Journal of Neurology

Nusinersen was the first disease modifying treatment approved for 5q spinal muscular atrophy (SMA). Long-term results of broad populations, particularly for adolescents and adults, remain limited. We conducted a population-based, ambispective observational study of all SMA patients living in the Valencian Community (Spain) between September 2017 and December 2022 and follow-up until December 2025. Demographic, clinical and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. The risk for nusinersen discontinuation was assessed with a Bayesian model, and SMA-FCR trajectories with mixed linear regression. Of 72 patients included, 18 were <12 years old (all treated with nusinersen) and 54 were [&ge;]12 years (28 treated; 26 untreated) at the baseline visit. After a median of 7 years, all patients <12 years were classified as responders versus 68% of patients [&ge;]12 years. Discontinuation rates were 11% in children compared to75% in the older cohort. In patients [&ge;]12 years, reasons for discontinuation included: treatment burden (71%), and loss(53%) or lack of benefit (43 %). Lower baseline SMA-FCR (expEstimate= 0.84 [0.718,0.93], prob:1) and older age (expEstimate=1.028 [1.011,1.055], prob:1) independently predicted higher discontinuation risk. Sustained nusinersen treatment was independently associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration over time. In this long-term population-based study, nusinersen use and persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy. However, a proportion of adolescents and adults (those younger and with higher baseline function) experienced sustained benefit.

Central Post Stroke Pain (CPSP) is a common, debilitating sequela of stroke that can occur within weeks to months after stroke onset, yet mechanistic insight and predictive biomarkers are lacking. To address this gap, we longitudinally studied patients with acute somatosensory stroke using structural and functional magnetic resonance imaging and assessed them for subsequent pain development. In the acute stage, patients who later developed CPSP had reduced grey matter concentration (GMC) in bilateral caudate nuclei and nuclei accumbens (NAc) and reduced functional connectivity from the contralesional caudate to the supplementary motor area (SMA) compared to those who remained pain-free. Reduced GMC of the contralesional caudate and reduced functional connectivity to SMA persisted after pain onset, furthermore, NAc exhibited reduced functional connectivity to bilateral sensorimotor cortices and SMA. Our findings provide evidence for neural changes that may predispose stroke patients to develop CPSP and point towards potential targets for pain prevention.

Late-onset Tay-Sachs (LOTS) disease and late-onset Sandhoff disease (LOSD) have long been considered indistinguishable due to similar clinical presentations and shared biochemical deficits. However, recent magnetic resonance imaging (MRI) studies have shown distinct cerebellar atrophy associated with LOTS. In this study, we furthered this investigation to determine if the cerebellar atrophy is globally uniform or preferentially targets certain cerebellar regions. We utilized DeepCERES, a deep learning cerebellar specific segmentation and cortical thickness pipeline to analyze differences between LOTS (n=20), LOSD (n=5), and neurotypical controls (n=1038). LOTS had smaller volumes of the whole cerebellum as well as cerebellar lobules IV, V, VI, VIIB, VIIIA, VIIIB, IX, and both Crus I and II compared to both LOSD and neurotypical controls. LOTS patients also had smaller cortical thickness of cerebellar lobules V, VI, VIIB, VIIIA, VIIIB, and both Crus I and II compared to both LOSD and neurotypical controls. Cerebellar functional and lesion localization studies have implicated lobules V and VI in speech articulation and execution while lobules VI, Crus I, VIIA, among others, have been implicated in a variety of behaviors and neuropsychiatric symptoms. Our observations provide a possible anatomical substrate to the higher prevalence of dysarthria and psychosis in our LOTS but not LOSD patients. Future studies are needed for direct comparisons considering phenotypic aspects such as age of symptom onset, presence and severity of dysarthria and ataxia, full characterization of neuropsychiatric profiles, molecular pathology and biochemical differences to fully understand the dichotomy observed in these two diseases.

ObjectiveTo describe the safety and efficacy of risdiplam in non-sitter adult patients with 5q spinal muscular atrophy (SMA). MethodsType 2 SMA adult patients, who were not eligible for nusinersen, were offered risdiplam through the expanded access program. Patients were followed up with a battery of scales and clinical measures. ResultsSix non-sitter patients (17 - 46 years old) were treated with risdiplam. One patient reported mild adverse events (dyspepsia and headache). After one year of treatment, all patients showed clinically meaningful improvements in at least one scale and none of them showed any clinically meaningful deterioration. Two patients showed a clinically significant increase in the body mass index and other two in the revised upper limb module. Moreover, clinically meaningful improvements were found in motor (axial and upper limbs), bulbar (speech and swallowing) and respiratory (coughing) domains of functional scales, in five patients. Four subjects achieved at least one of the goals set with the goal attainment scale (GAS). DiscussionThis series suggests the safety and efficacy of risdiplam in non-sitter adult SMA patients. In these patients, functional scales and GAS are more appropriate than motor scales to detect changes, because they include axial, bulbar and respiratory domains.

Background and ObjectiveGM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are rare, inherited neurodegenerative disorders with no available symptomatic or disease modifying treatments. This clinical trial aimed to investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms of pediatric ([&ge;] 6 years) and adult patients with GM2 gangliosidosis. Methods\We conducted an 8-center, multi-national, open-label, rater-blinded Phase IIb study (IB1001-201). Patients with a genetically confirmed diagnosis of GM2 gangliosidosis were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients [&ge;]13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar rating scales (namely Scale for the Assessment and Rating of Ataxia), clinical global impression, and quality of life assessments. Results30 patients aged 6 to 55 years with a confirmed diagnosis of GM2 gangliosidosis (Tay-Sachs or Sandhoffs disease) were enrolled. 29 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.044), as well as secondary endpoints. No treatment-related serious adverse events occurred. ConclusionsThis study showed NALL led to a statistically significant improvement in symptoms, functioning, and quality of life in patients with GM2 gangliosidosis. It is a safe, well-tolerated, easily administered oral therapy, therefore offering a favorable risk/benefit profile for this serious, debilitating disorder. NALL is a new therapeutic option for the treatment of this rare disease that has no other approved therapies worldwide. Classification of EvidenceThis study provides Class IV evidence NALL is safe, well-tolerated, and improves neurological symptoms and quality of life in patients with GM2 gangliosidosis. Trial Registration InformationThe trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

Post-stroke depression (PSD) represents one of the most prevalent psychiatric complications after stroke, affecting up to one-third of survivors, and it can substantially influence both the extent of functional impairments and the recovery trajectory. A reciprocal relationship between depressive symptoms and cognitive dysfunction in this population has been commonly demonstrated, underscoring the need to clarify their intercorrelation and shared neuroanatomical underpinnings. To address this a combined cognitive dysfunction linked to PSD and imaging study, a total of 125 unilateral stroke patients were classified into two groups based on the presence of depressive symptoms using a BDI cutoff score of 14. Using principal component analysis (PCA) on 16 cognitive test variables from 64 patients with PSD and 61 without PSD, four principal components of cognitive function were extracted. Among these, the attention factor showed a significant group difference, with the PSD group exhibiting greater attentional impairments than the non-PSD group. Voxel-based lesion-symptom mapping (VLSM) further revealed that attentional performance was significantly associated with lesions in the left insula across groups. Importantly, the lesion clusters were more extensive in patients with PSD, suggesting a more pronounced role of insular damage in depressive symptomatology following stroke. Taken together, these findings highlight the pivotal contribution of the insula to both attentional processing and the pathophysiology of PSD, suggesting that the insula mediates attentional networks closely linked to depressive symptoms in stroke survivors.

BackgroundIn this genome wide association study (GWAS) we aimed to discover single nucleotide polymorphisms (SNPs) associated with motor recovery post-stroke. MethodsWe used the Vitamin Intervention for Stroke Prevention (VISP) dataset of 2,100 genotyped patients with non-disabling stroke. Of these, 488 patients had motor impairment at enrollment. Genotyped data underwent strict quality control and imputation. The GWAS utilized logistic regression models with generalized estimating equations (GEE) to leverage the repeated NIH Stroke Scale (NIHSS) motor score measurements spanning 6 time points over 24 months. The primary outcome was a decrease in the motor drift score of [&ge;] 1 vs. < 1 at each timepoint. Our model estimated the odds ratio of motor improvement for each SNP after adjusting for age, sex, race, days from stroke to visit, initial motor score, VISP treatment arm, and principal components. ResultsAlthough no associations reached genome-wide significance (p < 5 x 10-8), our analysis detected 115 suggestive associations (p < 5 x 10-6). Notably, we found multiple SNP clusters near genes with plausible neuronal repair biology mechanisms. The CLDN23 gene had the most convincing association which affects blood-brain barrier integrity, neurodevelopment, and immune cell transmigration. ConclusionWe identified novel suggestive genetic associations with the first ever motor-specific post stroke recovery GWAS. The results seem to describe a distinct stroke recovery phenotype compared to prior genetic stroke outcome studies that use outcome measures, like the mRS. Replication and further mechanistic investigation are warranted. Additionally, this study demonstrated a proof-of-principle approach to optimize statistical efficiency with longitudinal datasets for genetic discovery.

The clinical status and treatment response of patients with peripheral neuropathies (PN) rely on subjective and inaccurate clinical scales. Wearable sensors have shown success in evaluating gait and balance in individuals with other neurological disorders. We aimed to explore the ability of biomechanical analysis via wearable technology to monitor disease activity in PN by conducting a single-center, longitudinal study to analyze gait parameters in PN patients and healthy controls using wearable sensors. First, we analyzed the sensors ability to detect changes in ataxia and steppage gait severity and found significant differences in spatiotemporal and angular variables. Second, we found correlations between biomechanical features and clinical scales linked to specific gait phenotypes. Finally, we demonstrated that this technology captures clinical changes in gait features over time. Our study provides proof-of-concept that wearable technology effectively detects and grades gait impairment, captures clinically relevant changes, and could enhance gait assessment in routine care and research for PN patients.

BackgroundWith treatment trials on the horizon, this study aimed to identify candidate digital-motor gait outcomes for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), capturable by wearable sensors with multi-center validity, and ideally also ecological validity during free walking outside laboratory settings. MethodsCross-sectional multi-center study (4 centers), with gait assessments in 36 subjects (18 ARSACS patients; 18 controls) using three body-worn sensors (Opal, APDM) in laboratory settings and free walking in public space. Sensor gait measures were analyzed for discriminative validity from controls, and for convergent (i.e. clinical and patient-relevance) validity by correlations with SPRSmobility (primary outcome) and SARA, SPRS and FARS-ADL (exploratory outcomes). ResultsOf 30 hypothesis-based digital gait measures, 14 measures discriminated ARSACS patients from controls with large effect sizes (|Cliffs {delta}| > 0.8) in laboratory settings, with strongest discrimination by measures of spatiotemporal variability Lateral Step Deviation ({delta}=0.98), SPcmp ({delta}=0.94) and Swing CV ({delta}=0.93). Large correlations with the SPRSmobility were observed for Swing CV (Spearmans {rho} = 0.84), Speed ({rho}=-0.63) and Harmonic Ratio V ({rho}=-0.62). During supervised free walking in public space, 11/30 gait measures discriminated ARSACS from controls with large effect sizes. Large correlations with SPRSmobility were here observed for Swing CV ({rho}=0.78) and Speed ({rho}=-0.69), without reductions in effect sizes compared to lab settings. ConclusionWe identified a promising set of digital-motor candidate gait outcomes for ARSACS, applicable in multi-center settings, correlating with patient-relevant health aspects, and with high validity also outside lab settings, thus simulating real-life walking with higher ecological validity.

BackgroundGiven the increasing diversity among neurological patients, standardized protocols are essential for evaluating the severity and complexity of the variety of conditions. Aim of the present work was to standardize the assessment of the severity and complexity of neurological impairment in an acute setting by using a modified version of the Neurological Impairment Scale (mNIS). Methodsconsecutively hospitalized neurological inpatients underwent a multidimensional standardized assessment of multimorbidity, frailty, functional dependency, and neurological impairment using mNIS and other validated scales. Inter-rater reliability of the mNIS total and sub-scores was evaluated. Construct validity was assessed separately in patients with Cerebrovascular disease performing correlations between corresponding sub-scores of mNIS, original NIS, and National Institutes of Health Stroke Scale (NIHSS). mNIS Complexity Index (mNIS-CI) for neurological severity was used to classify patients into subtle, mild, moderate, and severe impairment. Resultsone thousand eighty-one neurological patients admitted to a neurological ward from the emergency setting were enrolled. The inter-rater reliability was remarkable for mNIS total and sub-scores (ICC 0.90, 95% CI 0.82-0.95). The mNIS showed strong construct validity for total and sub-scores compared to other clinical scales (r 0.47-0.97, p<0.001) and 52.7% of patients scored at least one in one of the four newly listed items. The stratification of patients according to mNIS-CI exhibited high construct validity distinguishing the extent of impairment and involved domains. ConclusionsThe mNIS is valuable for measuring neurologic severity and complexity in acute inpatients and holds significant potential for application in different settings. What is already known on this topicStandardization of neurological assessment and development of functional rating scales of global impairment are pivotal to characterize and follow up patients both in the clinical practice and in the research setting. What this study addsmNIS is a valuable tool to measure neurologic severity and complexity in acute inpatients: the four added items are useful for capturing a broader spectrum of signs and symptoms; the severity and complexity scores provide different information about neurological status and domain imapired at individual level. How this study might affect research, practice, or policymNIS can be instrumental in grading the severity of neurological conditions, tracking clinical progress, and gauging response to treatments in the acute setting.

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.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by profound fatigue, cognitive impairment, autonomic dysfunction, and exertional intolerance with strongly impaired physical functioning. Hyperbaric oxygen therapy (HBOT) has been proposed as a potential treatment, but its effects on ME/CFS patients remain largely unexplored. This study aimed to evaluate the effectiveness and feasibility of HBOT in ME/CFS patients and to investigate its effects on functional brain changes. Methods: 30 ME/CFS patients (mean age: 42{middle dot}3 {+/-} 11{middle dot}7 years; seven males, 23 females) received 40 HBOT sessions each. Outcomes were assessed at baseline, during treatment, and four weeks post-treatment. The primary outcome was change in the Physical Functioning subscale of the Short Form-36 Health Survey (SF-36 PF). Secondary outcomes included severity of core symptoms assessed via questionnaires, exercise capacity, handgrip strength, cognitive per-formance, orthostatic intolerance, and brain MRI (volumetry and functional connectivity, (FC)). Thirty age- and sex-matched healthy controls (HCs) (mean age: 42{middle dot}3 {+/-} 11{middle dot}3 years; seven males, 23 females) were included for MRI comparison. Findings: In the linear mixed model, SF-36 PF significantly improved during HBOT compared with baseline (g = 0.71, p = 0.006). SF36 pain (p = 0{middle dot}002, g = 0{middle dot}79) and CFQ fatigue showed clinically meaningful reductions (p < 0{middle dot}001, g = - 0{middle dot}87) during HBOT. Exercise capacity (g = 0{middle dot}66), muscle strength (g = 0{middle dot}40), and information processing speed (g = 0{middle dot}52), all improved significantly after HBOT compared to baseline (all p < 0{middle dot}05). Treatment adherence was high, and tolerability was favorable, with no major side effects reported. Functional MRI analyses revealed increased thalamic FC in ME/CFS patients compared to HCs in bilateral sensorimotor (p < 0{middle dot}001, t = 5{middle dot}65, FDR-corrected) and visuo-occipital regions (p < 0{middle dot}001, t = 5{middle dot}4, FDR-corrected) at baseline. After HBOT, thalamic hyperconnectivity normalized. Responders (defined as a [&ge;] 10 point increase in SF-36 PF) showed greater reductions in thalamic hyperconnectivity than non-responders (p < 0{middle dot}001, t = - 4{middle dot}34 to -5{middle dot}18, FDR-corrected). Interpretation: HBOT was well-tolerated and was associated with significant improvements in physical functioning, fatigue, pain, and cognitive performance and provides the rationale for a controlled trial in ME/CFS to confirm thera-peutic efficacy. The normalization of thalamic hyperconnectivity following HBOT and its association with clinical re-sponse highlights the role of thalamic FC in ME/CFS pathophysiology and underscores the need for larger, controlled trials in ME/CFS to confirm therapeutic efficacy.

BackgroundEpileptic seizures (SZ) and postictal neurological deficits are common stroke mimics that challenge acute clinical decision-making, especially in emergency settings with limited diagnostic resources. MRI or EEG is often unavailable at initial presentation. We aimed to determine whether routinely available serum lactate levels could distinguish SZ from stroke based on information accessible immediately on hospital arrival. MethodsWe retrospectively reviewed 22,430 consecutive emergency department visits and analyzed 637 patients transferred by ambulance with suspected neurologic emergencies identified via keyword screening at the regional emergency call center. All patients underwent venous blood gas analysis and non-contrast CT on arrival. We evaluated whether serum lactate and other routine laboratory variables (pH, actual base excess, glucose, WBC count, platelet count, and PT-INR) correlated with final neurological diagnoses. Classification and Regression Tree (CART) analysis was used to identify cutoffs predictive of SZ. ResultsAge, pH, lactate, and actual base excess were significantly associated with final diagnoses. Lactate levels were significantly higher in SZ and subarachnoid hemorrhage groups than in other groups. For distinguishing SZ from ischemic stroke (infarction and TIA), CART analysis yielded a serum lactate cutoff of 4.05 mmol/L. Among patients with lactate [&ge;]4.05 mmol/L and age <59.5 years, SZ probability was 100%. A four-quadrant model combining lactate and age stratified SZ probabilities from 9.1% to 100%. The area under the ROC curve for lactate in distinguishing SZ from stroke was 0.800. ConclusionsSerum lactate, when assessed upon emergency department arrival, may contribute significantly to differentiating seizures from acute ischemic stroke. A simple decision model using only lactate and age may aid in diagnostic stratification in neurologic emergencies--even in resource-limited settings where advanced imaging or EEG is not readily available. RegistrationNone.

Background and Objectives Patients with peripheral neuropathies (PN) commonly exhibit balance impairment. In clinical practice, balance is typically assessed using the Rombergs test and ataxia scales, which rely on examiner interpretation, while objective biomarkers for quantifying balance remain lacking. Wearable sensors are valuable tools for objectively quantifying gait abnormalities in PN patients and may capture clinically meaningful changes over time. By integrating these parameters, artificial intelligence (AI) can assist in generating a digital score that enables easy, objective, and reproducible monitoring of patients postural balance. This study aims to generate and assess an AI-generated digital Rombergs test to quantify balance impairments in a cohort of PN patients. Methods PN patients were assessed in a longitudinal study using a wearable system composed of inertial sensors placed on the trunk and plantar pressure sensors integrated in insoles. Patients performed the Rombergs test under both eyes-open and eyes-closed conditions and were classified according to ataxia severity (mild, moderate, or severe) following the score obtained in item 1 of MICARS and SARA scales. Results We included 97 patients with PN (including autoimmune and hereditary polyneuropathies), and 117 healthy controls (HC). Significant differences in trunk sway and center of pressure (COP) were observed between groups, particularly with eyes closed. Using wearable sensor parameters, we developed an AI digital Rombergs test, which correlated with clinician-rated Rombergs test performance and distinguished patients with and without ataxia (AUC=0.632) and across different PN pathologies. Longitudinally, digital Rombergs test and iRODS showed concordant trajectories. Also, changes [&ge;]25% in the score were associated with clinical changes in ataxia severity measured by an increase in MICARS-SARA score (+1.42 points), whereas improvement was associated with a decrease (-0.20 points) in the scale. Discussion This study demonstrates that wearable sensors are useful to detect and quantify balance impairment. The AI-generated Rombergs test is an objective and reproducible tool for postural balance assessment, with robust discriminatory performance across clinical ataxia severity in PN. Scores longitudinal changes aligned with clinical severity, supporting its potential for monitoring disease progression and treatment response. Its strong association with balance measures reinforces its role as a quantitative biomarker of postural control in ataxia patients.

ObjectiveThis study examined whether the timing of targeted add-on therapy initiation influences clinical outcomes in acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG), based on the hypothesis that earlier escalation may improve treatment response by intervening before structural or immunological consolidation occurs. MethodsIn this multicenter, retrospective real-world cohort study, 153 patients with AChR antibody-positive gMG were included from eight German tertiary centers. All received either complement C5 inhibitors (eculizumab, ravulizumab) or the FcRn antagonist efgartigimod as add-on therapy. Patients were grouped by treatment initiation within 24 months of diagnosis (Early Intensified Treatment; EIT) or later (Late Intensified Treatment; LIT). MG-ADL, QMG, and MG-QoL15 scores, as well as daily corticosteroid and pyridostigmine doses, were assessed at baseline and at 1, 3, and 6 months. ResultsThe EIT group (n = 36) showed more pronounced and consistent clinical improvement. Significant differences emerged in maximum MG-ADL (p{square}={square}0.013) and QMG (p{square}={square}0.002) reductions. Patient-acceptable symptom states (MG-ADL [&le;]{square}2, QMG [&le;]{square}7) were more often reached with EIT (p{square}={square}0.038, p{square}={square}0.006). QMG worsening occurred only in the LIT group (n = 117) (p{square}={square}0.021). Prednisone declined more steeply in EIT patients (p{square}={square}0.001), alongside a trend toward reduced pyridostigmine use. InterpretationInitiating add-on therapy within two years of diagnosis was associated with stronger and more consistent clinical responses, fewer deteriorations, and a steeper reduction of treatment burden. These findings support timely escalation as a strategy to enhance both efficacy and tolerability in gMG care. Summary for Social Media If PublishedO_ST_ABSWhat is the current knowledge on the topic?C_ST_ABSComplement and FcRn inhibitors have demonstrated efficacy in patients with AChR antibody-positive generalized myasthenia gravis (gMG) and are approved as add-on therapies in treatment-refractory disease. However, data guiding the optimal timing for their initiation in the treatment course remain limited. What question did this study address?This study investigated whether earlier initiation of add-on therapy improves clinical outcomes in AChR antibody-positive gMG. It compared patients escalated within 24 months of diagnosis to those treated later. What does this study add to our knowledge?Earlier treatment escalation was associated with significantly greater clinical improvements in MG-ADL and QMG scores, fewer symptom deteriorations, and steeper reductions in corticosteroid and pyridostigmine use, suggesting a potential benefit of timely intervention. How might this potentially impact the practice of neurology?The results support consideration of earlier escalation in the gMG treatment pathway. They may prompt re-evaluation of current stepwise approaches in favor of more proactive strategies. Suggested social media postEarlier add-on therapy in AChR+ gMG linked to better outcomes and lower treatment burden - real-world data suggest a benefit from timely escalation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/25340299v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@16fb592org.highwire.dtl.DTLVardef@f9997eorg.highwire.dtl.DTLVardef@cc52fcorg.highwire.dtl.DTLVardef@5c3e99_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Impact of Early Versus Late Initiation of Targeted Therapy in AChR-Positive Generalized Myasthenia Gravis. This graphical abstract illustrates the design and main findings of a multicenter, retrospective cohort study conducted across eight specialized MG centers in Germany. The study included 153 patients with acetylcholine receptor antibody-positive (AChR) generalized myasthenia gravis who received targeted add-on treatment with complement inhibitors (C5-I; eculizumab or ravulizumab) or an FcRn inhibitor (FcRn-I; efgartigimod). Participants were stratified based on the timing of escalation: those who initiated treatment within 24 months of diagnosis (Early Intensified Treatment; EIT) and those who escalated later (Late Intensified Treatment; LIT). Clinical outcomes were assessed using MG-ADL and QMG scores over a six-month period. Patients in the EIT group demonstrated more robust improvements in both functional and strength-based measures, with higher rates of clinically meaningful response and symptom resolution. The data support the notion that earlier introduction of targeted therapies may enhance treatment efficacy and improve patient outcomes in real-world settings. This figure was created with BioRender.com. C_FIG

Withdrawal StatementThe authors have withdrawn this manuscript because of updates to the original manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Semantic cognition allows us to represent, process and manipulate verbal and nonverbal knowledge about the surrounding environment. Semantic cognition plays a critical role in language, communication and many nonverbal behaviours and can be disrupted by several neurological diseases, including stroke and dementias. Therefore for clinical practice, it is essential to evaluate semantic cognition and to do so using culturally-appropriate assessments (given that some facets of semantic knowledge and associations are culturally-specific). Here, we developed and standardized a new verbal and nonverbal semantic assessment, called semantic knowledge test (SKT), for Korean-speaking populations. The SKT was developed and standardized on a large and demographically diverse sample of 325 healthy adults, confirming its high reliability and validity. To explore its clinical utility and added value, we collected data from 101 post-stroke patients alongside the Western Aphasia Battery (WAB). We run a principal component analysis (PCA) using SKT and WAB scores and Voxel-based lesion-symptom mapping (VLSM) using the factor loadings that yielded from the PCA. The principal component analysis (PCA) of behavioural test scores produced two distinctive factors, one with the WAB scores and the other with the SKT scores. VLSM revealed that the neuroanatomical correlates of the WAB factor covered the peri-Sylvian areas, while that of SKT was in the left superior anterior temporal lobe (ATL) and posterior middle temporal gyrus (pMTG). These findings underscore the utility of the SKT in uncovering both behavioural and neuroanatomical facets of semantic cognition that are not captured by the traditional language batteries such as the WAB and emphasize the importance of independent assessment of semantic deficits in clinical populations.

Tracking disease progression and treatment effect of spinal bulbar muscular atrophy, or Kennedys disease, is challenging given its slowly progressive nature. To achieve success in SBMA clinical trials, a reliable, responsive, and validated patient-reported motor function scale must capture progression of SBMA-specific motor dysfunction. Here, we conducted a systematic review, meta-analysis, and appraisal of core measurement properties of the SBMA functional rating scale (SBMAFRS). We established that the SBMAFRS has satisfactory internal consistency, inter-rater reliability, and construct validity for measuring progressive motor dysfunction over similar neurodegenerative motor function scales but inadequate sensitivity to change over time. Further development to validate and improve the SBMAFRS ability to capture longitudinal responsiveness in larger cohorts is warranted.

We report a case of acute myelitis in a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A 66-year-old man with coronavirus disease 2019 was admitted with acute flaccid paralysis of the bilateral lower limbs and urinary and bowel incontinence. All serum microbiological test results were negative, except for SARS-CoV-2 nucleic acid testing. Clinical findings indicated post-infectious acute myelitis. He received treatment containing ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, human immunoglobulin, and mecobalamin. With a diagnosis of post-infectious acute myelitis and comprehensive treatment, paralysis of the bilateral lower extremities ameliorated. After two negative novel coronavirus RNA nasopharyngeal swab tests, he was discharged and transferred to a designated hospital for isolation and rehabilitation therapy.

Background: Clinical evidence on the contemporary management and functional outcomes of patients with Wernicke encephalopathy remains limited. This study aimed to clarify the nationwide patterns of thiamine administration and functional outcomes at discharge. Methods: Using the Japanese nationwide inpatient Diagnosis Procedure Combination database, we identified patients hospitalized with Wernicke encephalopathy between July 2010 and March 2024. Initial intravenous thiamine doses were categorized as low ([&le;]300 mg/day), medium (301-900 mg/day), or high (>900 mg/day). Outcomes included in-hospital mortality and functional status (Barthel Index) at discharge. Results: We identified 7856 patients with Wernicke encephalopathy. Over the 13-year study period, the proportion of patients receiving initial high-dose thiamine increased markedly from 5.4% to 49.0%, while the frequency of low-dose therapy decreased from 83.0% to 37.9%. Despite prompt intervention [median time to initial administration: 0 days (interquartile range, 0 to 0 days)], 56.1% of patients were discharged with impaired activities of daily living (Barthel Index <90), and the in-hospital mortality rate was 3.8%. Conclusions: High-dose thiamine treatment is increasingly implemented for Wernicke encephalopathy in Japan. Although in-hospital mortality was relatively low, the high prevalence of functional impairment at discharge, despite early treatment initiation, indicates substantial burden of Wernicke encephalopathy. Given the limited clinical evidence, further research investigating the optimal thiamine dose and develop effective primary prevention strategies for Wernicke encephalopathy is needed.