Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Teaching NeuroImage: Rapidly Changing Symptoms With Multistep Migration of Clot in the Posterior Circulation After Tenecteplase for Acute Ischemic Stroke.

A 70-year-old man presented with acute vertigo and ataxia. CT angiogram revealed left V3 segment vertebral artery occlusion (Figure 1, A and B). He received tenecteplase (0.25 mg/kg IV bolus) and was transferred to our comprehensive stroke center due to the risk of early neurologic deterioration from clot migration that would necessitate thrombectomy. Repeat CT angiogram revealed migration to V4 segment with posterior inferior cerebellar artery reopacification and improving symptoms (Figure 1, C and D). Two hours post-tenecteplase, he developed aphasia, right hemianopia, and sensorimotor symptoms (National Institutes of Health Stroke Scale 15). Angiogram showed a left P1 posterior cerebral artery thrombus. Attempted thrombectomy resulted in further migration to P2. MRI demonstrated multiple infarcts (Figure 2), representing stepwise ischemia from dynamic clot movement. Clot reformation from hypercoagulability or re-embolization seemed unlikely, given short time course and exclusive posterior circulation involvement.

Recanalization and outcomes after cerebral venous thrombosis: a systematic review and meta-analysis.

Background: Recanalization in cerebral venous thrombosis (CVT) can begin as early as 1 week after initiating therapeutic anticoagulation. The clinical significance of recanalization remains uncertain. Objectives: We aimed to investigate the association between recanalization and functional outcomes and explored predictors of recanalization. Methods: A systematic literature search was conducted (EMBASE, MEDLINE, Cochrane library) to identify: (1) patients with CVT aged ≥18 years treated with anticoagulation only; (2) case series, cohort, or randomized controlled trial studies; and (3) reported recanalization rates and functional outcomes using either a modified Rankin Scale (mRS) or sequelae of CVT at last follow-up. Meta-analysis was performed using pooled odds ratios (ORs) with exploration of sex and age effects using meta-regression. Results: Twenty-three studies were eligible with 1418 individual patients in total. Timing of reimaging and clinical reassessment was variable. Absence of recanalization was associated with increased odds of an unfavorable functional outcome (mRS 2-6 versus 0-1; OR, 3.66; 95% CI, 1.73-7.74; p = 0.001), CVT recurrence (OR, 8.81; 95% CI, 1.63-47.7; p = 0.01), and chronic headache (OR, 2.78; 95% CI, 1.16-6.70; p = 0.02). On meta-regression, the relationship between recanalization and mRS differed by the proportion of female patients, where lower proportions of women were associated with higher likelihood of a worse outcome, but not by mean participant age. There was no incremental benefit of full compared with partial recanalization with respect to favorable mRS or recurrence, but odds of chronic headache were higher with partial versus full recanalization (OR, 3.80; 95% CI, 1.43-10.11; p = 0.008). Epilepsy and visual sequelae were not associated with recanalization. Conclusions: Absence of recanalization was associated with worse functional outcomes, CVT recurrence, and headache, but outcomes were modified by sex. The degree of recanalization was significant in relation to headache outcomes, where partial compared with complete recanalization resulted in a greater likelihood of residual headache. Prospective studies with common timing of repeat clinical-neuroimaging assessments will help to better ascertain the relationship and directionality between the degree of recanalization and outcomes.

Updates in Cerebral Venous Thrombosis.

PURPOSE OF REVIEW: Cerebral venous thrombosis (CVT) is a rare cause of stroke that most commonly affects younger women. Here, we review new literature relevant to the management and prognosis of individuals with CVT and ongoing areas of uncertainty. RECENT FINDINGS: Direct-acting oral anticoagulants (DOACs) are being increasingly integrated into routine care but are not yet recommended by guidelines. Recent randomized clinical trials and available case series offer reassuring safety data. Routine use of endovascular therapy is not associated with improved outcomes. The relationship between recanalization and prognosis is uncertain. The evidence base for management of CVT continues to improve. Ongoing areas of uncertainty include duration of therapy and whether certain subgroups of patients may benefit from neurointervention or personalized approaches to antithrombotic strategy. The state of knowledge will continue to benefit from large collaborative international efforts, and integration of patient partnerships to identify research priorities.

LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development.

During limb development, fibroblast growth factors (Fgfs) govern proximal⁻distal outgrowth and patterning. FGFs also synchronize developmental patterning between the proximal⁻distal and anterior⁻posterior axes by maintaining Sonic hedgehog (Shh) expression in cells of the zone of polarizing activity (ZPA) in the distal posterior mesoderm. Shh, in turn, maintains Fgfs in the apical ectodermal ridge (AER) that caps the distal tip of the limb bud. Crosstalk between Fgf and Shh signaling is critical for patterned limb development, but the mechanisms underlying this feedback loop are not well-characterized. Implantation of Fgf beads in the proximal posterior limb bud can maintain SHH expression in the former ZPA domain (evident 3 h after application), while prolonged exposure (24 h) can induce SHH outside of this domain. Although temporally and spatially disparate, comparative analysis of transcriptome data from these different populations accentuated genes involved in SHH regulation. Comparative analysis identified 25 candidates common to both treatments, with eight linked to SHH expression or function. Furthermore, we demonstrated that LHX2, a LIM Homeodomain transcription factor, is an intermediate in the FGF-mediated regulation of SHH. Our data suggest that LHX2 acts as a competency factor maintaining distal posterior SHH expression subjacent to the AER.

Multifaceted effects of noisy galvanic vestibular stimulation on manual tracking behavior in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder that is characterized clinically by slowness of movement, rigidity, tremor, postural instability, and often cognitive impairments. Recent studies have demonstrated altered cortico-basal ganglia rhythms in PD, which raises the possibility of a role for non-invasive stimulation therapies such as noisy galvanic vestibular stimulation (GVS). We applied noisy GVS to 12 mild-moderately affected PD subjects (Hoehn and Yahr 1.5-2.5) off medication while they performed a sinusoidal visuomotor joystick tracking task, which alternated between 2 task conditions depending on whether the displayed cursor position underestimated the actual error by 30% ('Better') or overestimated by 200% ('Worse'). Either sham or subthreshold, noisy GVS (0.1-10 Hz, 1/f-type power spectrum) was applied in pseudorandom order. We used exploratory (linear discriminant analysis with bootstrapping) and confirmatory (robust multivariate linear regression) methods to determine if the presence of GVS significantly affected our ability to predict cursor position based on target variables. Variables related to displayed error were robustly seen to discriminate GVS in all subjects particularly in the Worse condition. If we considered higher frequency components of the cursor trajectory as "noise," the signal-to-noise ratio of cursor trajectory was significantly increased during the GVS stimulation. The results suggest that noisy GVS influenced motor performance of the PD subjects, and we speculate that they were elicited through a combination of mechanisms: enhanced cingulate activity resulting in modulation of frontal midline theta rhythms, improved signal processing in neuromotor system via stochastic facilitation and/or enhanced "vigor" known to be deficient in PD subjects. Further work is required to determine if GVS has a selective effect on corrective submovements that could not be detected by the current analyses.

Noisy galvanic vestibular stimulation modulates the amplitude of EEG synchrony patterns.

Noisy galvanic vestibular stimulation has been associated with numerous cognitive and behavioural effects, such as enhancement of visual memory in healthy individuals, improvement of visual deficits in stroke patients, as well as possibly improvement of motor function in Parkinson's disease; yet, the mechanism of action is unclear. Since Parkinson's and other neuropsychiatric diseases are characterized by maladaptive dynamics of brain rhythms, we investigated whether noisy galvanic vestibular stimulation was associated with measurable changes in EEG oscillatory rhythms within theta (4-7.5 Hz), low alpha (8-10 Hz), high alpha (10.5-12 Hz), beta (13-30 Hz) and gamma (31-50 Hz) bands. We recorded the EEG while simultaneously delivering noisy bilateral, bipolar stimulation at varying intensities of imperceptible currents - at 10, 26, 42, 58, 74 and 90% of sensory threshold - to ten neurologically healthy subjects. Using standard spectral analysis, we investigated the transient aftereffects of noisy stimulation on rhythms. Subsequently, using robust artifact rejection techniques and the Least Absolute Shrinkage Selection Operator regression and cross-validation, we assessed the combinations of channels and power spectral features within each EEG frequency band that were linearly related with stimulus intensity. We show that noisy galvanic vestibular stimulation predominantly leads to a mild suppression of gamma power in lateral regions immediately after stimulation, followed by delayed increase in beta and gamma power in frontal regions approximately 20-25 s after stimulation ceased. Ongoing changes in the power of each oscillatory band throughout frontal, central/parietal, occipital and bilateral electrodes predicted the intensity of galvanic vestibular stimulation in a stimulus-dependent manner, demonstrating linear effects of stimulation on brain rhythms. We propose that modulation of neural oscillations is a potential mechanism for the previously-described cognitive and motor effects of vestibular stimulation, and noisy galvanic vestibular stimulation may provide an additional non-invasive means for neuromodulation of functional brain networks.

Developmental and peri-postnatal study in cynomolgus monkeys with belimumab, a monoclonal antibody directed against B-lymphocyte stimulator.

Belimumab is a fully human monoclonal antibody antagonist for soluble B-lymphocyte stimulator, and is a potential therapeutic for various autoimmune disorders. To support clinical use, belimumab was administered intravenously to pregnant cynomolgus monkeys every 2 weeks throughout gestation at dosages of 5 and 150 mg/kg. Fetuses were delivered by C-section on Gestation Day 150 from one-half of the mothers, and evaluated for teratologic effects (external, visceral, skeletal, and heart), pharmacodynamics (PD) and toxicokinetics (TK). Remaining mothers delivered their infants naturally, enabling extensive assessment of PD and TK during a 1-year postnatal period. Effects attributed to belimumab were limited to the expected pharmacology, primarily decreased numbers of B-lymphocytes in peripheral blood of mothers and infants, and in fetal lymphoid tissues. Infants demonstrated full recovery upon cessation of exposure. In conclusion, belimumab was well tolerated at pharmacologically active dose levels in pregnant cynomolgus monkeys and their infants after exposure throughout pregnancy.