Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Combined Anticoagulation and Antiaggregation in Acute Cervical Artery Dissection.

Cervical artery dissection (CAD) is a frequent cause of stroke in young adults. Previous studies investigating the efficiency of anticoagulation (AC) versus antiplatelet therapy (AT) found an insignificant difference. We therefore retrospectively evaluated a combination of AC plus AT in patients with acute CAD regarding safety and efficacy. Twenty-eight patients with CAD and minor neurological symptoms/no major infarction received either single (n = 14) or dual AT (n = 14) combined with AC. Angiographic follow-up during hospitalization, 4-8 weeks and 3-6 months after CAD focused on occlusion, residual stenosis, and functional recanalization. Possible adverse events were surveyed. We compared the AC plus AT group to 22 patients with acute CAD treated with AC or AT. Compared to preceding AC-/AT-only studies, AC plus single or dual AT resulted in more frequent, faster recanalization. Frequency and severity of adverse events was comparable. No major adverse events or death occurred. Preceding works on conservative treatment of CAD are discussed and compared to this study. Considerations are given to pathophysiology and the dynamic of CAD. Combining AC plus AT in CAD may result in more reliable recanalization in a shorter time. The risk for adverse events appears similar to treatment with only AC or AT.

Thrombocytopenia and Intracranial Venous Sinus Thrombosis after "COVID-19 Vaccine AstraZeneca" Exposure.

BACKGROUND: As of 8 April 2021, a total of 2.9 million people have died with or from the coronavirus infection causing COVID-19 (Corona Virus Disease 2019). On 29 January 2021, the European Medicines Agency (EMA) approved a COVID-19 vaccine developed by Oxford University and AstraZeneca (AZD1222, ChAdOx1 nCoV-19, COVID-19 vaccine AstraZeneca, Vaxzevria, Covishield). While the vaccine prevents severe course of and death from COVID-19, the observation of pulmonary, abdominal, and intracranial venous thromboembolic events has raised concerns. OBJECTIVE: To describe the clinical manifestations and the concerning management of patients with cranial venous sinus thrombosis following first exposure to the "COVID-19 vaccine AstraZeneca". METHODS: Patient files, laboratory findings, and diagnostic imaging results, and endovascular interventions of three concerning patients were evaluated in retrospect. RESULTS: Three women with intracranial venous sinus thrombosis after their first vaccination with "COVID-19 vaccine AstraZeneca" were encountered. Patient #1 was 22 years old and developed headaches four days after the vaccination. On day 7, she experienced a generalized epileptic seizure. Patient #2 was 46 years old. She presented with severe headaches, hemianopia to the right, and mild aphasia 13 days after the vaccination. MRI showed a left occipital intracerebral hemorrhage. Patient #3 was 36 years old and presented 17 days after the vaccination with acute somnolence and right-hand hemiparesis. The three patients were diagnosed with extensive venous sinus thrombosis. They were managed by heparinization and endovascular recanalization of their venous sinuses. They shared similar findings: elevated levels of D-dimers, platelet factor 4 antiplatelet antibodies, corona spike protein antibodies, combined with thrombocytopenia. Under treatment with low-molecular-weight heparin, platelet counts normalized within several days. CONCLUSION: Early observations insinuate that the exposure to the "COVID-19 vaccine AstraZeneca" might trigger the expression of antiplatelet antibodies, resulting in a condition with thrombocytopenia and venous thrombotic events (e.g., intracranial venous sinus thrombosis). These patients' treatment should address the thrombo-embolic manifestations, the coagulation disorder, and the underlying immunological phenomena.

Seasonal patterns and associations in the incidence of acute ischemic stroke requiring mechanical thrombectomy.

BACKGROUND: In order to identify risk periods with an increased demand in technical and human resources, we tried to determine patterns and associations in the incidence of acute ischemic stroke due to embolic large vessel occlusions (eLVO) requiring mechanical thrombectomy (MT). METHODS: We conducted a time series analysis over a 9-year period (2010-2018) based on observational data in order to detect seasonal patterns in the incidence of MT due to eLVO (n = 2628 patients). In a series of sequential negative binominal regression models, we aimed to detect further associations (e.g., temperature, atmospheric pressure, air pollution). RESULTS: There was a 6-month seasonal pattern in the incidence of MT due to eLVO (p = 0.024) peaking in March and September. Colder overall temperature was associated with an increase in MT due to eLVO (average marginal effect [AME], [95% CI]: -0.15 [-0.30-0.0001]; p = 0.05; per °C). A current increase in the average monthly temperature was associated with a higher incidence of MT due to eLVO (0.34 [0.11-0.56]; p = 0.003). Atmospheric pressure was positively correlated with MT due to eLVO (0.38 [0.13-0.64]; p = 0.003; per hectopascal [hPa]). We could detect no causal correlation between air pollutants and MT due to eLVO. CONCLUSIONS: Our data suggest a 6-month seasonal pattern in the incidence of MT due to eLVO peaking in spring and early autumn. This might be attributed to two different factors: (1) a current temperature rise (comparing the average monthly temperature in consecutive months) and (2) colder overall temperature. These results could help to identify risk periods requiring an adaptation in local infrastructure.

Predictors of outcome after mechanical thrombectomy for anterior circulation large vessel occlusion in patients aged ≥80 years.

BACKGROUND: There is uncertainty about the role of endovascular recanalization procedures for the treatment of acute ischemic stroke in patients aged ≥80 years. Therefore, careful patient selection is mandatory. Our aim was to find valid predictors of clinical outcome after mechanical thrombectomy (mTE) based on the sparse information available in the emergency setting. METHODS: We included consecutive patients aged ≥80 years treated by mTE for anterior circulation thromboembolic vessel occlusion in our department between January 2008 and January 2013. Successful recanalization was defined as a thrombolysis in cerebral infarction (TICI) score of 2b or 3. The rates of parenchymal hemorrhage types I (PHI) and II (PHII) according to the ECASS definition and the rate of focal and diffuse subarachnoid hemorrhage (SAH) were reported. A modified Ranking scale (mRS) score of 0-2 at 90 days was defined as a favorable outcome. We evaluated the influence of gender, smoking habits, atrial fibrillation, diabetes, hypertension, hyperlipidemia, coronary artery and peripheral artery disease, National Institutes of Health Stroke Scale (NIHSS) score, Totaled Health Risks in Vascular Events (THRIVE) score, Alberta Stroke Program Early CT Score (ASPECTS), and duration of symptoms on favorable outcome. Significant predictors were then included in a stepwise logistic regression analysis. Odds ratios (OR), 95% confidence intervals (CI), and receiver operating characteristics (ROC) curves were calculated. p < 0.05 was considered statistically significant. RESULTS: In the defined period, we treated 109 patients aged ≥80 years with 116 occluded anterior circulation target vessels. Successful recanalization was achieved in 87.9% of the targets. The rates of PHI, PHII, and focal and diffuse SAH were 6.4, 5.5, 12.8, and 7.3%, with an overlap between PH and SAH. The combined rate of PHII and/or diffuse SAH was 9.2%. Despite good recanalization rates and reasonable rates of hemorrhage, only 19 patients (17.4%) were functionally independent at 90 days. An additional 12 patients (11.0%) suffered from moderate disability (mRS score 3), 26 (23.9%) were severely disabled (mRS score 4-5) and 52 (47.7%) were deceased. NIHSS, ASPECTS, and THRIVE scores significantly predicted a favorable outcome. Stepwise logistic regression identified NIHSS (OR 0.89; 95% CI 0.82-0.96; p = 0.009) and ASPECTS (OR 2.27; 95% CI 1.28-4.02; p = 0.005) as independent predictors. The ROC area was 0.81. CONCLUSION: ASPECTS and NIHSS were independent predictors of a favorable outcome in patients aged ≥80 years after mTE for anterior circulation large vessel occlusion and may support decision making with regard to the treatment modality. Since the chances of gaining functional independence are limited, careful consideration of each individual case is mandatory. Further studies comparing endovascular and standard treatment in octogenarians are warranted.

The modified Bose method for the endovascular treatment of intracranial atherosclerotic arterial stenoses using the Enterprise stent.

BACKGROUND: Balloon dilatation and deployment of a self-expanding stent is a safe treatment for intracranial atherosclerotic stenoses. The significant recurrence rate might be related to the high radial force of the Wingspan stent. OBJECTIVE: To evaluate the procedural safety and stenosis recurrence rate by the use of a stent with reduced radial force (Enterprise). METHODS: Two hundred nine atherosclerotic stenoses (189 patients) were treated (median age, 68 years; 132 male) in a single center. Lesion locations included internal carotid artery (n = 27), middle cerebral artery (n = 62), vertebral artery (n = 64), basilar artery (n = 55), and posterior cerebral artery (n = 1). Pre- and postmedication included acetylsalicylic acid and Clopidogrel for at least 12 months. Preprocedural and follow-up examinations included magnetic resonance imaging (MRI), neurological assessment, and digital subtraction angiography (6, 12, 26, and 52 weeks). Data registry included age, sex, normal vessel diameter, degree of stenosis, residual stenosis after stent, minimal in-stent diameter, and occurrence of ischemic symptoms during follow-up. RESULTS: Median pre- and postprocedural stenosis rate was 65.4 ± 1% vs 25.1 ± 1%. Technical success rate was 100%. Major procedural complications occurred in 16 patients (8.1%). Combined neurological morbidity and mortality rate at 30 days was 2 patients (0.9%). In 174 stenoses (83%) angiographic follow-up was obtained (mean, 10.2 months). A restenosis (>50%) was observed in 43 (24.7%) cases after 4.2 months (mean) with 4 (9.3%) symptomatic lesions. Incidence of recurrent ischemia related to the stented artery was 2.2% during 10.2 months of mean follow-up. CONCLUSION: Undersized balloon angioplasty and deployment of an Enterprise stent is safe and effective for intracranial stenoses. Follow-up results were equal to or better than those reported for bare-metal balloon-expandable or self-expanding stents and yielded excellent protection from recurrent ischemia.

Diagnosis of Parkinson's disease--transcranial sonography in relation to MRI.

Displaying the echo pattern (echogenicity) of brain tissue transcranial sonography (TCS) may provide new and complementary information to other neuroimaging methods. In contrast to conventional magnetic resonance imaging (MRI), TCS is able to detect highly characteristic changes in signal brightness of the substantia nigra (SN) in patients with idiopathic Parkinson's disease. In this review, TCS findings are related to conventional and advanced high-field brain MRI findings. On the basis of the MRI findings, especially with T2-relaxometry, the possible role of trace metals in the genesis of altered echogenicity on TCS of brain parenchyma, especially of the SN, are discussed.

Diffusion tensor imaging of the corpus callosum differentiates corticobasal syndrome from Parkinson's disease.

Differential diagnosis between patients with Corticobasal syndrome (CBS) and Parkinson's disease (PD) may be confusing, particularly in early disease stages. However, in contrast to PD, CBS shows a widespread cortical atrophy that suggests an involvement of the corpus callosum (CC). To test this hypothesis, we used diffusion tensor imaging (DTI) with a 1.5T scanner to compare 14 CBS patients, 14 PD patients, and an age-matched control group. The mean diffusivity (MD) and fractional anisotropy (FA) were determined in the whole CC and in five subdivisions. Group comparisons were performed using the Mann-Whitney U-test. We found a significantly increased MD and decreased FA in CBS patients compared to PD, particularly in the posterior truncus. No differences were found between PD patients and controls. A receiver-operating characteristics (ROC) analysis shows that the MD is particularly useful for discriminating between the two neurodegenerative diseases. Our data suggest that abnormal CC diffusivity in CBS reflects an atrophy and degraded transcallosal connectivity, making the CC a potential target to differentiate CBS from PD patients.

Increased echogenicity of the substantia nigra in children and adolescents with attention-deficit/hyperactivity disorder.

BACKGROUND: Recent neurobiological models on attention-deficit/hyperactivity disorder (ADHD) as well as findings from imaging studies suggest a crucial involvement of dopaminergic midbrain nuclei, especially the substantia nigra (SN), in the pathogenesis of ADHD symptoms. The current study aimed to investigate whether alterations in the sonographic features of the SN could serve as a biological marker in ADHD patients. METHODS: The current study employed transcranial sonography in 29 children and adolescents with ADHD and 27 healthy control participants to assess midbrain abnormalities in ADHD. RESULTS: The ADHD patients showed an increase in echogenic size of the SN that was correlated with symptoms of inattention, hyperactivity, and impulsivity but not oppositional or dissocial symptoms. Hyperechogenicity, defined as echogenic size above the 90th percentile in the control group, was present in 48% of ADHD patients. CONCLUSIONS: Our findings indicate an increased vulnerability of the nigrostriatal system in ADHD. Transcranial sonography could be successfully used in the future to explore whether ADHD patients with distinct SN hyperechogenicity constitute a specific subgroup or whether hyperechogenicity relates functionally to differences in reward processing, learning, and motor function.

Involvement of motor pathways in corticobasal syndrome detected by diffusion tensor tractography.

Corticobasal syndrome (CBS) is a progressive parkinsonian disease characterized by cortical and subcortical neuronal loss. Although motor disabilities are a core feature of CBS, the involvement of motor pathways in this condition has not been completely clarified. We used magnetic resonance diffusion tensor imaging (DTI) to study corticospinal and transcallosal motor projections in CBS, and applied fiber tractography to analyze the axonal integrity of white matter projections. Ten patients with CBS were compared with 10 age-matched healthy controls. Fiber tracts were computed using a Monte-Carlo simulation approach. Tract-specific mean values of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were determined. CBS patients showed a reduction of corticospinal tract (CST) fibers on the first affected side with significantly increased ADC and reduced FA values. In the corpus callosum (CC), particularly in the posterior trunk, patients also had significantly reduced fiber projections, with a higher ADC and lower FA than controls. This pattern indicates changes of the white matter integrity in both CST and CC. Thus, magnetic resonance DTI can be used to assess motor pathway involvement in CBS patients.

Contemporary ultrasound systems allow high-resolution transcranial imaging of small echogenic deep intracranial structures similarly as MRI: a phantom study.

Transcranial sonography (TCS) of small deep brain structures, such as substantia nigra and brainstem raphe, is increasingly used for assessment of neurodegenerative disorders. Still, there are reservations against TCS because of the smallness of evaluated structures and constraints on image resolution that is discussed to be lower compared to magnetic resonance imaging (MRI). To evaluate two different-generation TCS systems in visualizing fine intracranial structures, we studied image resolution on a phantom consisting of 0.80 mm x 1.05 mm regular meshwork of nylon threads embedded in a wet, gel-filled ex vivo human skull. Imaging was performed with a former-generation and a present-day clinical ultrasound system and for comparison with MRI. In axial direction of insonation both TCS systems resolved 0.80-mm and 1.05-mm thread-to-thread distance at depths between 55 and 120 mm using transmission frequencies > or =2.5 MHz. The meshwork, however, was recognizable as such only with the contemporary TCS system at depths between 60 and 85 mm due to its higher lateral resolution. MRI resolved the meshwork if image resolution was chosen sufficiently high but not if realistic clinical conditions were applied with its trade-offs between image SNR, resolution, total scan time, and unavoidable head motion during the latter. Hence, if the requirements for optimal TCS image resolution are fulfilled, i.e. sufficient acoustic bone window, increased echogenicity of target structure and its localization in a distance of maximum +/-15 mm from midsagittal plane, findings suggest that contemporary TCS systems achieve higher image resolution of intracranial structures in comparison not only to former-generation systems, but also to MRI under clinical conditions.

Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder.

BACKGROUND: Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD) the fundamental neuropsychological characterization of left DLPFC hypoactivity and right DLPFC hyperactivity in MDD remains poorly understood. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects. RESULTS: The MDD patients showed hypoactivity in the left DLPFC during both unattended and attended emotional judgment and hyperactivity in the right DLPFC during attended emotional judgment. In contrast to healthy subjects, left DLPFC activity during emotional judgment was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence in MDD patients. Hyperactivity in the right DLPFC correlated with depression severity. CONCLUSIONS: Results demonstrate that left DLPFC hypoactivity is associated with negative emotional judgment rather than with emotional perception or attention while right DLPFC hyperactivity is linked to attentional modulation. Left-right DLPFC imbalance is characterized in neuropsychological regard, which bridges the gap from resting metabolism and therapeutic repetitive transcranial magnetic stimulation effects to functional neuroanatomy of altered emotional-cognitive interaction in MDD.

Ageing and early-stage Parkinson's disease affect separable neural mechanisms of mesolimbic reward processing.

The ability to learn stimulus-reward associations on the basis of reward prediction errors critically depends on the mesolimbic dopaminergic system including the dopaminergic midbrain and the ventral striatum. It is known that healthy elderly and patients with Parkinson's disease are less proficient than healthy young adults in learning stimulus-reward contingencies, but it is unclear whether this is due to dysfunctional mesolimbic reward prediction or due to deficiency in processing the rewards per se. We used a well-established event-related fMRI reward-prediction paradigm to address this question. Young adults showed the well-replicated pattern of midbrain and ventral striatal activation for stimuli that predicted monetary reward when compared with stimuli that predicted neutral feedback. Also, as expected, the predicted reward feedback itself did not elicit a mesolimbic response. Healthy elderly subjects and unmedicated early-stage idiopathic Parkinson's disease patients showed the opposite pattern with an absent mesolimbic reward prediction response, but mesolimbic activation to the reward feedback itself. This suggests that the healthy elderly and Parkinson's disease patients were less proficient in learning the predictive value of the reward cues despite preserved mesolimbic processing of reward prediction errors. Parkinson's disease patients additionally displayed a relatively increased response of the anterior cingulate during reward feedback processing and diminished functional connectivity of the midbrain and ventral striatum. Our results are compatible with existing behavioural evidence that both groups exhibit a particularly pronounced deficit in learning from positive feedback and support the view that a tendency to underestimate expected values of reward cues might underlie this deficit. Furthermore, alterations in reward processing in Parkinson's disease extend beyond accelerated ageing effects and include altered connectivity within the mesolimbic system.

Transcranial brain parenchyma sonography in movement disorders: state of the art.

The present paper summarizes recommendations on transcranial sonography (TCS) application in neurodegenerative diseases, resulting from a consensus meeting of the European Society of Neurosonology and Cerebral Hemodynamics. TCS of distinct infra- and supratentorial brain structures detects characteristic changes in several movement disorders, such as abnormal hyperechogenicity of substantia nigra (SN) in Parkinson's disease and of lenticular nucleus in dystonia, Wilson's disease and atypical Parkinsonian disorders. In healthy adults, the TCS finding of marked SN hyperechogenicity indicates a subclinical functional impairment of the nigrostriatal dopaminergic system. The finding of marked SN hyperechogenicity in combination with normal lenticular-nucleus echogenicity discriminates idiopathic Parkinson's disease from multiple-system atrophy and progressive supranuclear palsy with a positive predictive value of more than 90%. As TCS is a quick and noninvasive method, using the same duplex-ultrasound machines as for investigation of intracranial vessels, applicable even in agitated patients, this method has a great potential to be more widely used.

Effects of right unilateral electroconvulsive therapy on motor cortical excitability in depressive patients.

Electroconvulsive therapy (ECT) is a widely acknowledged effective treatment for severe major depression. ECT produces considerable anticonvulsant effects that may be related to an increased GABA-ergic neurotransmission. We aimed to explore whether motor cortical excitability as assessed with single and paired pulse transcranial magnetic stimulation (TMS) could be used to investigate these anticonvulsant effects. Therefore, parameters of motor cortical excitability were investigated in 10 patients before and after 10 sessions of right unilateral ECT. After 10 sessions of right unilateral ECT, an enhanced activity of inhibitory circuits in human motor cortex had been observed, as measured by both increased intracortical inhibition and cortical silent period duration, whereas intracortical facilitation and resting motor threshold remained unchanged. The reduction of seizure duration in the course of ECT was associated with clinical improvement and an increase in intracortical inhibition. We interpret this finding as further indirect evidence for changes in inhibitory circuits in the course of ECT in patients with major depression.

Visual cortex excitability in migraine evaluated by single and paired magnetic stimuli.

OBJECTIVE: To determine the excitability of the visual cortex by phosphene thresholds (PT) in patients with migraine using transcranial magnetic stimulation (TMS) with single- and paired-pulses. METHODS: Nineteen patients with migraine with aura (MWA), 19 patients with migraine without aura (MWoA), and 22 control subjects were included. Patients were free from preventive anti-migraine treatment and were investigated within 3 days before or after an acute migraine attack. In each subject, PT were assessed by single-pulse and paired-pulse TMS with an interstimulus interval of 50 ms. RESULTS: The main effect of diagnosis indicated that mean PT were significantly lower in migraine patients than in control subjects (P = .001). Using single-pulse TMS, mean PT tended to be lower in MWoA-patients (57.7 +/- 11.8%) compared with control subjects (64.4 +/- 10.5%) (P = .064). In MWA-patients, mean PT (53.1 +/- 5.7%) were significantly lower compared with controls (P < .001). Using TMS with paired pulses, mean PT were significantly reduced in MWoA-patients (40.3 +/- 4.9%, P = .017) as well as in MWA-patients (39.6 +/- 4.2%, P = .005) compared with controls (44.6 +/- 6.0%). The main effect of stimulation type indicated that mean PT were lower determined with paired-pulse stimulation than with single pulses (P < .001). CONCLUSIONS: PT are reduced in patients with migraine in the interictal state suggesting an increased excitability of visual cortical areas. Compared with single-pulse TMS, paired-pulse magnetic stimulation is more efficient to elicit phosphenes. This technique provides the opportunity to evaluate visual cortex excitability with lower stimulus intensities and less discomfort.