Cerebral lesions sites in neurosarcoidosis: a lesion mapping study.

BACKGROUND AND PURPOSE: Sarcoidosis is a granulomatous disease of unknown etiology affecting the central nervous system in up to 15% of the patients. Diagnosis of neurosarcoidosis is very challenging due to the heterogeneity of its clinical manifestation. This study intended to evaluate the distribution of cerebral lesion sites and the potential presence of specific lesion clusters in neurosarcoidosis patients using voxel-based lesion symptom mapping (VLSM). METHODS: Patients with neurosarcoidosis were retrospectively identified and included between 2011 and 2022. Cerebral lesion sites were correlated voxel-wise with presence and absence of neurosarcoidosis using non-parametric permutation test. Multiple sclerosis patients served as controls for the VLSM-analysis. RESULTS: Thirty-four patients (mean age 52 ± 15 years) of whom 13 were diagnosed with possible, 19 with probable and 2 with confirmed neurosarcoidosis were identified. Lesion overlap of neurosarcoidosis patients demonstrated a distribution of white matter lesions in all brain areas, with a periventricular predilection similar to multiple sclerosis. In contrast to multiple sclerosis controls, no propensity for lesions in proximity of the corpus callosum was observed. Neurosarcoidosis lesions appeared smaller and lesion volume was lower in the neurosarcoidosis cohort. The VLSM analysis showed minor associations between neurosarcoidosis and damaged voxels in the bilateral frontobasal cortex. CONCLUSIONS: The VLSM analysis yielded significant associations in the bilateral frontal cortex, suggesting that leptomeningeal inflammatory disease with following cortical involvement is a quite specific feature in neurosarcoidosis. Lesion load was lower in neurosarcoidosis than in multiple sclerosis. However, no specific pattern of subcortical white matter lesions in neurosarcoidosis was revealed.

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation.

BACKGROUND: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. METHODS: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. RESULTS: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. CONCLUSION: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

Acute right insular ischaemic lesions and poststroke left ventricular dysfunction.

INTRODUCTION: Myocardial 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. METHODS: Of 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 (<25%). Patient age, stroke severity, ischaemic lesion volume, prevalence of troponin I increase (>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: p<0.05). A multivariate voxelwise lesion analysis correlated LVEF after stroke with sites of ischaemic lesions. RESULTS: Of 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%, p<0.001) and atrial fibrillation (60.0% vs 26.2%, p<0.001) than patients with LVEF of >50%. The multivariate voxelwise lesion analysis yielded associations between decreased LVEF and damaged voxels in the insula, amygdala and operculum of the right hemisphere. CONCLUSION: Our 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.

Prognostic Accuracy of CTP Summary Maps in Patients with Large Vessel Occlusive Stroke and Poor Revascularization after Mechanical Thrombectomy-Comparison of Three Automated Perfusion Software Applications.

Background: Innovative automated perfusion software solutions offer support in the management of acute stroke by providing information about the infarct core and penumbra. While the performance of different software solutions has mainly been investigated in patients with successful recanalization, the prognostic accuracy of the hypoperfusion maps in cases of futile recanalization has hardly been validated. Methods: In 39 patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation and poor revascularization (thrombolysis in cerebral infarction (TICI) 0-2a) after mechanical thrombectomy (MT), hypoperfusion analysis was performed using three different automated perfusion software solutions (A: RAPID, B: Brainomix e-CTP, C: Syngo.via). The hypoperfusion volumes (HV) as Tmax > 6 s were compared with the final infarct volumes (FIV) on follow-up CT 36−48 h after futile recanalization. Bland−Altman analysis was applied to display the levels of agreement and to evaluate systematic differences. Based on the median hypoperfusion intensity ratio (HIR, volumetric ratio of tissue with a Tmax > 10 s and Tmax > 6 s) patients were dichotomized into high- and low-HIR groups. Subgroup analysis with favorable (<0.6) and unfavorable (≥0.6) HIR was performed with respect to the FIV. HIR was correlated to clinical baseline and outcome parameters using Pearson's correlation. Results: Overall, there was good correlation without significant differences between the HVs and the FIVs with package A (r = 0.78, p < 0.001) being slightly superior to B and C. However, levels of agreement were very wide for all software applications in Bland-Altman analysis. In cases of large infarcts exceeding 150 mL the performance of the automated software solutions generally decreased. Subgroup analysis revealed the FIV to be generally underestimated in patients with HIR ≥ 0.6 (p < 0.05). In the subgroup with favorable HIR, however, there was a trend towards an overestimation of the FIV. Nevertheless, packages A and B showed good correlation between the HVs and FIVs without significant differences (p > 0.2), while only package C significantly overestimated the FIV (−54.6 ± 56.0 mL, p = 0.001). The rate of modified Rankin Scale (mRS) 0−3 after 3 months was significantly higher in favorable vs. unfavorable HIR (42.1% vs. 13.3%, p = 0.02). Lower HIR was associated with higher Alberta Stroke Program Early CT Score (ASPECTS) at presentation and on follow-up imaging, lower risk of malignant edema, and better outcome (p < 0.05). Conclusion: Overall, the performance of the automated perfusion software solutions to predict the FIV after futile recanalization is good, with decreasing accuracy in large infarcts exceeding 150 mL. However, depending on the HIR, FIV can be significantly over- and underestimated, with Syngo showing the widest range. Our results indicate that the HIR can serve as valuable parameter for outcome predictions and facilitate the decision whether or not to perform MT in delicate cases.

Acute care and secondary prevention of stroke with newly detected versus known atrial fibrillation.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Monitoring of direct oral anticoagulants plasma levels for secondary stroke prevention.

BACKGROUND: 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. OBJECTIVES: We aim to investigate the clinical implications and the prognostic value of DOAC plasma level measurement during steady state. METHODS: 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. RESULTS: Three hundred ninety-seven patients (201 female, mean age 78 [±9] years, median CHA2 DS2 VASc-Score 6 [interquartile range 5-7]) were included. Mean DOAC plasma trough level was 95.9 (±66.9) ng/ml. A high glomerular filtration rate (GFR) was an independent predictor of lower levels in a multivariate model (R coefficient: -0.174, P = .014). During follow-up, 10 patients (3%) suffered from early ischemic stroke recurrence despite the use of DOAC, while 10 clinically relevant bleeding complications occurred (3%). Ischemic stroke recurrence was associated with numerical lower plasma levels for patients on apixaban and dabigatran after propensity score matching. CONCLUSIONS: Monitoring 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.

IV-Thrombolysis in Ischemic Stroke With Unknown Time of Onset-Safety and Outcomes in Posterior vs. Anterior Circulation Stroke.

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.

The anesthetic approach for endovascular recanalization therapy depends on the lesion site in acute ischemic stroke.

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.

Multimodal CT or MRI for IV thrombolysis in ischemic stroke with unknown time of onset.

OBJECTIVE: To 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. METHODS: Patients 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. RESULTS: IV 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]). CONCLUSION: IV 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 EVIDENCE: This 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.

Ischemic stroke and dose adjustment of oral Factor Xa inhibitors in patients with atrial fibrillation.

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 < 0.001], was associated with higher NIHSS scores on admission [median 5 (IQR 1-10) vs. 3 (1-7); 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.

Pain-related evoked potentials in patients with large, mixed, and small fiber neuropathy.

OBJECTIVE: To investigate A-delta fiber pathways in patients with large, mixed, and small fiber neuropathies using pain-related evoked potentials (PREP). METHODS: 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. RESULTS: 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). CONCLUSION: 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. SIGNIFICANCE: 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.

Direct Oral Anticoagulant Plasma Levels for the Management of Acute Ischemic Stroke.

INTRODUCTION: The management of acute ischemic stroke in patients on direct oral anticoagulants (DOACs) is challenging. However, the substance-specific plasma level could guide treatment decisions on recanalization therapies. We present a plasma-level-based protocol for emergency treatment of stroke patients on oral anticoagulants. Bleeding complications and clinical outcome for patients on DOACs are reported and compared to patients on vitamin K antagonists (VKAs). METHODS: In patients with acute ischemic stroke and suspected use of DOACs within 48 h prior to hospital admission, plasma levels were measured using the calibrated Xa-activity (apixaban, edoxaban, rivaroxaban) or the Hemoclot®-assay (dabigatran). Levels <50 ng/mL were supportive for thrombolysis, while high values >100 ng/mL excluded patients from recombinant tissue plasminogen activator use. For patients on VKAs, the cutoff was set at international normalized ratio of 1.7. Endovascular thrombectomy of a large vessel occlusion was performed independently from coagulation testing. Consecutive patients were included in an observational registry. RESULTS: Five hundred and twenty-two patients (261 on VKAs and 261 on DOACs) were included. Thirty patients (11.5%) on VKAs and 24 (9.2%) on DOACs received thrombolysis, followed by mechanical thrombectomy in 10 and 14 patients, respectively. Seventeen patients in each group received thrombectomy only. Symptomatic intracranial hemorrhage associated with thrombolysis occurred in 1 patient on VKA (3.3%) and 1 on DOAC (4.2%; p = 0.872). The turnaround time of specific assays did not show a significant delay in comparison to standard coagulation parameters. CONCLUSION: DOAC plasma levels could support decisions on emergency treatment of ischemic stroke. Systemic thrombolysis below suggested thresholds appears preliminary feasible and safe without an excess in bleeding complications.

[Diagnostik Lumbar Puncture - Step by Step]. / Liquorpunktion ­ Schritt für Schritt.

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.

Heart Failure in Ischemic Stroke: Relevance for Acute Care and Outcome.

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 (<1.5% in both groups). 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.

Cerebral Ischemia in Patients on Direct Oral Anticoagulants.

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]; P<0.001) and higher risk of persisting neurological deficits or cerebral infarction on imaging (85.7% versus 75.6% versus 54.0%; P<0.001). 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.

Dyshidrosis is associated with reduced amplitudes in electrically evoked pain-related potentials in women with Fabry disease.

OBJECTIVE: To investigate A-delta fiber conduction in mild to moderate Fabry disease (FD) patients using pain-related evoked potentials (PREP). METHODS: 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. RESULTS: 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. CONCLUSION: A-delta fiber conduction investigated using PREP is impaired in mild to moderately affected female FD patients with clinical signs of hypohidrosis. SIGNIFICANCE: Small fiber assessment in FD is of diagnostic value already in mild to moderate stages of disease.

Sensory profiles and skin innervation of patients with painful and painless neuropathies.

We assessed pain characteristics and sensory profiles of a large and extensively phenotyped cohort of patients with polyneuropathies (PNPs) and small fiber neuropathy (SFN) using quantitative sensory testing (QST). Our aim was to detect potentially discriminative QST profiles of patient subgroups determined by pain, etiology, or skin innervation. We prospectively recruited 350 patients with painful and painless PNPs and with SFN at 1 neuromuscular center. After neurological work-up, patients underwent QST at the dorsal foot and 5-mm skin punch biopsy at the lower leg and upper thigh for intraepidermal nerve fiber counts. A healthy control group of 273 volunteers was investigated accordingly. Pain was present in 50% of the patients with PNP with a median intensity of 6/10 on a numeric rating scale, and, by definition, in all patients with SFN, with a median intensity of 5/10 numeric rating scale. Axonal PNP was painful more often than demyelinating PNP (P < 0.01). Patients with PNP mostly had loss of function profiles, whereas most patients with SFN belonged to the gain of function (hyperalgesia) phenotype. In healthy controls, skin innervation positively correlated with sensory thresholds, whereas this correlation was lost in patients with PNP and SFN. Quantitative sensory testing did not distinguish between painful and painless neuropathies regarding small fiber function, but revealed higher mechanical pain (P < 0.01) and detection thresholds (P < 0.05) and lower mechanical pain sensitivity in the group of patients with painful neuropathies. Etiological neuropathy subgroups were not distinguished by QST.

Capsaicin 8% patch reversibly reduces A-delta fiber evoked potential amplitudes.

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.