The CREST-2 trial demonstrated that carotid artery stenting combined with intensive medical management (IMM) significantly reduces stroke risk in patients with high-grade asymptomatic carotid stenosis compared with IMM alone. Careful patient selection and operator skill are critical factors for procedural success and can provide real-world validation of stenting as an important adjunct to IMM for stroke prevention. Continued advances in medical management and stenting are expected. It remains vital to engage in shared decision-making when considering moving forward with stenting of asymptomatic carotid stenosis.
BACKGROUND AND OBJECTIVES:Cerebral amyloid angiopathy (CAA) is currently diagnosed using MRI-based Boston criteria. However, imaging markers represent downstream consequences of vascular injury and may not fully reflect disease severity. CSF biomarkers, particularly β-amyloid 1-42 (Aβ42) and β-amyloid 1-40 (Aβ40), may provide a more direct measure of vascular amyloid burden. We investigated the association between CSF biomarkers and hemorrhagic and nonhemorrhagic MRI markers of disease severity in probable CAA. METHODS:We conducted a retrospective multicenter cohort study including consecutive patients diagnosed with probable CAA according to Boston criteria v2.0 at 2 tertiary centers (2014-2023) who underwent lumbar puncture (LP) as part of clinical evaluation. CSF Aβ42, Aβ40, total tau, and phosphorylated-tau 181 (p-tau181) were measured using standardized immunoassays. MRI markers included lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), white matter hyperintensity burden, Fazekas score, and enlarged perivascular spaces in the centrum semiovale. Multivariable linear regression models were adjusted for age, sex, MRI sequence type, and delay between onset and LP. False discovery rate correction was applied for multiple testing. We also used principal component analysis to explore associations between MRI and CSF biomarkers. RESULTS:A total of 102 patients were included (mean age at LP 72.0 ± 7.5 years; 65% male). Initial presentations were cognitive impairment in 53%, intracerebral hemorrhage in 34%, and transient focal neurologic episodes in 13%. Lower CSF Aβ40 and Aβ42 levels were significantly associated with greater cSS burden (standardized β -0.49 [95% CI -0.8 to -0.17], p = 0.002 and -0.42 [-0.73 to -0.11], p = 0.007, respectively) and higher Fazekas score (β -0.18 [-0.33 to -0.03], p = 0.02 and -0.23 [-0.38 to -0.08], p = 0.002) but not with CMB count. No significant association was found between tau species and MRI markers. Associations remained significant after stratification by CSF Aβ42/Aβ40-defined Alzheimer-like profile. DISCUSSION:In probable CAA, lower CSF Aβ40 and Aβ42 levels are associated with established MRI markers of disease severity, independently of clinical presentation and concomitant Alzheimer-like profile. These findings suggest that CSF Aβ levels may reflect vascular amyloid burden rather than downstream neurodegeneration. Prospective longitudinal studies are needed to determine their prognostic value.
BACKGROUND AND OBJECTIVES:Temporal lobe epilepsy (TLE) co-occurs with interictal impairments in autonomic regulation and respiratory chemoreception, which have been related to higher risk of sudden unexpected death in epilepsy (SUDEP). Studies indicate that seizures lead to reorganization of central autonomic circuits extending beyond the temporal lobe. However, the relationship between brain network disruptions and interictal cardiorespiratory dysfunction remains largely unknown. The goal of this work was to test whether central autonomic network alterations underlie interictal cardiorespiratory dysfunction and higher SUDEP risk. METHODS:We included simultaneous fMRI and peripheral physiology from patients with drug-resistant unilateral TLE and healthy controls. We used mediation and correlation analyses to relate atypical functional connectivity strength and structural volume of central autonomic regions in TLE to alterations of high-frequency and low-frequency heart rate variability (HF-HRV/LF-HRV), breathing rate (BR), and respiratory rate variability (RRV). Multivariate models were then used to investigate associations with disease variables and risk factors of SUDEP. Finally, we analyzed a subcohort of patients with postsurgical data and examined whether autonomic connectivity changes following surgery impact cardiorespiratory function. RESULTS:Patients with TLE (n = 72, 49% female, 40.0 ± 12.8 years) exhibited widespread reductions in autonomic connectivity and volume compared with controls (n = 105, 53% female, 36.7 ± 12.8 years) (pFDR < 0.05). Reduced connectivity mediated higher BR, lower RRV, and lower LF-HRV in TLE relative to controls (|z| = 2.14 to 5.28, pFDR < 0.05). Left seizure laterality was independently related to reduced LF-HRV and RRV (Cohen's f = 0.42, 0.45; pFDR = 0.0055, 0.0046), and canonical correlation analysis linked atrophy in autonomic regions to generalized seizure occurrence and earlier age at onset (r = 0.61, pFWER = 0.018). In the postsurgical subcohort (n = 34), autonomic connectivity alterations after surgery were positively correlated with changes in LF-HRV and RRV (ρ = 0.52, 0.41; pFDR = 0.0076, 0.029). DISCUSSION:Our results suggest that reorganization of the central autonomic network may contribute to chronic autonomic and interoceptive deficits in TLE. Mapping these brain network disruptions may help guide novel strategies to restore cardiorespiratory function. Validation in SUDEP cases is needed to establish clinical utility as biomarkers of SUDEP.
BACKGROUND AND OBJECTIVES:Pregnancy alters the pharmacokinetics of antiseizure medications (ASMs). The aim of this study was to quantify gestational changes in ASM concentrations and identify independent covariates among women with epilepsy in China. METHODS:In this prospective, multicenter observational cohort study in China, women with epilepsy aged 18-45 years were enrolled and followed longitudinally. Steady-state trough ASM concentrations were measured, with concentration-to-dose (C/D) ratio as the primary pharmacokinetic parameter. Linear mixed-effects models with model averaging were used to evaluate the independent effects of gestational age, concomitant ASMs, and demographic covariates on ASM C/D ratios. RESULTS:A total of 947 women were included and contributed 1,638 samples between 2019 and 2025, including 1,187 samples collected during nonpregnant periods (821 women, mean age 29.31 ± 8.38 years) and 451 during pregnancy (228 women, mean age 28.67 ± 4.30 years), with 64.3% receiving polytherapy. Lamotrigine exhibited the greatest gestational effect, with C/D ratios declining by 28.8% (β = -0.339; 95% CI -0.508 to -0.339; p < 0.001), 54.3% (β = -0.784; 95% CI -0.938 to -0.629; p < 0.001), and 63.2% (β = -1.001; 95% CI -1.192 to -0.809; p < 0.001) in the first, second, and third trimesters, respectively, reaching a nadir of -65.8% at 32 weeks. Levetiracetam declined by 26.2% (β = -0.303; 95% CI -0.446 to -0.160; p < 0.001), 40.1% (β = -0.512; 95% CI -0.645 to -0.379; p < 0.001), and 31.0% (β = -0.371; 95% CI -0.525 to -0.217; p < 0.001), reaching a nadir of -35.5% at 24 weeks. The metabolite of oxcarbazepine declined by 23.1% (β = -0.262; 95% CI -0.373 to -0.152; p < 0.001), 32.6% (β = -0.394; 95% CI -0.489 to -0.299; p < 0.001), and 44.3% (β = -0.585; 95% CI -0.695 to -0.475; p < 0.001). Lacosamide significantly decreased in the second trimester (-10.8%; β = -0.207; 95% CI -0.399 to -0.014; p = 0.035). Perampanel showed an increasing trend but was limited by sample and polytherapy. Concomitant ASMs primarily shifted baseline C/D ratios without altering gestational changes, and several drug-drug interactions were identified. Higher body weight was associated with lower C/D ratios for most ASMs, except for perampanel. Interindividual variability remained the dominant factor determining C/D ratios over measured covariates. DISCUSSION:Pregnancy was the primary driver of declining C/D ratios, and concomitant ASMs and body weight acted as secondary modifiers. These findings support individual therapeutic drug monitoring. TRIAL REGISTRATION INFORMATION:ChiCTR2100046318 (Chinese Clinical Trial Registry, chictr.org.cn).
There is a long history of early- and mid-phase amyotrophic lateral sclerosis (ALS) clinical trial data being used to make claims of clinical benefit that fail to translate into successful phase 3 outcomes. It is suggested that fallacious scientific reasoning is being encouraged by perverse incentives arising from a "clinical trial industrial complex" that greatly influences trial design, data interpretation, and results communication. Recurring fallacies include false premises underlying outcome comparisons, misuse and incorrect interpretation of biomarkers, mismatches between study design and stated objectives, selective reporting of outcomes, over-reliance on post hoc analyses and open-label extension data, and overly optimistic framing of inconclusive data. We argue that these practices, reinforced by misaligned incentives across industry and academia, lead to premature claims of therapeutic promise and tangible harm to patients. To address the resulting ALS clinical trial credibility gap, we call for rigorous adherence to established standards for reporting clinical trial results, clearer distinction between hypothesis generation and hypothesis testing, more measured description of trial results, and more disciplined triage of phase 2 programs. A cultural shift toward scientific skepticism and methodological rigor is essential to accelerate the development of genuinely effective ALS therapies.
BACKGROUND AND OBJECTIVES:Immigration status is associated with stroke incidence and outcomes; however, its association with admission to and length of stay in the intensive care unit (ICU) in patients with stroke is unknown. We aimed to determine the association between immigration status and intensity of ICU care among patients with ischemic stroke. METHODS:We conducted a population-based retrospective cohort study of adults hospitalized for ischemic stroke in Ontario, Canada, between April 1, 2014, and March 30, 2023. People born outside Canada and who arrived after 1985 were defined as immigrants. We reported rates of thrombolysis, thrombectomy (reperfusion treatments), ventilatory support, and feeding tube insertion in immigrants and long-term residents. We calculated adjusted odds ratios (aOR) of ICU admission using logistic models and adjusted risk ratios (aRR) of longer ICU stays using negative binomial models, comparing immigrants with long-term residents, in the entire cohort and among those who did not receive reperfusion treatments. RESULTS:Of 85,507 patients included (45% female), 12.9% were immigrants. Immigrants were younger (median age 69 years vs 76 years, standardized difference = 0.38), had lower stroke severity and rates of reperfusion, and had higher rates of life-sustaining treatments compared with long-term residents. Immigrants had similar odds of ICU admission compared with long-term residents (18.2% vs 19.7%; aOR 0.97; 95% CI 0.91-1.04), but their ICU stays were longer (mean 5.6 ± 18.5 days vs 3.8 ± 7.7 days; aRR 1.30; 1.13-1.48) in the adjusted models, and this remained the case for those who did not receive reperfusion treatments (length of stay; aRR 1.27; 1.09-1.49). These associations did not vary by whether a hospital cared for a higher-than-median proportion of immigrants across all hospitals. Immigrants who came as refugees, and those who came from Africa, East Asia, and the Middle East, had longer ICU stays than long-term residents. DISCUSSION:Immigrant ischemic stroke patients have similar ICU admission rates, but longer ICU stays. The longer ICU stays among immigrant stroke patients may in part be driven by higher rates of life-saving treatments; however, the impact of these differences on the long-term functional outcomes remains to be studied.
BACKGROUND AND OBJECTIVES: Endovascular thrombectomy (EVT) improves outcome in acute ischemic stroke (AIS) due to large vessel occlusion, yet the optimal anesthetic strategy remains controversial. Previous meta-analyses using frequentist methods reported no significant differences between general anesthesia (GA) and non-GA techniques; however, a recently published trial reported a high posterior probability of functional benefit with GA. We aimed to update the existing systematic review and to re-examine the cumulative randomized evidence using Bayesian statistical methods. METHODS: We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. PubMed/MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to January 3, 2026, for randomized controlled trials (RCTs) comparing GA with non-GA strategies during EVT in adults with AIS. Primary outcomes were functional independence (modified Rankin Scale [mRS] 0-2) at 90 days, successful reperfusion (thrombolysis in cerebral ischemia 2b-3), and 90-day mortality. Bayesian random-effects meta-analyses with weakly informative priors were performed. Results are reported as odds ratio (OR) or mean difference (MD) with 95% credible intervals (CrIs). A posterior probability of superiority exceeding 80% was considered substantial evidence of benefit. Meta-regression and sensitivity analyses were conducted. RESULTS: Ten RCTs (n = 1,601; mean age 70.0 years; 46.6% female) were included. For functional independence, GA was associated with a 94.2% posterior probability of superiority (OR 1.24, 95% CrI 0.94-1.66). GA was associated with higher successful reperfusion rates (OR 1.73, 95% CrI 1.23-2.43; P (superiority) > 99%). No substantial differences were observed for 90-day mortality (OR 0.92, 95% CrI 0.67-1.27; P [superiority] 69%), excellent functional outcome (mRS 0-1; OR 1.06, 95% CrI 0.80-1.41; P [superiority] 67%), or symptomatic intracranial hemorrhage (OR 0.93, 95% CrI 0.56-1.52; P [superiority] 62%). GA was associated with increased intraoperative hypotension (OR 4.28, 95% CrI 2.35-7.86; P [superiority] 0.01%) and increased pneumonia risk (OR 1.60, 95% CrI 0.95-2.81; P [superiority] 3%). DISCUSSION: This meta-analysis using a Bayesian approach provides evidence that GA during EVT for AIS is associated with improved functional outcomes, challenging previous conclusions of equivalence. These findings should be interpreted considering open-label designs and heterogeneous non-GA comparators. They suggest that GA may be preferred but confirmatory evidence is needed.
Dipeptidyl-peptidase-like protein-6 antibody-associated encephalitis (DPPXE) is an autoimmune, multisystem disorder characterized by a triad of gastrointestinal prodrome, cognitive-psychiatric change, and CNS hyperexcitability. We report a 57-year-old man with 2 months of progressive gastrointestinal symptoms despite extensive normal gastrointestinal evaluation. He then developed tremor, myoclonus, gait ataxia, hyperekplexia, insomnia, emotional lability, memory impairment, and abnormal eye movements. Examination showed ocular flutter, tremor, ataxia, and cognitive impairment. Brain MRI revealed bilateral T2/fluid-attenuated inversion recovery hyperintensities in the brainstem and limbic regions. CSF demonstrated lymphocytic pleocytosis and 10 unique oligoclonal bands. DPPX-immunoglobulin G was detected in serum and CSF, confirming the diagnosis of DPPXE. Acute immunotherapy with intravenous methylprednisolone and plasma exchange followed by maintenance treatment with rituximab led to dramatic improvement of his symptoms, with residual memory impairment and tremor at 3 months. This case underscores the characteristic gastrointestinal prodrome and syndromic breadth of DPPXE, highlights the diagnostic value of panel-based screening, and supports treatment with immunomodulation.
A 74-year-old man presented with a 5-year history of progressive feet numbness followed by gait unsteadiness. Neurologic examination revealed absent tendon reflexes, markedly reduced vibration sense in the lower limbs with sensory ataxia, and preserved motor strength. The clinical picture was consistent with a chronic sensory-predominant neuropathy causing sensory ataxia. Nerve conduction studies demonstrated a sensory axonal polyneuropathy with absent sensory nerve action potentials and preserved compound motor action potentials. Extensive screening for potential acquired causes of polyneuropathy (including metabolic, autoimmune, infectious, and toxic etiologies) yielded negative results, and the condition was initially classified as an idiopathic sensory polyneuropathy. Nerve ultrasound showed bilateral reduction of upper-limb nerve cross-sectional area, predominantly in the median and ulnar nerves at the forearm. Skin biopsy revealed loss of somatic intraepidermal fibers with relative preservation of autonomic innervation. This multimodal assessment refined diagnostic reasoning, shortened the diagnostic odyssey associated with establishing an etiologic diagnosis in idiopathic axonal sensory polyneuropathy, and prompted targeted genetic testing. Such an approach may improve diagnostic yield in idiopathic sensory-predominant axonal polyneuropathies.
BACKGROUND AND OBJECTIVES:Chronic active lesions (CALs) reflect chronic inflammation in multiple sclerosis (MS). Slowly expanding lesions (SELs) are CALs identified on conventional MRI by linear, concentric expansion over time, while paramagnetic rim lesions (PRLs) are CALs characterized by a paramagnetic rim on susceptibility-sensitive MRI. However, the prevalence of SELs and their overlap with PRLs remain unclear. The aims of this study were to (1) estimate the proportion of SELs among all T2 lesions and the proportion of patients with at least 1 SEL and (2) assess the proportion of SELs overlapping with PRLs. METHODS:We systematically searched PubMed, Scopus, Web of Science, and Embase on February 1, 2026, for studies evaluating SELs in MS. At least 2 authors independently assessed study eligibility. Primary outcomes were the pooled proportion of SELs among T2 lesions and the proportion of patients with at least 1 SEL. We estimated mean per-patient volumes of SELs and total T2 lesions and the proportion of SELs overlapping with PRLs. Random-effects generalized linear mixed-effects models and inverse-variance methods were used, with between-study heterogeneity assessed using τ2 and I2 and robustness using sensitivity analyses. Univariable meta-regression explored heterogeneity. PROSPERO: CRD42024603778. RESULTS:Of 5,980 records, 20 studies comprising 4,786 patients with MS were included (mean age: 43.6 ± 6.3 years; 63.7% female). Sample sizes varied by outcome. SELs accounted for 14% (95% CI 10-21) of all T2 lesions, and 78% (67-85) of patients had at least 1 SEL. After sensitivity analysis, per-patient mean volumes were 1.42 mL (0.79-2.06) for SELs and 10.6 mL (8.53-12.67) for total T2 lesions. In total, 11% (6-20) of SELs overlapped with PRLs. In subgroup analyses, proportions of SELs were similar in relapsing-remitting and progressive MS (15%), but the proportion of patients with at least 1 SEL was higher in progressive MS. Between-study heterogeneity was high across analyses with no significant sources identified. DISCUSSION:Although SELs represent a minority of T2 lesions, most patients have at least 1 SEL and a subset overlaps with PRLs, suggesting a partial correspondence between these 2 imaging markers of chronic inflammatory activity. Limitations include possible publication bias, high unexplained heterogeneity, differences in SEL identification methods, and differences in MRI time point number/timing.
BACKGROUND AND OBJECTIVES:Adults with Down syndrome (DS) have an increased risk of developing early Alzheimer disease. While our previous cross-sectional study investigated the blood proteome in the context of Alzheimer in DS, identifying CBLN4, CD14, C-X-C motif chemokine 17 (CXCL17), ectodysplasin A2 receptor (EDA2R), glial fibrillary acidic protein (GFAP), insulin-like growth factor binding protein-2 (IGFBP2), neurofilament light (NFL), SEPTIN3, and SPON1 as proteins of interest, longitudinal trajectories remain mostly unexplored. We aimed to characterize the longitudinal dynamics of these plasma proteins to evaluate their potential contribution to disease pathophysiology and associated cognitive decline. METHODS:Adults with diagnosis of DS and ability to understand instructions of neuropsychological assessments were recruited at Ludwig Maximilians University Hospital Munich, returning for at least 1 annual follow-up visit for repeated clinical assessment, neuropsychological testing, and blood sample collection after baseline visit. Longitudinal blood protein dynamics were assessed using OLINK technology. Bayesian modeling analyzed longitudinal protein trajectories and their impact on cognitive performance. Spearman correlations of regression-derived rates of change investigated relationships between proteins and cognitive subdomains stratified by clinical diagnosis. RESULTS:We included 59 adults with DS (46% female, median age = 32 years [interquartile range: 27-47]). All completed the first annual follow-up visit (median duration 13.37 months [12.35-20.95]), with 14 of them returning for a follow-up 2 visit (median 25.43 months [24.79-33.8]). Stratified analysis included 13 individuals with DS with (38% female, 54 years [49-58]) and 41 without diagnosis of cognitive decline (49% female, 29 years [24-35]). Cluster of differentiation 14, CXCL17, EDA2R, GFAP, IGFBP2, NFL, SEPTIN3, and SPON1 exhibited longitudinal increase, while CBLN4 decreased (all posterior distributions ≥ 99.12%), with age. Protein baseline levels were associated with cognitive decline over time while controlling for age in the whole cohort (all posterior distributions ≥ 94.75%). After correction for multiple comparisons, no longitudinal changes in protein markers exhibited a significant relationship when correlated with changes in cognitive subdomain performance within subcohorts. DISCUSSION:In DS, longitudinal characterization of all previously identified proteins revealed distinct trajectories over time and an association of baseline levels with future cognitive decline. This suggests potential contributions of these proteins to the complex underlying pathophysiology of Alzheimer in DS and should motivate further investigation.
