were further stratified for gender, disease severity as reflected by renal and cardiac function, and genetics.An- or hypohidrosis (i.e. dyshidrosis) was reported by 7/32 (22%) women and 15/26 (58%) men with FD (p 0.01). QST showed small fiber impairment in female and male patients regardless of clinical symptoms, while SSR was obtained in all patients except one man with hypohidrosis. IENFD was reduced in 50% of FD patients, with no differences between groups with and without autonomic symptoms. However, PREP amplitudes were reduced independent of the stimulation site only in female patients with dyshidrosis (p 0.01). Genetics had no influence on PREP parameters.A-delta fiber conduction investigated using PREP is impaired in mild to moderately affected female FD patients with clinical signs of hypohidrosis.Small fiber assessment in FD is of diagnostic value already in mild to moderate stages of disease.

Introduction Cortical pain-related evoked potentials (PREP) are elicited by activation of the A δ -fibers using cutaneous electrical stimulation and objectively reflect the A δ -pathways. PREP were applied in an unselected patient population with acral neuropathic pain to explore its diagnostic usefulness in detecting small fiber impairment compared to quantitative sensory test (QST) and skin punch biopsy. Methods Thirty-two patients (13 male and 19 female, median age 50 years, range 26–83) suffering from acral neuropathic pain were examined clinically and with nerve conduction studies, QST, skin punch biopsy and PREP. Results The study cohort consisted of 16 patients with small fiber neuropathy (SFN), 18 patients with mixed fiber neuropathy (MFN, i.e. large and small fiber neuropathy), and 8 patients with acral neuropathic pain without signs of a large fiber neuropathy or SFN. QST and skin biopsy were pathological in terms of elevated thermal thresholds and reduced distal skin innervation in patients with SFN and MFN, while patients with acral neuropathic pain had normal findings. PREP was the only method showing a pathological finding, namely reduced peak-to-peak amplitudes also in patients with acral neuropathic pain ( p Conclusion PREP was the only method revealing small fiber dysfunction in patients suffering from acral neuropathic pain with otherwise normal QST and skin biopsy. As a non-invasive test giving reproducible results, PREP may contribute to the diagnostic portfolio of small fiber tests in patients with neuropathic pain.

The capsaicin 8% patch is a treatment option in patients with localized peripheral neuropathic pain. We provide first data on the effect of capsaicin on the electrophysiological properties of A-delta fibers., Introduction: The capsaicin 8% patch is a treatment option in patients with localized peripheral neuropathic pain. Better understanding of its mechanisms of action and knowledge on predictive biomarkers for a treatment response is warranted. Objectives: To use electrically evoked pain-related potentials for investigation of A-delta fiber conduction after capsaicin 8% patch treatment. Methods: We studied 11 healthy controls at the dorsal hand and the foot and 12 patients with neuropathic pain at the area affected by neuropathic pain before and 2 hours after application of a capsaicin 8% patch (Qutenza). Patients were additionally phenotyped using quantitative sensory testing and skin biopsy. Results: Peak-to-peak N1-P1 amplitudes (PPA) were reduced after Qutenza application by a median of 60% in 6/11 controls and by 33% in patients with neuropathic pain compared with baseline; they were increased in 3 controls that did not develop capsaicin-induced pain. Patients with elevated cold detection thresholds more often had reduced PPA after Qutenza than those with normal cold detection threshold. Patients with reduced PPA after capsaicin application and with capsaicin-induced pain were more likely to achieve pain reduction on Qutenza. Conclusion: The capsaicin 8% patch induces a reduction in A-delta PPA in healthy persons and in patients with neuropathic pain adding to the mechanistic understanding of its effect.