Journal of the Neurological Sciences

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic hereditary cerebral small vessel disease (CSVD). Existing studies have confirmed that it is caused by mutations in the NOTCH3 gene, but the specific mechanisms underlying its pathogenesis and progression remain elusive. Existing research indicates that inflammation plays a critical role in the development and progression of CSVD. The Systemic Immune-Inflammation Index (SII) has revealed to be a reliable new marker to assess immune status and inflammatory response intensity. This study reveals the relationship of SII with cognitive impairment and magnetic resonance imaging (MRI) markers of CSVD in patients with CADASIL. MethodsThis cross-sectional investigate included patients diagnosed with CADASIL who had confirmed NOTCH3 gene mutations and complete clinical data. Cognitive function in patients with CADASIL was appraised by the Mini-Mental State Examination (MMSE). SII is obtained by calculating the number of platelets, neutrophils and lymphocytes in blood routine examination. Summary SVD score and imaging markers of CSVD, including cerebral microbleeds, lacunae, white enlarged perivascular space and matter hyperintensity were evaluated based on magnetic resonance imaging. The association between cognitive impairment and SII and MRI markers in CADASIL were evaluated using logistic regression models and Spearman correlation. ResultsAt baseline, A total of 96 Patients with CADASIL were enrolled in this cross-sectional study. the median age of patients with CADASIL was 59.00 (interquartile range 52.25-66.75) years, and 58.3% of patients were male. The correlation analysis results indicate that the SII level was negatively correlated with MMSE scores in patients with CADASIL (rs=-0.336, P <0.001). An elevated SII was statistically significantly linked with the risk of cognitive impairment (Q4 vs. Q1: OR 5.230, 95% CI 1.040-26.297; P=0.045) after adjusting for age, sex and education. In contrast, there was no considerable difference between SII and summary SVD score or MRI imaging markers. ConclusionsElevated SII was linked with cognitive impairment in CADASIL patients. Nevertheless, there were no significant differences between SII and summary SVD score or MRI imaging markers.

ObjectiveTo identify patient characteristics and medication factors associated with perceived comfort with migraine treatments and control of migraine symptoms. BackgroundPatient perceptions of migraine treatment influence adherence and outcomes, yet little is known about their underlying drivers. Our study objective was to identify clinical features of migraine associated with comfort and perceived control of symptoms, and medication classes associated with higher patient comfort and efficacy. MethodsParticipants in the Headache Assessment via Digital Platform in United States (HeAD-US) study completed a cross-sectional survey on demographics, migraine burden, mood, disability, and medication use. Comfort and control were defined using corresponding items from the Migraine Treatment Optimization Questionnaire (mTOQ-6) and categorized as "high" or "low". We compared patient characteristics, clinical features, and medication classes by reported comfort and control. ResultsAmong 5717 participants (mean age 41.5 {+/-} 13.1 years, 91.2% female), 58.5% reported high comfort with migraine treatments, while only 27.5% reported high control of migraine symptoms. High comfort was associated with fewer monthly headache days (mean 9.9 vs. 14.2, p<0.001), lower migraine symptom severity (median MSSS 18 vs. 19, p<0.001), and lower disability (MIDAS severe: 72.7% vs 91.2%, p<0.001) and mood symptom scores (PHQ-4 severe: 9.5% vs. 21.0%, p<0.001). High perceived control showed similar associations with employment (OR=1.25, CI 1.15-1.48, p = 0.013), monthly headache days (mean 9.0 vs 12.7,p<0.001), migraine severity (median MSSS 18 vs 19, p<0.0001), disability (severe: 66.0 vs 85.8, p<0.001), and mood symptoms (severe: 7.6 vs 16.9, p<0.001) but was not associated with income or education. Among those on monotherapy, gepants and triptans were associated with higher comfort and efficacy than OTC medications or opioids/barbiturates. For preventive therapy, beta blockers and botulinum toxin were associated with the lowest perceived comfort and efficacy. ConclusionPerceived comfort and control were linked to headache frequency, severity and disability and mood symptoms. Medication class use influenced perceptions, with gepants and triptans rated most favorably. These findings underscore the importance of incorporating patient perspectives into treatment planning, with particular attention to mood, disability, and choice of medication.

ObjectiveWe aimed to do an updated meta- analysis comparing outcomes of mechanical thrombectomy (MT) associated with standard medical treatment (SMT), compared to SMT alone, in adult patients with acute ischemic stroke (AIS) due to medium or distal vessel occlusion (MDVO). MethodologyWe systematically searched PubMed, LILACS, Scielo, Cochrane, and ClinicalTrials.gov databases. Randomized controlled trials (RCTs), retrospective cohort studies, and systematic reviews with meta-analysis comparing MT+SMT with SMT alone in adults with AIS due to MDVO, evaluating at least one of the outcomes of interest, were included. The evaluated outcomes were functional recovery (modified Rankin Scale [mRS] 0-1 and mRS 0-2) at 90 days, all-cause mortality at 90 days, and the occurrence of intracranial hemorrhage (ICH). Risk of bias was assessed using RoB 2, Newcastle-Ottawa, and AMSTAR 2 tools. Heterogeneity was assessed with Chi{superscript 2} and I{superscript 2}, and publication bias with funnel plots and Egger/Begg tests. ResultsTwelve studies (4 RCTs, 7 cohorts, 1 systematic review) were included. Meta-analyses showed no significant difference between MT+SMT and SMT alone for: mRS 0-1 (Excellent Recovery), mRS 0-2 (Good Recovery), mortality at 90 days, and Symptomatic Intracranial Hemorrhage. ConclusionCurrent evidence, combining RCTs and observational studies, does not support the routine use of MT over SMT alone for MDVO in terms of functional improvement at 90 days (mRS 0-1 or 0-2). Non-significant trends towards increased mortality and sICH risk with MT were observed, with considerable heterogeneity for sICH. KEY MESSAGESeveral randomized controlled trials (RCTs) have demonstrated the benefit of mechanical thrombectomy associated with standard medical treatment (SMT), in patients with IS caused by large vessel occlusion (LVO). There for the boundaries of MT began to be questioned, raising the possibility of performing it for medium and distal vessel occlusions (MDVO). As a result of this study, there was no evidence to support the use of MT over SMT alone for MDVO, therefore the therapeutic decisions should remain individualized and further research is crucial to define the exact role of the MT.

ObjectiveTo compare early cerebrospinal fluid (CSF) cytokine profiles in intracerebral hemorrhage (ICH) versus subarachnoid hemorrhage (SAH), with a focus on angiography-negative SAH (anSAH). MethodsWe conducted a retrospective observational cohort study of adults with spontaneous hemorrhagic stroke (ICH or SAH). For cytokine analyses, we included patients with external ventricular drains (EVDs) and analyzed the first CSF sample obtained within 72 hours of symptom onset. Cytokines were measured using a multiplex bead-based assay and included interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A (VEGF-A), C-C motif chemokine ligand-2 (CCL2), and granulocyte colony-stimulating factor (G-CSF). Cytokine concentrations were log-transformed due to non-normal distribution. Functional outcomes were assessed using the modified Rankin Scale (mRS) at discharge and 3 months. ResultsCSF cytokine analyses included 120 patients with available CSF samples (43 ICH and 77 SAH), while functional outcome analyses included a broader cohort of 490 patients with ICH or SAH to characterize discharge and 3-month outcomes across hemorrhage subtypes. Compared with SAH, ICH demonstrated higher early CSF log[IL-8] and log[VEGF-A] and had worse functional outcomes at discharge and 3 months. Within SAH, anSAH had higher log[IL-8] and log[VEGF-A] than aSAH, and its cytokine profile more closely aligned with that of primary ICH in hemorrhages without vascular malformations. DiscussionEarly CSF cytokine patterns suggest anSAH shares a more ICH-like inflammatory signature than aneurysmal SAH, supporting anSAH as a potentially biologically distinct SAH phenotype.

BackgroundStenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small vessel disease (cSVD) remain contentious. We investigated associations of large artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. MethodsWe prospectively recruited patients with lacunar or mild non-lacunar stroke, with demographic, stroke-related, cognitive, functional, and MRI (index and incident infarcts, cSVD markers) assessments at baseline and one year. LAS was defined as [&ge;]50% intracranial or cervical artery stenosis; basilar artery dolichoectasia (BADE) by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated using multivariable regression adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large artery pathology and cSVD. ResultsAmong 229 patients (mean age 65.9{+/-}11.1 years; 131 [57.2%] lacunar stroke), LAS and BADE were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio [OR], 0.49; 95%CI, 0.23-0.99) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, BADE was strongly associated with lacunar stroke (OR, 4.67; 95%CI, 1.87-13.14), higher cSVD scores (ordinal analysis; OR, 2.57; 95%CI, 1.28-5.25), incident infarcts (75% subcortical; OR, 2.29; 95%CI, 1.01-5.14), and greater progression of white matter hyperintensities over one year ({beta}, 0.15; 95%CI, 0.01-0.29; per log10-transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. ConclusionscSVD, including lacunar stroke, was unrelated to LAS, but strongly associated with dolichoectasia and wider arteries. These findings support a non-atheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABS[bullet] Large artery stenosis was unlikely to represent a causal mechanism for lacunar stroke and showed no association with cerebral small vessel disease (cSVD) imaging markers. [bullet]Dolichoectasia and intracranial arterial widening emerged as vascular phenotypes strongly associated with cSVD, including its progression and lacunar stroke subtype. What Are the Clinical Implications?[bullet] Distinct large artery phenotypes have divergent etiopathological implications for cSVD. Our findings support a non-atheromatous, intrinsic microvascular pathology as the principal mechanism of lacunar stroke and cSVD. [bullet]Mechanism-based therapeutic strategies for lacunar stroke and cSVD, moving beyond conventional approaches focused on atherosclerosis or cardioembolism, are warranted.

BackgroundSuccessful recanalisation without functional independence is a frequent phenomenon following endovascular thrombectomy for large vessel occlusion stroke. AimTo demonstrate safety and efficacy of adjunct tirofiban therapy after endovascular thrombectomy in patients with anterior circulation large vessel occlusion stroke achieving successful recanalization defined as modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3. DesignThe study of adjunct tirofiban treatment after successful endovascular thrombectomy recanalisation (ATTRACTION) is a multicenter, prospective, double-blind, randomized trial enrolling 1360 patients in China. Eligible patients will be randomised 1:1 to either the tirofiban or placebo group. OutcomeThe primary efficacy outcomes is assessed as the proportion of participants with a modified Rankin Scale (mRS) score of 0-2 at 90 days, and the primary safety outcome is symptomatic intracranial haemorrhage within 48 hours from randomisation. ConclusionThis study will provide evidence on the efficacy and safety of sequential tirofiban therapy after successful recanalisation in patients with anterior circulation large vessel occlusion stroke. Trial registration numberNCT06265051 WHAT IS ALREADY KNOWN ON THIS TOPICSuccessful recanalization without functional independence is a frequent phenomenon following endovascular thrombectomy and previous small-sample, retrospective studies supported the administration of adjunct tirofiban therapy in patients after endovascular thrombectomy achieving successful recanalization. WHAT THIS STUDY ADDSThe ATTRACTION trial aims to access the efficacy and safety of adjunct tirofiban therapy and the protocol describes the rationale and design of the trial. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYATTRACTION trial will inform whether tirofiban therapy after successful recanalisation by endovascular thrombectomy can improve patient outcomes.

IntroductionNeurodegenerative dementia syndromes are severely debilitating, progressive and increasing in incidence with an ageing population. A treatable differential diagnosis to neurodegenerative dementia is autoimmune encephalitis (AE), but AE patients are often misdiagnosed, delaying treatment. Previous work in the Netherlands has shown that 0.8% of patients with suspected neurodegenerative dementia suffer from AE. In Sweden, there is considerable variability in the prevalence of AE, possibly indicating under-diagnosis. We hypothesized that some Swedish individuals seeking care for memory impairment might suffer from an undetected AE and that these would show aberrances in available markers of neuroinflammation. MethodsWe retrospectively screened frozen sera from 1041 individuals seen between 2019 and 2023 at the Karolinska University hospital memory clinics in Stockholm for autoantibodies to contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), gamma-aminobutyric acid receptor B (GABABR), the n-methyl-d-aspartate receptor (NMDA-R) and Immunoglobulin superfamily containing LAMP, OBCAM, and Neurotrimin family member 5 (IgLON5) using live cell-based assays (CBAs) and scored them by microscopy. Serum and CSF from suspected positive patient samples were re-tested and titrated by live CBA, commercial fixed CBAs and tissue based assays. Results8 of the 1021 individuals, or 0.8% of the cohort, tested positive in at least three different tests for antibodies to CASPR2 (n=3), GABABR (n=2), LGI1 (n=1) and NMDAR (n=2). Seven of these patients had not been previously diagnosed with AE. Apart from two CASPR2-antibody positive patients showing neuropathic pain and seizures and neuromyotonia, respectively, the patients lacked clinical signs of encephalitis aside from memory impairment and affect lability. The antibody-positive patients did not differ significantly from autoantibody-negative patients in any available clinical parameter. None showed signs of inflammation on brain magnetic resonance tomography, and 2/7 lacked any sign of neuroinflammation in the CSF with available tests, which is commonly seen in later-onset AE. ConclusionOur work identifies undiagnosed AE patients with subtle symptomatology among Swedish memory clinic visitors, that cannot be sensitively separated from antibody-negative patients with current diagnostic tests. Our results suggest the need for the introduction of more sensitive markers of neuroinflammation to the memory clinic to identify and treat individuals with AE among sufferers of memory impairment.

ObjectivesFunctional neurological symptoms which do not meet clinical definitions of functional neurological disorder (FND) are common in clinical practice. Understanding the distinction between these benign functional symptoms and FND is crucial in defining FND as an entity for study, and as a clinical syndrome. We aimed to measure the frequency of functional symptoms in people who do not have FND. MethodsA survey was administered to 95 clinicians who attended an international conference on FND. Participants were asked to report the occurrence and characteristics of experiences with features of functional sensory or motor symptoms, or dissociation. ResultsOf the 95 people who responded to the survey, 57.4% reported having experienced any functional symptoms, and 47.9% reported having experienced functional motor or sensory symptoms. The symptoms reported were generally short-lived and caused only mild distress and disruption. Most respondents who reported having experienced a functional symptom reported having had multiple events through their lives. InterpretationThe results suggest that the lifetime occurrence of functional neurological symptoms is at least two orders of magnitude higher than the prevalence of FND. The high prevalence of functional symptoms in people who have never had FND challenges the common assumption that the occurrence of functional neurological symptoms is synonymous with FND. We propose that FND is better conceived of as a failure of the mechanisms by which functional neurological symptoms resolve, rather than the occurrence of functional symptoms per se. This reconceptualization implies new research directions for the underlying aetiology of FND.

ObjectiveA comparative analysis was conducted on the rehabilitation effects of limb functions in patients with post-stroke yawning-induced parakinesia brachialis oscitansysis (PBO), patients without PBO, and patients whose PBO naturally disappeared after the onset of the disease. MethodsThe study included ischemic stroke patients diagnosed and treated in our hospital from March 2024 to June 2024. Patients were divided into two groups: the PBO group and the non-PBO group, based on whether PBO was administered. Propensity score matching was employed to account for all covariates and perform a 1:2 matching to balance the baseline characteristics of the two groups. The matched data were used for subsequent analysis to observe the Lovett scores and FMA scores of the two groups 3 months after the onset. For 33 patients with PBO, they were divided into two groups: the persistent group and the disappearing group, based on whether the PBO lasted for more than 1 month. The Lovett scores and FMA scores of the two groups were observed 3 months after the onset. ResultsAfter propensity score matching, there were 26 patients in the PBO group and 52 patients in the non-PBO group. The baseline characteristics of the two groups were basically balanced, and the difference was not statistically significant (P>0.05). Compared with the non-PBO group, the Lovett scores and FMA scores of the PBO group 3 months after the onset were higher, and the difference was statistically significant (P < 0.05). Compared with the PBO persistent group, the FMA score of the PBO disappearing group 3 months after the onset was higher than that of the persistent group, and the difference was statistically significant (P < 0.05). There was no statistically significant difference in Lovett muscle strength between the two groups (P > 0.05). ConclusionThe functional recovery of patients with PBO was better than that of patients without PBO manifestation 3 months after the initial diagnosis. Moreover, patients whose PBO appeared first and then disappeared had better functional recovery than those whose PBO persisted.

BackgroundTandem lesion strokes (TLS), defined by the coexistence of an intracranial large- or medium-vessel occlusion and a concomitant cervical internal carotid artery (ICA) stenosis or occlusion, represent a challenging subtype of acute ischemic stroke. Optimal endovascular management remains controversial, particularly regarding the role of emergent carotid artery stenting (eCAS) during mechanical thrombectomy. ObjectiveTo compare the safety and efficacy of emergent carotid artery stenting versus mechanical thrombectomy alone in patients with anterior circulation tandem lesion strokes treated at a comprehensive stroke center. MethodsWe conducted a retrospective observational cohort study of consecutive adults with anterior circulation TLS treated with endovascular therapy within 24 hours of symptom onset between January 2015 and July 2025. Patients were categorized into two groups according to treatment strategy: eCAS performed during thrombectomy or mechanical thrombectomy alone (MTa). Primary efficacy outcomes were ordinal shift in 90-day modified Rankin Scale (mRS), excellent outcome (mRS 0-1), and functional independence (mRS 0-2). Secondary efficacy outcome was successful recanalization (TICI [&ge;]2b). Primary safety outcomes included symptomatic intracranial hemorrhage (sICH), in-hospital mortality, and 90-day mortality. ResultsA total of 111 patients were included (mean age 71.2 {+/-} 12.6 years; 68.5% male), of whom 74 (67%) underwent eCAS and 37 (33%) received MTa. Patients treated with eCAS achieved higher rates of successful recanalization (97.3% vs 78.4%; OR 13.26, 95% CI 2.13-82.49; p = .006) and excellent functional outcomes at 90 days (41.9% vs 12.5%; OR 6.80, 95% CI 1.35-34.20; p = .020). There were no significant differences between groups in rates of sICH, early neurological deterioration, or mortality. Ordinal logistic regression showed a non-significant trend toward better functional outcomes with eCAS. ConclusionsIn this single-center experience, emergent eCAS during mechanical thrombectomy for TLS was associated with higher reperfusion rates and improved functional outcomes without increased hemorrhagic risk or mortality. These findings support eCAS as a feasible and safe strategy in selected patients and highlight the need for prospective randomized trials.

Structured AbstractO_ST_ABSObjectiveC_ST_ABSWe represent primary headaches of the ICHD3 in matrix form and show that this representation allows for automated diagnosis as well as additional insights into headache classification. MethodsEach diagnosis in the ICHD3 is defined by a list of characteristics; combinations of characteristics form phenotypes. Multiple phenotypes may fit a given diagnosis. We first translated all characteristics for primary headache diagnoses in the ICHD3 into true/false statements. We generated a matrix of valid ICHD3 diagnosis as follows: O_LIEach row of the matrix represents a phenotype. C_LIO_LIEach column of the matrix represents a characteristic. C_LIO_LIIf any phenotype contains a characteristic, then that element is encoded as 1. Otherwise, it is encoded as 0. C_LI From this matrix, we calculated its bipartite projection and Markov cluster. We also row reduced to derive the basis vectors that span the space of all headache phenotypes. ResultsChronic migraine diagnoses as well as the characteristics "greater than 15 days per month" and "more than 3 months" have the strongest associations based on bipartite projection. Markov clustering yields 64 clusters. These clusters can be organized by ICHD3 diagnoses and demonstrates the level of fragmentation of individual diagnosis in the classification: Migraine is composed of 1 cluster, for example, whereas paroxysmal hemicrania can be broken down into 9 clusters. Finally, row reduction of our matrix yields 63 basis vectors, implying that all headache diagnoses in the ICHD3 can be represented as linear combinations of 63 characteristics. These 63 characteristics corresponds to the following: duration, frequency, aura characteristics, size/location, laterality, clearly remembered onset, TAC features, total number of episodes, severity, nausea/vomiting, photophobia, pulsating, alleviation by triptans, and association with awakening, sexual activity, physical activity, temperature, compression or traction, coughing. ConclusionOur result demonstrates that ICHD3 is a mathematical entity and that headache diagnoses exist in a 63-dimensional vector space. This mathematical embodiment of classification allows us to conduct 1) large scale systematic investigations of relationships between headache and phenotypes, 2) generate a graphical representation of characteristics and phenotypes and 3) improves diagnostic accuracy and efficiency.

BackgroundLarge middle cerebral artery (MCA) infarctions can result in life-threatening cerebral edema. Quantitative brain atrophy may improve risk stratification for severe edema. We examined whether quantitative brain atrophy is associated with severe midline shift after large ischemic stroke and whether incorporating atrophy improves prediction beyond established clinical and radiographic predictors. MethodsThis was a retrospective observational cohort study of patients with [&ge;][1/2] MCA ischemic infarction, presentation within 24 hours of last known well, and at least one follow-up head CT, admitted to two academic hospitals with comprehensive stroke centers between 2006 and 2024. The study was approved by the institutional review boards of both centers. Brain atrophy was quantified as the inverse of standardized brain volume on admission head CT. The primary outcome was severe radiographic mass effect, defined as midline shift [&ge;]5 mm on follow-up CT. The secondary outcome was in-hospital mortality. Multivariable regression models assessed associations between quantified atrophy and outcomes. Incremental prognostic value was evaluated by comparing models with and without atrophy using measures of goodness of fit, calibration, and discrimination. ResultsAmong 565 patients (mean age 67.5{+/-}15.7 years; 49.9% female), 223 (39.5%) developed severe mass effect. Greater atrophy was associated with lower odds of midline shift [&ge;]5 mm (OR 0.44, 95% CI 0.34-0.58), but not with in-hospital mortality. Incorporation of atrophy significantly improved prediction of severe mass effect compared to the baseline model (likelihood ratio test {chi}{superscript 2} (1) = 41, p <0.001; AIC 703 vs. 741; BIC 733 vs. 767; AUC 0.68 vs. 0.60). ConclusionsQuantified brain atrophy is independently associated with a reduced risk of severe mass effect after large MCA stroke and improved the performance of established predictive models. Incorporation of this imaging biomarker may enhance early risk stratification, monitoring, and intervention planning for patients at risk of life-threatening cerebral edema.

IntroductionThe 2024 McDonald criteria incorporate the central vein sign (CVS) and paramagnetic rim lesions (PRL) as supportive imaging biomarkers for MS diagnosis. While susceptibility-weighted-imaging (SWI) and T2*-weighted echo-planar-imaging (EPI) are generally used to assess CVS/PRL, their relative performance remains unclear. This study compared high-resolution isotropic-T2*-EPI with non-isotropic SWI for CVS/PRL detection. Materials and MethodsIn this multi-centre study, 21 patients with MS underwent harmonized 3T-MRI including EPI and SWI. CVS and PRL were evaluated according to NAIMS criteria. Whole-brain and controlled lesion analyses on 120 pre-selected lesions were performed independently for each contrast, with EPI serving as reference standard. ResultsIn whole-brain analyses, SWI showed good sensitivity for CVS eligibility and positivity (AC1=0.68-0.78) but significant directional disagreement with EPI (p<0.0001). Discrepancies were primarily attributed to limited lesion-parenchyma contrast and venous visibility on SWI, which improved using low-flip-angle SWI. Controlled lesion analyses supported these observations. For PRL, SWI demonstrated high sensitivity (88%) and precision (97%) compared to EPI, though systematic bias persisted (p<0.001). Controlled lesion analyses showed more balanced, albeit moderate performance. ConclusionSWI diverged systematically from EPI for CVS and PRL detection. When available, EPI should be preferred, while optimised low-flip-angle SWI may serve as an alternative to conventional SWI.

Background / ObjectivesWe investigated whether the interthalamic adhesion (IA), a midline structure connecting the thalami, is altered in MS and associated with thalamic damages and cognition. MethodsWe prospectively included 32 clinically isolated syndrome/early MS, 31 RRMS, 31 PPMS patients, and 103 matched controls. All underwent anatomical 3T MRI and completed a comprehensive cognitive battery. IA presence, subtype, and volume were assessed by two blinded readers. Thalamic nuclei and other brain structures were segmented automatically. We compared IA subtypes/volumes across groups, analyzed their predictors and explored cognitive associations with multivariate regressions. ResultsIA prevalence did not differ between MS and controls (81.9% vs 74.7%). MS patients showed a shift toward a short IA subtype and reduced IA volume (mean [SD], 146.8 [117.9] vs 230.2 [138.2] mm3; p<0.0001), worsening across phenotypes. Reduced IA volume was independently associated with medial and posterior thalamic nuclei volumes, but not with white matter lesion load or global atrophy. Among cognitive domains, smaller IA volume was independently associated only with executive dysfunction (OR = 0.89 [0.77-0.99], p = 0.021). ConclusionIA volume reduction in MS reflects vulnerability of adjacent thalamic nuclei and is associated with executive dysfunction, supporting IA as a marker of thalamic neurodegeneration. Trial RegistrationMICROSEP: NCT03692975; AUBACOG: NCT03768648; PROCOG: NCT03455582.

BackgroundShort-term neurobiological effects of opioids are well characterized, yet the long-term consequences of substance exposure on malignancy risk remain poorly understood. Ethical constraints limit prospective analysis of opioid exposure and primary malignant brain tumor (PMBT) risk in human patients, making large-scale electronic health record (EHR) analyses essential. This study evaluates the 10-year incidence of PMBTs among adults with opioid-abuse disorder related diagnoses exposed to either buprenorphine or naltrexone. MethodsWe conducted a retrospective cohort study using the Epic Cosmos EHR database. Cohorts were defined by exclusive exposure to buprenorphine or naltrexone, with a non-exposed comparator cohort. PMBT incidence within 1-120 months post-exposure was identified. Due to platform constraints, multivariable regression could not be performed; instead, confounding was addressed using Mantel-Haenszel stratification across age, sex, and race. ResultsThere was no significant difference in 10-year PMBT incidence between patients exposed exclusively to buprenorphine versus naltrexone (Mantel-Haenszel OR = 1.028, 95% CI 0.968-1.092; p = 0.381), however PMBT risk was lower for opioid disorder patients receiving either drug than for the control group. Sex-specific analyses suggested women exposed to naltrexone had significantly lower PMBT incidence relative to buprenorphine exposure (OR = 0.783, 95% CI 0.617-0.994; p = 0.044), whereas men showed a non-significant increase (OR = 1.211, 95% CI 0.939-1.564; p = 0.139). ConclusionsBuprenorphine and naltrexone were associated with comparable overall 10-year PMBT risk among adults with opioid-related diagnoses. The sex-specific interaction suggests naltrexone may be associated with reduced PMBT incidence in women, warranting further investigation. These findings contribute to the long-term neuro-oncologic safety profiles of opioid use disorder treatments. Key PointsBuprenorphine and naltrexone were associated with comparable 10-year risks of developing primary malignant brain tumors among adults with opioid-related diagnoses. A significant sex-specific interaction was observed, with naltrexone exposure linked to lower primary malignant brain tumor incidence in women, suggesting a potential effect modifier warranting further investigation. Both buprenorphine and naltrexone prescription in opioid use disorder patients are associated with reduced long-term tumor incidence compared to the unexposed cohort.

AbstractsO_ST_ABSBackgroundC_ST_ABSSelf-management is essential for stroke survivors to maintain a healthy lifestyle and reduce recurrence risk. Although theory-based self-management interventions are widely recommended, the theoretical frameworks underpinning them and their comparative effectiveness remain unclear. AimsTo systematically identify the theories, models, and frameworks (TMFs) used in self-management interventions for stroke survivors, to explore how they guide interventions, and evaluate their effectiveness on self-management behaviors and self-efficacy. MethodsPubMed, Embase, Web of Science, ProQuest Health & Medical Collection and the Cochrane Library were searched from inception to July 15, 2025. Randomized controlled trials or quasi-experimental studies evaluating theory-based self-management interventions for stroke survivors were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias (Cochrane RoB 2.0). Meta-analyses were performed using random-effects models. ResultsFrom 11,495 records, 32 studies with 3,212 participants were included. Sixteen distinct TMFs were identified; self-efficacy theory was most frequent (13/32), followed by social cognitive theory (6/32). All TMFs were middle-range theories. Meta-analysis showed TMFs-based interventions significantly improved self-management behaviors (SMD = 4.26, 95%CI: 0.20-8.31, I{superscript 2} = 98.2%) and self-efficacy (SMD = 0.60, 95%CI: 0.32-0.88, I{superscript 2} = 72.8%). However, the effect for behaviors is likely inflated due to extreme heterogeneity and theoretical diversity. Theory-specific analysis of self-efficacy theory (k = 8) confirmed significant effects on self-efficacy (SMD = 0.64, 95%CI: 0.21-1.08). ConclusionsThis review identified 16 distinct theoretical models; self-efficacy theory was most frequently applied, followed by social cognitive theory. Theory-based interventions significantly improved self-management behaviours and self-efficacy.

aStructured abstractO_ST_ABSBACKGROUNDC_ST_ABSOver the past couple of decades, the role of infections, as well as the involvement of the immune system, have been highlighted in the development of dementia. METHODData from the Wisconsin Registry for Alzheimers Prevention cohort were utilized for the analysis. A history of medical conditions was searched across the cohort, and known infections and autoimmune conditions were recorded for each participant. These conditions were then compared with the diagnosis and cognitive performances of each participant. Furthermore, plasma markers were analyzed using two different protein quantification methods. RESULTSOur analysis revealed poorer cognitive performances among participants with listed medical conditions. In plasma samples, Ab42/ICAM1 was identified as a protein ratio with significant variation across condition statuses. DISCUSSIONOur study confirmed that infections and autoimmune conditions contribute to cognitive decline. Ab42/ICAM1 was identified as a relevant marker.

ObjectivesTo validate whether cerebrospinal fluid oxyhaemoglobin (CSF-Hb), measured from external ventricular or lumbar drains, is associated with secondary brain injury (SAH-SBI) after aneurysmal subarachnoid haemorrhage (aSAH), and to assess its value as a real-time monitoring biomarker. DesignPreregistered multicentre prospective observational cohort study. SettingEight neurosurgical tertiary centres in Switzerland, Germany, and Austria, between August 2021 and June 2024. Participants366 patients with aSAH (mean age 58 years; 65% women). Of these, 260 provided cerebrospinal fluid (CSF) samples via external ventricular drain (EVD; 2,467 samples, median 10 days per patient) and 66 via lumbar drain (LD; 379 samples, median 6 days). InterventionsDaily CSF samples were collected via EVD or LD from day 1 to day 14 after haemorrhage; no therapeutic interventions were tested. Main outcome measuresCSF-Hb and its metabolites were analysed post hoc in a blinded manner. The primary outcome was SAH-SBI, defined as a composite of angiographic vasospasm (aVSP), delayed cerebral ischaemia (DCI), and delayed ischaemic neurological deficits (DIND), assessed daily over 14 days. Secondary outcomes included temporal CSF-Hb profiles and associations with aneurysm location, haematoma volume, intraventricular haemorrhage, chronic hydrocephalus, and 3-month functional outcome. ResultsCSF-Hb showed a delayed peak pattern: concentrations were low after aSAH, rose to a maximum on day 10 (EVD-derived CSF-Hb median 11.3 {micro}M, IQR 2.64 to 25.90), and then declined. Larger haematoma volume (p<0.001) and intraventricular haemorrhage (p<0.001) were associated with higher EVD-derived CSF-Hb. SAH-SBI occurred in 209/366 patients (57%). Daily EVD-derived CSF-Hb showed no association with SAH-SBI (p=0.25) and only poor prognostic potential of same-day SAH-SBI (area under the curve 0.59, 95% confidence interval 0.56-0.63), with substantial between-centre heterogeneity. The oxidised haemoglobin metabolite methaemoglobin was positively associated with SAH-SBI (p=0.023; odds ratio 1.18 per log[{micro}M], 95% confidence interval 1.02-1.36). Acute-phase EVD-derived CSF-Hb correlated with chronic hydrocephalus (p=0.012) and poor 3-month functional outcome (p=0.008). Catheter-related infection rates were low (2.2%). ConclusionsIn this preregistered multicentre validation study, EVD-derived CSF-Hb did not perform as a robust real-time monitoring biomarker for SAH-SBI, showing limited same-day discrimination and substantial between-centre heterogeneity. These findings argue against clinical implementation of CSF-Hb point-measurement as a single-parameter biomarker. In contrast, CSF methaemoglobin remained consistently associated with SAH-SBI, supporting the mechanistic relevance of haemolysis-related pathways. Future work using the HeMoVal biobank will apply multi-marker, pathway-level analyses to define haemolysis-related biomarker signatures and provide a platform for robust external validation of future candidates. Study registrationClinicalTrials.gov NCT04998370; date of registration 10 August 2021. Summary BoxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPreclinical animal models link cell-free haemoglobin in cerebrospinal fluid (CSF-Hb) to secondary brain injury after aneurysmal subarachnoid haemorrhage (SAH-SBI). C_LIO_LIA single-centre study reported strong associations between daily external ventricular drain (EVD) derived CSF-Hb levels and SAH-SBI, and suggested a strong predictive potential(area under the curve 0.89). C_LIO_LICSF-Hb monitoring has therefore been proposed as a bedside biomarker, but it has not undergone multicentre validation. C_LI What this study addsO_LIIn a preregistered multicentre cohort of 366 patients from eight neurosurgical centres, once-daily EVD-derived CSF-Hb measurements showed poor same-day discrimination for SAH-SBI (area under the curve 0.59) and substantial between-centre heterogeneity. C_LIO_LIIn contrast, CSF methaemoglobin was consistently associated with SAH-SBI, and higher acute-phase CSF-Hb was related to chronic hydrocephalus and worse 3-month functional outcome. C_LIO_LIThese findings argue against routine adoption of CSF-Hb point-measurements as bedside single-analyte, while supporting haemolysis-related pathways as mechanistic targets. C_LI

ImportanceElevated circulating low-density lipoprotein (LDL) cholesterol is associated with an increased risk of amyotrophic lateral sclerosis (ALS) onset. Previous studies have explored the relationship between statin use and ALS onset. However, findings have been inconsistent, potentially due to methodological limitations, such as confounding by indication, and failure to account for baseline differences in LDL cholesterol levels. ObjectiveTo compare the risk of ALS onset between new users of statins and ezetimibe among patients with hypercholesterolemia. DesignActive-comparator, new-user cohort study using inverse probability of treatment-weighted Cox proportional hazards models. The study period spanned April 2012 to February 2024. SettingTwo administrative claims databases in Japan. ParticipantsPatients with hypercholesterolemia who newly initiated statins or ezetimibe, and patients with dyslipidemia who newly initiated fibrates. All participants were required to have at least 365 days of baseline observation and no prior diagnosis of ALS. Exposure(s)Statin use compared with ezetimibe use. Fibrate use was assessed for benchmarking. Main Outcome(s) and Measure(s)The outcome was incident ALS, defined as a first definitive diagnosis of ALS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare ALS risk between statins and ezetimibe. ResultsThe study included 607,292 statin users (median [IQR] age, 61 [51-71] years; 51.4% male), 26,963 ezetimibe users (median [IQR] age, 59 [49-71] years; 50.1% male), and 114,871 fibrate users (median [IQR] age, 61 [51-71] years; 51.4% male). The incidence rate per 100,000 person-years of ALS was 6.8, 15.9, and 4.3, respectively. Statin use was associated with a lower hazard of ALS onset than ezetimibe use (adjusted HR [95% CI]: 0.42 [0.19-0.92]). The mean (SD) LDL cholesterol immediately prior to treatment initiation was 171.0 (28.6) mg/dL in the statin group and 162.8 (30.8) mg/dL in the ezetimibe group. After treatment, mean LDL cholesterol levels decreased to and stayed below 140 mg/dL in both groups. Conclusions and RelevanceThis study suggests that statins may lower the risk of ALS onset among patients with hypercholesterolemia. The mechanism underlying this association is not yet clear and may involve pathways beyond circulating LDL cholesterol reduction. Key pointsO_ST_ABSQuestionC_ST_ABSDoes statin use lower the risk of amyotrophic lateral sclerosis (ALS) onset among patients with hypercholesterolemia? FindingsIn this active-comparator, new-user cohort study of 607,292 statin users and 26,963 ezetimibe users with hypercholesterolemia, statin use was associated with a lower hazard of ALS onset compared with ezetimibe use. Prior to treatment initiation, mean LDL cholesterol levels were similar between statin and ezetimibe users. MeaningThese findings suggest that statins may lower the risk of ALS among patients with hypercholesterolemia.

PurposeMyasthenia gravis (MG) is a rare neuromuscular disease. In-person appointments in specialized centers are not readily available, especially on short notice. The purpose of this study was to analyze patient-specialist communication through a telemedical platform. MethodsIn a randomized controlled study 45 MG patients were observed over three months. The intervention group (N=30) was monitored via a mobile application ( app) that enabled chat function and assessed MG-specific outcome measures and data from external devices. We quantitatively evaluated communication patterns for patients and specialists from the chat. Controls (N=15) received standard of care. Perceived MG specialist accessibility and contact with physicians outside the study team regarding MG-related issues was assessed in both groups. FindingsIn total, MG specialists were contacted a median of six times per patient via the chat concerning medical (54.5%), technical (25.3%), organizational (19.1%), and other (1.1%) topics. Specialists initiated contact a median of eight times per patient, most frequently addressing medical concerns (49.4%), 38.4% of which were recommendations for medication changes. Specialists also addressed technical (40.0%), organizational (9.4%) and other (1.3%) issues. Contacts with physicians outside the study team did not differ significantly between groups. Perceived specialist accessibility was rated significantly higher with telemedical support by the intervention group. ConclusionsMG patients have a significant demand for timely advice especially concerning treatment recommendations. Future studies should evaluate the potential of telemedical solutions to prevent worsening of symptoms. Trial registrationThe study was registered under DRKS00029907 on August 19, 2022.