Journals
2025 EN
Hassan Ameer E. · Abraham Michael G. · Blackburn Spiros
+68 more
Endovascular thrombectomy (EVT) was shown to be safe and efficacious in patients with large core stroke in multiple randomized controlled trials. However, the impact of reperfusion and other procedural metrics on EVT outcomes in this population has not been well‐characterized. Methods From the SELECT2 trial, we evaluated the association between reperfusion status, first‐pass effect (near‐complete or complete reperfusion [extended thrombolysis in cerebral infarction (eTICI) 2c‐3] in 1 pass), procedure time and primary technique (aspiration vs stent‐retriever) with functional outcomes in patients receiving EVT across ASPECTS (3 vs 4 vs 5) and core estimate strata (<70 vs ≥70ml, <100 vs ≥100ml, and <150 vs ≥150ml). Results Of 180 patients who received thrombectomy, 144 (80%) achieved successful reperfusion (eTICI 2b‐3) and demonstrated better clinical outcomes (adjusted generalized odds ratios [aGenOR]: 1.48, 95% confidence interval [CI]: 1.01–2.15), compared with unsuccessful reperfusion. Results were consistent across ASPECTS and core estimate strata. Additionally, complete or near‐complete reperfusion (eTICI 2c‐3) was associated with better functional outcome (aGenOR: 1.99, 95% CI: 1.33–2.97) in patients achieving successful reperfusion. Functional outcome point estimates favored those with first‐pass‐effect (42 of 167 (25%), aGenOR: 1.46, 95% CI: 0.96–2.24). Longer procedure time was associated with worse modified Rankin scale (mRS) distribution (aGenOR: 0.92, 95% CI: 0.87–0.96, p ‐value = 0.001 for 10 minutes increment). Aspiration‐first technique was used in 43 of 154 (25%) patients and was not associated with higher reperfusion (88% vs 78%, p = 0.18) or better functional outcome (aGenOR: 0.74, 95% CI: 0.50–1.10) as compared with stent‐retriever first. Interpretation Successful reperfusion resulted in improved clinical outcomes in large core patients across baseline ischemic core strata. Near complete or complete reperfusion was further associated with better outcomes, whereas prolonged procedures were associated with worse outcomes. Results were consistent regardless of the technique used. ANN NEUROL 2025;97:175–184
Journals
2025 EN
Simonyan Kristina · O'Flynn Lena C. · Hamzehei Sichani Azadeh
+5 more
Objective To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double‐blind placebo‐controlled 2‐period cross‐over clinical trial in patients with isolated laryngeal dystonia (LD). Methods The study was conducted from January 2018 to December 2021, pausing during the COVID‐19 pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol‐responsive (EtOH+) and alcohol‐non‐responsive (EtOH−) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures. Results Compared to baseline, EtOH+ but not EtOH− patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6–26.9; p = 0.008; EtOH−: 98.75% CI = −6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75–5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7–48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness. Interpretation Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2025;97:329–343
Journals
2025 EN
DiCarlo Julie A. · Jaywant Abhishek · Gochyyev Perman
+10 more
Objective Patient‐reported outcome measures (PROMs), which capture patients' perspectives on the consequences of health and disease, are widely used in neurological care and research. However, it is unclear how PROMs relate to performance‐rated impairments. Sociodemographic factors are known to affect PROMs. Direct damage to brain regions critical for self‐awareness (i.e., parietal regions and the salience/ventral‐attention network) may also impair self‐report outcomes. This study examined the relationship between PROMs and performance‐based measures in stroke survivors with arm motor impairments. We hypothesized that PROMs would be distinct from performance‐based outcomes, influenced by sociodemographic factors, and linked to damage in brain circuits involved in self‐perception. Methods We longitudinally assessed 54 stroke survivors using patient‐reported and performance‐rated measures at 4 timepoints. We used factor analysis to reveal the outcome battery's factorial structure. Linear regression examined the association between classes of measures and sociodemographics. Voxel‐lesion‐symptom‐mapping, region‐of‐interest‐based analysis, and voxel‐lesion‐network‐mapping investigated the relationship between classes of outcomes and stroke‐related injury. Results Performance‐based and patient‐reported measures formed distinct factors, consistent across recovery phases. Higher education (β1 = 0.36, p = 0.02) and income adequacy (β2 = 0.48, p = 0.05) were associated with patient‐reported, but not performance‐rated outcomes. Greater parietal lobe injury, irrespective of hemisphere, was associated with worse patient‐reported outcomes; greater corticospinal tract injury related to worse performance‐rated outcomes. Lesions with greater functional connectivity to the salience/ventral‐attention network were associated with worse patient‐reported outcomes ( r = −0.35, p = 0.009). Interpretation Our findings reveal important differences between performance‐rated and patient‐reported outcomes, each with specific associated factors and anatomy post‐stroke. Incorporating sociodemographic and neuroanatomic characteristics into neurorehabilitation strategies may inform and optimize patient outcomes. ANN NEUROL 2025;97:242–253
Journals
2025 EN
Kasner Scott E. · Mullen Michael T. · DeGeorgia Michael
+68 more
Objective Among patients with large vessel occlusion (LVO) and large ischemic cores, critical decisions often need to be made about decompressive hemicraniectomy (DHC) or early withdrawal of life‐sustaining therapy (WLST). In this study, we aimed to evaluate utilization of DHC and early WLST and factors associated with them in patients with large strokes from the SELECT2 trial. Methods We analyzed the entire SELECT2 trial population, which randomized 352 patients with stroke due to LVO and large ischemic cores to endovascular thrombectomy (EVT) or medical management. We used the as‐treated principle to compare the use of DHC and early WLST within 7 days after randomization. We further assessed functional outcomes (modified Rankin Score) after these decisions. Results Of 352 patients enrolled in this study, 55 received DHC and 81 transitioned to early WLST. Patients treated with EVT were as likely to undergo DHC (16% vs 15%, adjusted relative risk [aRR] = 1.19, 95% CI:0.75–1.88, p = 0.46) or WLST (22% vs 24%, aRR = 0.94, 95% CI: 0.66–1.34, p = 0.72) as those given medical management. DHC was used more frequently in younger patients and WLST more in older patients. EVT efficacy was maintained after adjusting for DHC (adjusted generalized odds ratio [aGenOR] = 1.68, 95% CI: 1.24–2.11, p < 0.001), with no interaction between DHC and treatment (p‐interaction = 0.93). At 1 year, 21% of DHC‐treated patients were ambulatory; the outcomes were universally poor after early WLST. Interpretation In the SELECT2 trial of patients with large ischemic core, DHC was performed in ~1 of 6 patients and early WLST in ~1 of 5 patients, without differences based on treatment with EVT or medical management, nor successful reperfusion. DHC or WLST did not detract from thrombectomy treatment benefit. Additionally, ~20% of patients achieved independent ambulation despite receiving DHC by the 1‐year follow‐up. The similar distribution of these critical care decisions provides reassurance that the overall trial outcomes were not biased by open‐label treatment allocation. ANN NEUROL 2025;97:698–708
Journals
2025 EN
Schwarz Anne · Feldman Marc · Le Vu
+18 more
Objective Vagus nerve stimulation (VNS) paired with rehabilitation therapy improved motor status compared to rehabilitation alone in the phase III VNS‐REHAB stroke trial, but treatment response was variable and not associated with any clinical measures acquired at baseline, such as age or side of paresis. We hypothesized that neuroimaging measures would be associated with treatment‐related gains, examining performance of regional injury measures versus global brain health measures in parallel with clinical measures. Methods Baseline magnetic resonance imaging (MRI) scans in the VNS‐REHAB trial were used to derive regional injury measures (extent of injury to corticospinal tract, the primary regional measure; plus extent of injury to precentral gyrus and postcentral gyrus; lesion volume; and lesion topography) and global brain health measures (degree of white matter hyperintensities, the primary global brain measure; plus volumes of cerebrospinal fluid, cortical gray matter, white matter, each thalamus, and total brain). Eight clinical measures assessed at baseline were also evaluated (treatment group, age, race, gender, paretic side, pre‐stroke dominant hand, time since stroke, and baseline Fugl‐Meyer upper extremity score). Bivariate analyses compared each measure with the primary trial end point (change in Fugl‐Meyer upper extremity score from baseline to end of 6 weeks of treatment) across all subjects, with secondary analyses examining trial groups separately. Results MRIs were available from 80 patients (age = 59.8 ± 9.5 years, 29 women). Across all patients, less white matter hyperintensities ( r = −0.25, p = 0.028) at baseline was associated with larger Fugl‐Meyer score change. In the VNS group, less white matter hyperintensities ( r = −0.37, p = 0.018) and larger ipsilesional thalamus volume ( r = 0.33, p = 0.046) were each associated with larger Fugl‐Meyer score change. Analysis of covariance (ANCOVA) analyses tested the interaction that each baseline measure had with treatment group and found that the model examining white matter hyperintensities had a significant interaction term, indicating 2.3 less change in Fugl‐Meyer Upper Extremity (FM‐UE) points in the VNS group relative to the control group for each point increase in modified Fazekas scale. Interpretation Neuroimaging measures are associated with extent of gains on the primary endpoint of a phase III stroke recovery trial. Among the neuroimaging measures examined, a measure of global brain health (extent of white matter hyperintensities) was better at explaining the change in arm impairment as compared with measures of regional injury; this was true when examining all study subjects as well as only those in the VNS group and is consistent with the global mechanism of action that VNS has throughout the cerebrum. Future studies can evaluate additional measures that further predict response to VNS therapy. The current findings suggest that individual patient neuroimaging results may be useful for a personalized medicine approach to stroke recovery therapeutics. ANN NEUROL 2025;97:709–719
Journals
2025 EN
NoguchiShinohara Moeko · Shuta Kazuyoshi · Murakami Hidetomo
+6 more
Objective The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted in less decline on measures of cognition and function than placebo. Herein, we aimed to characterize amyloid‐β (Aβ) protofibril (PF) captured by lecanemab in human cerebrospinal fluid (CSF) from living participants with different stages in AD, which enable an enhanced understanding of the dynamic changes of lecanemab‐associated Aβ‐PF (Lec‐PF) in vivo. Methods We newly developed a unique and highly sensitive immunoassay method using lecanemab that selectively captures Lec‐PF. The CSF level of Lec‐PF, Aβ42, Aβ40, p‐tau181, p‐tau 217, total tau, and neurogranin were measured in Japanese participants (n = 163). The participants in this study consisted of 48 cognitively unimpaired Aβ‐negative (CU–), 8 cognitively impaired diagnosed as suspected non‐Alzheimer's disease pathophysiology, 9 cognitively unimpaired Aβ‐positive (CU+), 34 Aβ‐positive with mild cognitive impairment (MCI+), and 64 Aβ‐positive with AD dementia (AD+). Results The CSF Lec‐PF levels significantly increased in the groups of MCI+ and AD+ compared with CU– group. Notably, CSF Lec‐PF showed modest correlation with plaque‐associated biomarkers in Aβ‐positive participants and stronger correlation with neurodegeneration biomarkers, such as CSF total tau and neurogranin, suggesting that CSF Lec‐PF levels proximally reflect neurodegeneration as well as the amount of senile amyloid plaques. Interpretation This is the first report describing Aβ‐PF species captured by lecanemab in human CSF and supporting that Lec‐PF is correlated with neurodegeneration in AD and may explain the mechanism of the clinical effect of lecanemab. ANN NEUROL 2025;97:993–1006
Journals
2025 EN
Olie Sabine E. · Staal Steven L. · Cruz Campos Ana C.
+4 more
Objective We aimed to evaluate the diagnostic accuracy of heparin‐binding protein (HBP) in cerebrospinal fluid for the diagnosis of bacterial meningitis in patients with a suspected central nervous system infection. Methods This prospective multicenter cohort study determined the diagnostic accuracy of HBP in cerebrospinal fluid (CSF) for bacterial meningitis among a cohort of consecutive patients with a suspected central nervous infection. The final clinical diagnosis was considered the reference standard. The results were validated in a separate cohort. Results A total of 631 Dutch patients were evaluated for the current study, of which 73 (12%) had a final diagnosis of bacterial meningitis. For the differentiation of bacterial meningitis from all other disorders, diagnostic accuracy was high with an area under the curve (AUC) of 0.98 (95% confidence interval [CI] 0.96–1.00). With the proposed cutoff of 5.2 ng/ml, sensitivity was 97% with a specificity of 96%. In the population of patients with a CSF leukocyte count of 5‐1,000/mm 3 , the AUC was 0.96 (95% CI 0.87–1.00), outperforming CSF leukocytes (AUC 0.88 [95% CI 0.79–0.97]). Combining HBP with CSF C‐reactive protein (CRP) significantly increased accuracy in this population and reached a 100% sensitivity (AUC 1.00 [95% CI 0.99–1.00], cutoff 0.07, sensitivity 100%, specificity 96%). These results remained robust in an external validation cohort of 120 Danish patients (AUC 0.97 [95% CI 0.93–1.00]). Interpretation HBP can correctly distinguish bacterial meningitis from other disorders. It can be of additional value to current diagnostics in cases where CSF leukocyte count is relatively low, particularly when combined with CSF CRP. ANN NEUROL 2025;97:1088–1095
Journals
2025 EN
Kennedy Eleanor · Guo Ting · Williams Sian
+10 more
Objective Moderate‐to‐late preterm (MLP) infants contribute to the greatest proportion of preterm children with neurodevelopmental impairments. White matter injury (WMI) is common and predicts adverse outcomes in very preterm (VP) infants. However, little is known about white matter abnormality (WMA) in MLP infants. We investigated the burden and distribution of WMA in MLP infants. Methods MLP infants were recruited from a randomized trial on neonatal nutrition and a prospective observational cohort in New Zealand, and underwent brain magnetic resonance imaging (MRI) soon after birth and at term‐equivalent age (TEA). WMA was manually segmented using an established method. Total and regional WMA volumes and percentage of WMA to total cerebral volume were calculated. Probabilistic WMA maps were generated and compared with WMI in VP infants and term infants with congenital heart disease. Results Of 101 infants (32 females), 40 (39.6%) had WMA on at least 1 scan. In 37 infants with WMA who had both scans, WMA was less visible in 22 (59.5%) or undetectable in 7 (18.9%) infants with a mean reduction of 72.7 ± 207.5 mm 3 in WMA volume from early‐life to term. Infants with and without WMA had mostly comparable pregnancy and neonatal characteristics. Probabilistic maps demonstrated a characteristic WMA topology, with most lesions in posterior followed by central and anterior regions. Trigonal areas were vulnerable across neonatal populations. Interpretation WMA is much more common in MLP infants than previously reported and occurs in a characteristic topology. WMA may be missed on TEA MRI, and its relationship with outcomes in MLP infants warrants attention. ANN NEUROL 2025;98:329–340
Journals
2025 EN
Brooker Sarah M. · Novelli Maria · Coukos Robert
+77 more
Objective A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss‐of‐function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders. Methods Cases with NUS1 ‐related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case‐note review. Results We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype–phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation. Interpretation Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561–572
Journals
2025 EN
Staal Steven L. · Olie Sabine E. · Weeghel Michel
+4 more
Objective To assess the diagnostic accuracy of metabolites in cerebrospinal fluid (CSF) for central nervous system (CNS) infections. Methods Patients were derived from three prospective cohort studies in the Netherlands. All studies included adults suspected of a CNS infection who underwent a diagnostic lumbar puncture. Metabolomics was performed on CSF using ultra‐high‐performance liquid chromatography with tandem mass spectrometry on a discovery and validation cohort. Metabolite quantification was the index test; a microbiologically confirmed diagnosis was the reference standard. Results In total, 343 episodes were included, of whom 170 (50%) had a CNS infections and 173 (50%) episodes had other diagnoses. CNS infections included bacterial meningitis in 88 (26%), viral meningoencephalitis in 50 (15%), and other CNS infections in 32 (9%) episodes. Other diagnoses consisted of CNS autoimmune disorders in 21 (6%), other neurological diseases in 84 (24%), and systemic infections in 68 (20%) episodes. A distinct metabolomic profile was observed in CSF of CNS infections, particularly bacterial meningitis. Glucose, glycerate, 1.3‐diphosphoglyceric acid, pyruvate, lactate, taurine, and alpha‐ketoglutarate had the highest diagnostic accuracy (area under the curve 0.87 to 0.95). Combinations further improved diagnostic accuracy, resulting in models that outperformed both individual metabolites and CSF leukocytes. Episodes with CSF leukocytes between 5 and 1,000 cells per mm 3 showed similar results. Interpretation CSF metabolites demonstrate high diagnostic accuracy for CNS infections, particularly bacterial meningitis. Combinations further improve the diagnostic performance, exceeding that of CSF leukocytes alone. These findings highlight the potential of cerebrospinal fluid metabolites to improve diagnostic accuracy in clinical practice. ANN NEUROL 2025;98:851–863