Annals of Neurology最新文献

Objective: Endovascular thrombectomy (EVT) is increasingly used for pediatric large vessel occlusion (LVO) stroke, however, its role in isolated M2 occlusions remains underexplored. This study compared clinical outcomes in children with isolated M2 occlusion treated with EVT versus best medical therapy (BMT).

Methods: This multicenter cohort study pooled data from 4 pediatric stroke registries (Save ChildS, KidClot, Pediatric LVO Study, and Save ChildS Pro). Children ages 28 days-17 years with isolated M2 occlusion presenting within 24 hours of last seen well were included. Primary outcome was the pediatric modified Rankin scale (ped-mRS) at 3 to 6 months. Secondary outcomes included changes in Pediatric National Institutes of Health Stroke Scale (PedNIHSS), Pediatric Stroke Outcome Measure (PSOM), and safety endpoints.

Results: Forty patients were included, of whom 20 were treated with EVT (median age, 12 years; interquartile range [IQR], 6-15; 40% female) and 20 with BMT only (10 years; IQR, 5-14; 50% female). Baseline demographics were similar. EVT patients showed superior outcomes: median ped-mRS at 3 to 6 months was 1 versus 2 (p = 0.015). EVT resulted in greater PedNIHSS reduction from admission to day 7 (-9 vs -1, p < 0.001) and lower PSOM at 3 to 6 months (0.5 vs 2.5, p = 0.009). This benefit persisted at 24 months with a median ped-mRS of 1 (IQR, 0-2) in the EVT group and 2 (IQR, 1-3) in the BMT group (p = 0.012). One symptomatic intracranial hemorrhage occurred in the BMT group, and no deaths or access-site complications were reported.

Interpretation: In children with isolated M2 occlusion, EVT was associated with better functional outcomes and neurological recovery than medical therapy alone, with an acceptable safety profile. ANN NEUROL 2025.

Objective: Assess the performance of serum phosphorylated tau 217 (p-tau217) and neurofilament light chain (NfL) in predicting risk of cognitive impairment or phenoconversion to dementia in individuals with iRBD.

Methods: We measured serum p-tau217 and NfL levels by electrochemiluminescence across 4 polysomnographically confirmed iRBD cohorts (n = 300), including individuals who phenoconverted to Parkinson's disease (PD) (n = 51), dementia with Lewy bodies (DLB) (n = 22), and multiple system atrophy (MSA) (n = 5).

Results: Serum p-tau217 levels were increased in individuals with iRBD and cognitive impairment (CI) on testing defined as Montreal Cognitive Assessment <26 or subthreshold parkinsonism. p-Tau217 differentiated individuals with iRBD who developed PD with CI (PD-CI) or DLB from PD phenoconverters with normal cognition (area under curve [AUC] = 0.82; 95% confidence interval, 0.70-0.93) and from iRBD non-phenoconverters with normal cognition (AUC = 0.83; 95% confidence interval, 0.77-0.89). NfL levels did not correlate with cognitive or motor scores and marginally improved p-tau217 performance (AUC = 0.85; 95% confidence interval, 0.78-0.92), but were notably elevated in iRBD individuals who phenoconverted to MSA. Individuals with p-tau217 in the top quartile were 8 times more likely to phenoconvert to PD-CI or DLB compared to the bottom quartile (hazard ratio = 8.30; 95% confidence interval, 2.49-27.65).

Interpretation: Serum p-tau217, but not NfL, is a useful biomarker of cognitive impairment in iRBD that could be integrated into a multimodal prognostic indicator when stratifying risk of phenoconversion. ANN NEUROL 2025.

Objective: Antiseizure medication (ASM) use during pregnancy has increased over the past decade. However, evidence linking prenatal ASM exposure to neurodevelopmental disorders (NDDs) in offspring remains inconsistent. This study evaluated whether prenatal ASM exposure increases the risk of NDDs in children.

Methods: We analyzed data from 5 population-based cohorts of live-born children in Canada (Alberta, Manitoba, Ontario, Quebec; the Canadian Mother-Child Cohort [CAMCCO] cohorts) and the United States (AM-PREGNANT cohort). ASM exposure was defined as maternal prescription fills overlapping the 60 days before birth. NDDs were identified using validated algorithm based on the International Classification of Disease-9/10 codes from inpatient and outpatient records. Within each cohort, Cox proportional hazards models were applied, with adjustment performed separately using (1) covariates and (2) propensity scores. Pooled estimates were obtained using random-effects meta-analysis.

Results: Of 2,910,206 children, 0.47% were exposed to ASMs in the 60 days before birth. Prenatal ASM exposure was associated with a 29% increased risk of NDDs (pooled-adjusted hazard ratio [p-aHR], 1.29; 95% CI: 1.22-1.37; 1,805 exposed cases). In the Canadian cohorts, risks of combined NDDs varied by medication: carbamazepine (p-aHR: 1.50; 95% CI: 1.20-1.87; 262 exposed cases), clonazepam (p-aHR 1.22; 95% CI: 1.12-1.33; 585 exposed cases), topiramate (p-aHR 1.56; 95% CI: 1.04-2.34; 69 exposed cases), and valproic acid (p-aHR 1.38; 95% CI: 1.16-1.65; 134 exposed cases). Although point estimates were higher for polytherapy than monotherapy, the difference was not statistically significant.

Interpretation: Prenatal exposure to certain ASMs was consistently associated with increased risks of NDDs in offspring. These findings support careful, individualized decision-making regarding prenatal ASM use to minimize neurodevelopmental risks. ANN NEUROL 2025.

Objective: The ketogenic diet, a high-fat, low-carbohydrate regimen, is often used to treat drug-resistant seizures and is being studied for Alzheimer's disease and other neuropsychiatric disorders. However, its mechanism of action remains unclear. β-hydroxybutyrate, a primary circulating ketone body produced by the ketogenic diet, may mediate its effects on seizures by binding to a recently identified Gi-coupled receptor: hydrocarboxylic acid receptor 2 (HCAR2).

Methods: RNAscope in situ hybridization assay and real-time quantitative polymerase chain reaction were used to assess HCAR2 expression in the mouse brain. We generated HCAR2^-/^- using the CRISPR-Cas technique on an S129 mouse background. Whole-cell current-clamp was performed to measure the passive and active membrane properties of hippocampal dentate granule cells. The voltage-clamp was performed to record synaptic currents. Two complementary in vivo mouse models-continuous hippocampal stimulation to induce status epilepticus (SE) and kindling-were used to induce seizures.

Results: HCAR2 was localized in dentate granule cells and microglia. In mice with HCAR2, β-hydroxybutyrate reduced neuronal excitability by hyperpolarizing the resting membrane potential, raising the action potential threshold, and reducing the firing frequency of dentate granule cells. β-hydroxybutyrate suppressed excitatory synaptic transmission. These effects were nullified in HCAR2^-/^- mice. HCAR2^-/^- mice showed no cognitive impairment. Moreover, β-hydroxybutyrate did not affect seizures in HCAR2^-/^- mice. However, it diminished both the duration and severity of seizures in HCAR2⁺/⁺ mice.

Interpretation: These findings demonstrate that HCAR2 mediates β-hydroxybutyrate's antiseizure effects by regulating neuronal excitability and synaptic transmission. These studies propose a new mechanism for the antiseizure action of the ketogenic diet. ANN NEUROL 2025.

Objective: Aneurysm wall enhancement (AWE) may predict aneurysm growth and rupture in the short-term, but there is a lack of long-term follow-up studies. We aimed to determine whether unruptured intracranial aneurysms (UIAs) with AWE have a higher probability of aneurysm instability during long-term follow-up compared with those without AWE.

Methods: For this longitudinal cohort study, we obtained individual patient data from two international cohorts. We included patients with ≥ 1 untreated UIA who underwent gadolinium-enhanced aneurysm wall imaging and magnetic resonance angiography (MRA) between 2012 and 2016, and had follow-up imaging and/or had a rupture during follow-up. The outcome was aneurysm instability, defined as time to growth, morphological change, or rupture during follow-up. We calculated the 7.5-year probability of aneurysm instability with 95% confidence interval (CI) with the Kaplan-Meier estimator. We used Cox regression survival analysis to calculate the crude hazard ratio (HR) with corresponding 95% CI of AWE for aneurysm instability, and the HR adjusted for age and aneurysm size at baseline.

Results: We included 198 patients (median age = 58 years, interquartile range = 50-68, 139 women, 70%) with 224 aneurysms. Aneurysm instability was observed in 15 of 72 aneurysms (21%) with AWE and 13 of 152 aneurysms (9%) without AWE during a median follow-up duration of 6.8 years (IQR = 3.3-7.9). The 7.5-year probability of instability was 29.2% (95% CI = 14.5%-41.3%) in aneurysms with AWE and 9.3% (95% CI = 2.9%-15.3%) in aneurysms without AWE (crude HR = 4.29, 95% CI = 1.90-9.72, adjusted HR = 5.06, 95% CI = 2.13-12.02).

Interpretation: UIAs with AWE have a higher probability of 7.5-year aneurysm instability compared with those without AWE. ANN NEUROL 2025.

Objective: Frontotemporal lobar degenerations (FTLD)-TDP type C (TDP-C) is distinguished from other FTLD-TDP subtypes by 3 unique features: (1) invariable onset in the anterior temporal lobe (ATL), (2) phosphorylated TDP-43 (pTDP) neurites in cortex, and (3) colocalization of all pTDP deposits with annexin A11 (ANXA11). This article provides a whole-brain anatomical account of TDP-C disease progression in relation to clinical, imaging, and neuropathologic patterns.

Methods: Thirty-two cases with TDP-C were studied, including neuropathologic findings and longitudinal magnetic resonance imaging. In 6 of these cases, cortical and subcortical areas were analyzed using whole hemisphere sections. Five control cases were used for comparison.

Results: Progression was reconstructed with the assumption that regions displaying more severe neurodegeneration at postmortem represented earlier onset sites, an assumption supported by longitudinal imaging. Four stages of cortical TDP-C neuropathology were identified. Subcortically, the fascia dentata contained dense round bodies of pTDP, which did not seem to cause neuronal loss. These deposits were also seen in the nucleus accumbens, islands of Calleja, and the nucleus of the stria terminalis. Cortical predilection sites had higher densities of neurites especially in cases without much tissue destruction. However, cases with more severe overall neurodegeneration displayed a paradoxical scarcity of pTDP deposits at predilection sites. Neurodegeneration patterns identified in whole-hemisphere cases were corroborated by 26 additional cases processed for neuropathologic diagnosis. All pTDP inclusions contained ANXA11. In control cases, the distribution of ANXA11-rich neurons was largely concordant with the pattern of susceptibility to TDP-C.

Interpretation: Neurodegeneration originates in upper cortical layers of ATL and spreads posteriorly along paralimbic mediodorsal and associative ventrolateral pathways. In normal cortex, nuclear TDP-43 is distributed throughout the cortex, whereas normal ANXA11 shows variations that largely mirror TDP-C predilection patterns. The possibility is raised that ANXA11 may be a factor in determining the distribution of TDP-C neurodegeneration. ANN NEUROL 2025.

Neurologists regularly care for patients with complex, chronic, and often incurable conditions. These circumstances impose profound emotional burdens on the patient and physician. Whereas empathy is central to therapeutic effectiveness in clinical practice, sustained empathic engagement can contribute to emotional exhaustion and physician burnout, a condition now endemic in neurology. This review synthesizes insights from neuroscience, psychology, and clinical education to propose "skillful empathy" as a trainable capacity that integrates affective resonance with cognitive perspective-taking. We describe how emotional contagion harms clinician well-being and advocate for the integration of empathy training into medical education to support sustainable, compassionate neurological care. ANN NEUROL 2025.