Journal of Neurology, Neurosurgery & Psychiatry

Background: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with no known cure. Disease progression in people living with ALS is heterogeneous, hindering personalized treatment development. The current gold standard for measuring disease progression in ALS, the ALS Functional Rating Scale - Revised (ALSFRS-R), is widely used but based on subjective measurements. Blood-based neurofilament light (NfL) has been studied as a diagnostic and prognostic biomarker but less information exists on its utility as a disease progression biomarker. Methods: We present results from blood draws of 300 participants in the FDA-funded Clinic-Based Multi-Site ALS Natural History and Biofluid study of the ALS Natural History Consortium (NHC). Plasma NfL levels were measured and analyzed against different disease progression metrics based on the ALSFRS-R. Results: NfL levels were found to be correlated with the ALSFRS-R average rate of change (r=-0.53, 95% CI -0.62 to -0.42). This association differed at a cutoff value of 61 pg/mL, with stronger correlations below this cutoff (r=-0.51 vs r=-0.18). Survival differed stratifying by this cutoff value, with participants under the cutoff having higher survival probabilities. The predictive value of NfL when predicting time to death was higher compared with the first ALSFRS-R across different event horizons. A model including both was better when predicting events up to 2 years after diagnosis. Conclusions: These results highlight the utility of NfL as a disease progression biomarker in ALS alongside ALSFRS-R based disease progression metrics. The cutoff value can aid in clinical trial stratification, pragmatic trial planning, and clinical care.

T-cell activation may be contributing to severe psychiatric disorders. Soluble CD27 (sCD27) - a marker for T-cell activation and disease activity in several autoimmune diseases - was evaluated as a tool for distinguishing T-cell activity in selected patients with severe psychiatric disorders, multiple sclerosis (MS), and controls. We hypothesise that elevated sCD27 levels will be associated with comorbid autoimmune disease (AID). sCD27 was measured in cerebrospinal fluid (CSF) and blood from a population enriched for suspected immunological comorbidity: the Immunopsychiatry Cohort (IP; n=115) and patients with MS (n=37), where levels in both groups were higher when compared with age matched controls undergoing surgery (n=154). Positive sCD27 (sCD27+), was defined as values >97.5% of controls. In IP, 23% were CSF-sCD27+ and 15% blood-sCD27+, compared to patients with MS where 88% were CSF-sCD27+ and 22% were blood-sCD27+. CSF-sCD27+ was confirmed as a sensitive marker for MS. In IP, CSF-sCD27+ was associated with comorbid AID (X2=4.847, p =0.028;) and AID disease activity (OR=5.14, p=0.029). Associations with AID were stronger when CSF and/or blood sCD27+ were combined (X2=8.559, p=0.003). CSF-sCD27+ in IP was also associated with pleocytosis, CSF-Total-tau, and CSF-NfL. In patients with severe psychiatric disorders, the sCD27+ cases were more likely to have comorbid AID and established markers for neuroinflammation in CSF. Combining analyses of CSF and blood improved sensitivity and specificity for AID suggesting compartmentalized T-cell activation. Psychiatric symptoms may precede somatic symptoms - or be the prominent symptom - of AID and sCD27 is a candidate marker for identification of this subgroup.

ImportanceFirst-episode psychosis (FEP) may result from a variety of secondary etiologies, making lumbar puncture (LP) for cerebrospinal fluid (CSF) investigations an important diagnostic consideration in this context. However, the lack of high-quality evidence on the prevalence of clinically-relevant CSF abnormalities hampers clinical consensus on when to pursue LP in FEP. ObjectiveDetermine a meta-analytic estimate of the prevalence of clinically-relevant CSF abnormalities in FEP. Data SourcesElectronic databases Ovid, Medline, Embase, PsychoINFO, and Web of Science were searched from inception to October, 2024. References of included articles were also screened. Study SelectionWe included studies that performed LP on a cohort of FEP and reported results of clinically available CSF analysis, enabling prevalence-estimates of abnormalities. Data Extraction and SynthesisData was extracted following PRISMA and MOOSE guidelines. Pooled prevalences were calculated by random-effects models. Moderators were tested using meta-regression analysis, and heterogeneity assessed by I2 index. Main Outcomes and MeasuresPrevalence of CSF abnormalities, focusing on clinically-relevant markers and number needed to assess (NNA). ResultsThirty-seven papers comprising 3,330 FEP patients who underwent LP were included, allowing calculation of prevalence-estimates for 12 CSF abnormalities. Of clinically-relevant abnormalities, the prevalence of CSF-restricted oligoclonal bands (OCB2) was 7.1% (95% CI 3.3-12.0, NNA 14), pleocytosis was 3.2% (95% CI 2.1-4.4, NNA 31) and anti-NMDAR antibodies was 2.3% (95% CI 0.1-6.4, NNA 43). Subgroup analysis showed that anti-neuronal antibodies were mainly detected in studies that selected patients with high suspicion of secondary causes and were low in studies which excluded patients with a high index of suspicion of a secondary cause, based on clinical and ancillary testing. OCBs and pleocytosis also had higher prevalence in the high-suspicion subgroup but were still detected at prevalence even in the low-suspicion subgroup. Conclusions and RelevanceThe meta-analytic estimate of the prevalence of the most common clinically relevant CSF abnormality was 7.1%, which is similar to the prevalence of finding any clinically-relevant radiologic abnormality with an MRI brain. Subgroup-analysis supports the usefulness of methods to estimate the pre-LP probability of clinically-relevant CSF abnormalities, albeit these methods are better applied for some abnormalities (CNS-reactive antibodies) than others (OCB2). Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of clinically actionable cerebrospinal fluid abnormalities in first-episode psychosis (FEP)? FindingsIn this systematic review and meta-analysis including 3330 patients with FEP who systematically received a lumbar puncture, at least 7.1% had a clinically-relevant abnormality detected in the cerebrospinal fluid; prevalence of oligoclonal bands was 7.1%, pleocytosis was 3.2%, anti-NMDAR antibodies were 2.3%, and other anti-neuronal antibodies were 0.4%. Subgroup-analysis identified association between prior suspicion of secondary causes and prevalence-estimates. MeaningLumbar puncture detects clinically-relevant abnormalities in FEP at a similar rate to brain MRI and may be especially informative when there is heightened suspicion for secondary psychosis.

BackgroundAdvanced cell therapeutics are emerging as potentially effective treatments for chronic neurological diseases, including secondary progressive multiple sclerosis (SPMS). Here we report the results of a phase I trial in which good manufacturing practice-grade foetal allogeneic human neural stem cells (hNSCs) were implanted via intracerebroventricular (ICV) injection in 15 individuals with active and non-active SPMS. MethodsThis is a phase I, open-label, multicentre, dose-escalation, international study. The primary objective was to assess the feasibility, safety, and tolerability of ICV injections of allogeneic hNSCs in patients affected by SPMS over a study follow up of 12 months. We also evaluated the number and type of adverse events (AEs) leading to a maximum tolerated dose, the general health status, and mortality. The secondary objectives were the therapeutic benefit of allogeneic hNSCs using assessment scales, magnetic resonance imaging (MRI), and laboratory and neurophysiologic parameters. FindingsFifteen unrelated SPMS patients were enrolled and treated between 2018 and 2020. The participants had a median age of 49.8 years. Their mean extended disability status scale (EDSS) at enrolment was 7.6, the mean disease duration was 22 years, and mean time from diagnosis to progression was 10.1 years. Neither treatment-related deaths nor serious AEs were reported during the study (1 year follow up after treatment). All the other AEs were classified as non-serious and were associated to non-study concomitant therapy or other medical conditions not connected to the experimental treatment. During the study, none of the participants worsened in the progression of their SPMS as shown by the evaluation scales implemented to assess their progress. Laboratory and neurophysiologic parameters showed no clinically significant variations. MRI follow-up showed non-clinically significant type 1, 2, and 3 changes. InterpretationThe intracerebroventricular injection of foetal allogeneic hNSCs in people with SPMS is feasible, tolerated and safe. Study participants displayed a substantial clinical stability during the 12-month follow-up. The absence of relevant adverse reactions (Ars) arising from the transplantation of hNSCs indicates a short-term neutral balance between benefits and risks and suggests a concrete, though perspective therapeutic possibility for SPMS patients. Further studies are needed to confirm and extend the findings herein and evaluate the actual therapeutic potential of advanced cell therapeutics for a condition where the lack of effective disease modifying therapies is a major unmet clinical need.

SOD1 is the second most mutated gene in European amyotrophic lateral sclerosis (ALS) patients, after C9orf72 expansion. Given the recent authorisation of SOD1-directed antisense oligonucleotide for use in SOD1-ALS patients, prompt screening for SOD1 mutations in ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS, with important implications for early therapeutic intervention in presymptomatic carriers. We analysed variants in the SOD1 gene within exome sequencing data from 470,000 individuals over 40 years old at the time of recruitment. We evaluated their pathogenic role using referenced databases and according to ACMG guidelines. Leveraging the carrier frequency in UKB and age at onset distribution data, we estimated the disease prevalence of SOD1-ALS. We identified 122 individuals with monoallelic SOD1 coding variants. 93.4% of them were asymptomatic at enrollment. In addition, the low penetrance disease allele p.Asp91Ala was observed in heterozygosis in 535 subjects, while it was never found in homozygosis. Based on this data, the expected number of people developing SOD1-ALS in the UK population, excluding the p.Asp91Ala allele, is 1.1:100,000, four times higher than the prevalence derived from clinical data. Incomplete and age-related penetrance and heterogeneous phenotypic expression likely account for the reduced number of symptomatic patients identified. Our findings highlight the need for systematic genetic screening in the general population, which could dramatically expand the pool of individuals who might benefit from novel molecular-silencing therapies presymptomatically. Given the existence of a therapeutic option, an in-depth follow-up of these subjects is highly recommended.

BackgroundDepression in Parkinsons disease (PD) is common, disabling and responds poorly to standard antidepressant medication. Motivational symptoms of depression, such as apathy and anhedonia, are particularly prevalent in depression in PD and predict poor response to antidepressant treatment. Loss of dopaminergic innervation of the striatum is associated with emergence of motivational symptoms in PD, and mood fluctuations correlate with dopamine availability. Accordingly, optimising dopaminergic treatment for PD can improve depressive symptoms, and dopamine agonists have shown promising effects in improving apathy. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. AimsWe hypothesised that there would be dissociable effects of dopaminergic medications on different depression symptom dimensions. We predicted that dopaminergic medication would specifically improve motivational symptoms, but not other symptoms, of depression. We also hypothesised that antidepressant effects of dopaminergic medications with mechanisms of action reliant on pre-synaptic dopamine neuron integrity would attenuate as pre-synaptic dopaminergic neurodegeneration progresses. MethodsWe analysed data from a longitudinal study of 412 newly diagnosed PD patients followed over five years in the Parkinsons Progression Markers Initiative cohort. Medication state for individual classes of Parkinsons medications was recorded annually. Previously validated "motivation" and "depression" dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging. ResultsLinear mixed-effects modelling was performed across all simultaneously acquired data points. Dopamine agonist use was associated with relatively fewer motivation symptoms as time progressed (interaction: {beta}=-0.07, 95%CI [-0.13,-0.01], p=0.015) but had no effect on the depression symptom dimension (p=0.6). In contrast, monoamine oxidase-B (MAO-B) inhibitor use was associated with relatively fewer depression symptoms across all years ({beta}=-0.41, 95%CI [-0.81,-0.01], p=0.047). No associations were observed between either depression or motivation symptoms and levodopa or amantadine use. There was a significant interaction between striatal DAT binding and MAO-B inhibitor use on motivation symptoms: MAO-B inhibitor use was associated with lower motivation symptoms in patients with higher striatal DAT binding (interaction: {beta}=-0.24, 95%CI [-0.43,-0.05], p=0.012). No other medication effects were moderated by striatal DAT binding measures. ConclusionsWe identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists may be effective for treatment of motivational symptoms of depression. In contrast, MAO-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect appears to be attenuated in patients with more severe striatal dopaminergic neurodegeneration, which may be a consequence of dependence on pre-synaptic dopaminergic neuron integrity.

ImportanceMultiple sclerosis (MS) is an immune-mediated neurological disorder that affects 2.4 million people world-wide, and up to 60% experience anxiety. ObjectiveWe investigated how anxiety in MS is associated with white matter lesion burden in the uncinate fasciculus (UF). DesignRetrospective case-control study of participants who received research-quality 3-tesla (3T) neuroimaging as part of MS clinical care from 2010-2018. Analyses were performed from June 1st to September 30th, 2024. SettingSingle-center academic medical specialty MS clinic. ParticipantsParticipants were identified from the electronic medical record. All participants were diagnosed by an MS specialist and completed research-quality MRI at 3T. After excluding participants with poor image quality, 372 were stratified into three groups which were balanced for age and sex: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). ExposureAnxiety diagnosis and anxiolytic medication. Main Outcome and MeasureWe first evaluated whether MS+severeA patients had greater lesion burden in the UF than MS+noA. Next, we examined whether increasing anxiety severity was associated with greater UF lesion burden. Generalized additive models were employed, with the burden of lesions (e.g. proportion of fascicle impacted) within the UF as the outcome measure and sex and spline of age as covariates. ResultsUF burden was higher in MS+severeA as compared to MS+noA (T=2.02, P=0.045, Cohens f2=0.19). A dose-response effect was also found, where higher mean UF burden was associated with higher anxiety severity (T=2.08, P=0.038, Cohens f2=0.10). Conclusions and RelevanceWe demonstrate that overall lesion burden in UF was associated with the presence and severity of anxiety in patients with MS. Future studies linking white matter lesion burden in UF with treatment prognosis are warranted. KEY POINTSO_ST_ABSQuestionC_ST_ABSAre white matter lesions that impact the uncinate fasciculus (UF) associated with anxiety in patients with multiple sclerosis (MS)? FindingsThis retrospective, case-control study of 372 patients with MS included 3 anxiety severity groups: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). We identified associations between anxiety and UF lesion burden. Specifically, we showed that MS+severeA had higher UF lesion burden than MS+noA, and worsening anxiety severity increased with greater UF burden. MeaningLesion burden in the UF may contribute to anxiety comorbidity in MS.

BackgroundMotivational symptoms such as apathy and anhedonia are common in Parkinsons disease, respond poorly to treatment, and have been hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in Parkinsons disease, but the association has never been examined longitudinally. We investigated whether the progression of dopaminergic neurodegeneration was associated with emergent apathy and anhedonia symptoms in Parkinsons disease. MethodsLongitudinal cohort study of 412 newly diagnosed Parkinsons disease patients followed over five years as part of the Parkinsons Progression Markers Initiative (PPMI) cohort. Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item geriatric depression scale (GDS-15) and part I of the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS). Dopaminergic neurodegeneration was measured using repeated ioflupane [123-I] single photon emission computed tomography imaging of striatal dopamine transporters (DAT). ResultsLinear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio(SBR) and apathy/anhedonia symptoms, which emerged as Parkinsons disease progressed (interaction: {beta}=-0.09, 95%CI[-0.15 -0.03], p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average two years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) ({beta}=-0.06, 95%CI[-0.13 0.01]) or motor symptoms indexed by the MDS-UPDRS part III ({beta}=0.20, 95%CI[-0.25 0.65]). ConclusionThe relationship between the progression of dopaminergic neurodegeneration and emergent apathy/anhedonia symptoms supports a central role for dopaminergic dysfunction in motivational symptoms in Parkinsons disease. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.

BackgroundDefinitive diagnosis of amyotrophic lateral sclerosis (ALS) is only possible through a postmortem examination. Extracellular vesicles (EVs) have emerged as promising minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. MethodsFollowing PRISMA guidelines, we searched PubMed and EMBASE from inception to October 15, 2025. Thirty-nine studies met inclusion criteria. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. ResultsEV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in ALS vs. controls (SMD = 1.30) with high heterogeneity (I{superscript 2} = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. ConclusionsEV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. Standardized protocols, transparent data sharing, and independent validation are needed.

BackgroundAutoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). MethodsClinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. ResultsOf the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0% vs 34.9%, p = 0.008), whereas involuntary movements were significantly less prevalent (31.3% vs 69.8%, p = 0.007), among anti-gAChR antibody-positive compared with - negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. ConclusionsAn autoimmune mechanism mediated by anti-gAChR antibodies may be involved in the etiology of FNSD/CD in a subgroup of patients.

IntroductionAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. MethodsStudy AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional, open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). ResultsAmong 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population) and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. ConclusionsMasitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinibs effect on pro-inflammatory microglia may help identify responsive patients.

BackgroundSpontaneous intracerebral haemorrhage (ICH) has high rates of death and disability, and no proven haemostatic treatment. Tranexamic acid might limit haematoma expansion and improve outcomes. We conducted the first individual patient data meta-analysis to evaluate the effect of tranexamic acid on functional outcomes in spontaneous ICH. MethodsThis systematic review and individual patient data meta-analysis included randomised controlled trials comparing intravenous tranexamic acid to placebo in adults with spontaneous ICH treated within 12 hours of onset. MEDLINE, EMBASE, CENTRAL, Web of Science, and WHO ICTRP were searched to November 2024. The primary outcome was functional status at 90 days after randomisation, measured by the modified Rankin Scale. Adverse events (seizures, thromboembolic events) were also summarised. Analyses used generalised linear mixed models with random intercepts for trial. Risk of bias was assessed using the Cochrane RoB 2 tool. The study was registered with PROSPERO (CRD42022345775). ResultsWe identified 1,131 records; nine trials (3,194 participants) were eligible for inclusion and five trials (2860 participants; 90% of those available) provided individual patient data for the primary analysis. Risk of bias was low across all included trials. At 90 days, 757/1423 (53.2%) patients assigned to tranexamic acid had a worse functional outcome compared with 759/1415 (53.6%) assigned to placebo, the difference was not statistically significant (adjusted common odds ratio 0.93 (95% CI 0.81 to 1.07; p = 0.30). Serious adverse events were similar between the groups, with no significant differences observed. There was no evidence of between-trial heterogeneity based on model fit (likelihood ratio test). DiscussionCompleted clinical trials provide no evidence that tranexamic acid improves functional outcome after spontaneous ICH. However, given the reduction in hematoma expansion and early mortality it remains to be seen if this translates to improved functional outcome in larger ongoing clinical trials. Even a small beneficial effect could have potential for global impact given the burden of ICH. FundingNo funding source.

BackgroundWe report our experience of patients with generalised MG (gMG) treated with Efgartigimod, an FcN antagonist, under the Early Access to Medicine Scheme (EAMS) in the UK. MethodsData from all UK patients treated with Efgartigimod under the EAMS June 22-July 23 were collected retrospectively. Efgartigimod was administered as per the ADAPT protocol (consisting of a treatment cycle of 4 infusions at weekly intervals with further cycles given according to clinical need). Results48 patients with AChR antibody-positive gMG were treated in 12 centres. Most (75%) were female and most had a disease duration of over 10 years. The average MG-ADL score at baseline was 11.2. Most (72.9%) patients had undergone thymectomy. 77.0% were taking prednisolone at baseline. All patients had utilized non-steroidal immunosuppressant treatments, the average number tried was 2.6 (range 1-6). 51% had received Rituximab. 54.2% of patients required regular IVIg/PLEX. 75% of patients had a mean reduction in the MG-ADL of [&ge;]2 points in the first cycle and this remained stable throughout the study. The mean intracycle reduction in the MG-ADL score in the 1st, 2nd, 3rd and 4th cycles were -4.6, -3.9, -3.4 and -4.2 respectively. Side effects were generally mild though one patient stopped treatment due to severe hypokalemia. No rescue treatments were required. At the end of the study, 96% of patients remained on Efgartigimod. ConclusionEfgartigimod is a safe and effective treatment for patients with refractory, treatment-resistant gMG.

Persistent neurological symptoms are among the most disabling manifestations of post-COVID-19 syndrome (PCS), yet the contribution of ongoing CNS immune activation remains uncertain. CSF studies including clinically relevant COVID-19 recovered control cohorts are scarce. In this prospective single-center study, we enrolled 50 patients fulfilling the WHO criteria for PCS (COVIDpost, mean age +/- standard deviation [SD] 43.41 +/- 11.99 years, 30 % male, 70 % female) and 50 individuals who had fully recovered from COVID-19 (COVIDreco, mean age +/- SD 39.38 +/- 13.45, 42 % male, 58 % female). Both cohorts were comparable regarding age (p = 0.07), sex (p = 0.30), and education (p = 0.84). All participants underwent paired CSF and serum analyses together with comprehensive neuropsychological assessment. Routine CSF parameters, blood-CSF barrier integrity, oligoclonal bands (OCB), SARS-CoV-2 RNA in CSF and blood, pathogen-specific antibody indices, and neuronal autoantibodies were investigated. Despite marked differences in cognitive performance (p < 0.001) and fatigue severity (p < 0.001), patients with PCS showed no evidence of disease-specific CSF abnormalities compared to recovered controls. Routine CSF parameters, blood-CSF barrier dysfunction, CSF-restricted OCB, SARS-CoV-2 RNA in CSF and blood, intrathecal SARS-CoV-2 antibody synthesis, polyspecific antiviral immune responses, and neuronal autoantibodies were comparable between groups. SARS-CoV-2-specific IgG concentrations in CSF correlated positively with serum concentrations (COVIDpost: r [95%CI] = 0.78 [0.62 - 0.87]; COVIDreco: r [95%CI] = 0.86 [0.75 - 0.92]; both p < 0.001) and albumin quotient (COVIDpost: r [95%CI] = 0.52 [0.26 - 0.71], p < 0.001; COVIDreco: r [95%CI] = 0.37 [0.10 - 0.60]; p = 0.01), consistent with passive transfer across the blood-CSF barrier rather than compartmentalized intrathecal immune activation. Furthermore, SARS-CoV-2-specific antibody measures were not associated with cognitive performance (p > 0.72) or fatigue severity (p > 0.88). This study provides no evidence that persistent neurological symptoms after COVID-19 are accompanied by ongoing adaptive CNS immune activation, disease-specific neuronal autoimmunity, or intrathecal SARS-CoV-2-specific humoral immune responses. The inclusion of a carefully phenotyped COVID-19 recovered comparison cohort strengthens the conclusion that routine CSF abnormalities largely do not seem to reflect mechanisms specific to PCS. These findings argue against routine CSF diagnostics as a source of disease-specific biomarkers in unselected PCS patients and support future studies focusing on alternative mechanisms underlying persistent neurological symptoms.

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

BackgroundAccumulating studies have suggested associations between peripheral inflammation and neurodegenerative disorders, including Parkinsons disease (PD). ObjectiveTo evaluate the causal associations between 91 plasma inflammatory proteins and 4 neurodegenerative disorders. MethodsTwo-sample Mendelian randomization studies were performed using summary statistics extracted from genome-wide association studies of 91 plasma inflammatory proteins and 4 neurodegenerative disorders. ResultsGenetically proxied tumor necrosis factor receptor superfamily member 9 levels were causally associated with reduced risk of PD (odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.74-0.92, p = 4.18 x 10-4, Bonferroni-corrected p < 0.05 for 91 proteins). Additionally, we identified potential causal associations between the levels of C-C motif chemokine 20 (OR = 1.14, 95%CI = 1.03-1.25, p = 1.29 x 10-2) and Alzheimers disease, between levels of leukemia inhibitory factor receptor (OR = 0.91, 95%CI = 0.84-0.98, p = 1.12 x 10-2) and tumor necrosis factor-{beta} (OR = 0.95, 95%CI = 0.93-0.98, p = 1.01 x 10-3) and amyotrophic lateral sclerosis, between levels of adenosine deaminase (OR = 0.81, 95%CI = 0.71-0.94, p = 5.14 x 10-3) and interleukin-18 (OR = 0.81, 95%CI = 0.69-0.96, p = 1.68 x 10-2) and multiple sclerosis. ConclusionsOur study unveils plausible causal associations between circulating inflammatory factors and risk of 4 neurodegenerative disorders. These findings hold promise for promoting risk assessment and prevention of neurodegenerative disorders, meriting further exploration.

Multiple sclerosis is a heterogeneous disease with an unpredictable course. We applied machine learning to generate individualised risk scores of disability worsening and stratify patients into subgroups with different prognosis. Clinical data and MRI scans from published randomised clinical trials in patients with relapsing-remitting and progressive MS were divided into training (n=5,483) and external validation data sets (n=2,668). We processed brain MRI scans to obtain 18 measures for lobar grey matter, deep grey matter and lesion volumes, and T1-/T2-weighted ratio of the normal-appearing white matter regions. We developed a machine learning model, called subpopulation risk stratification (SunRiSe), that combines multi-parametric clinical and MRI data to estimate individualised risk scores and stratify patients into subgroups on the basis of this risk; in particular, we entered MRI measures, the Expanded Disability Status Scale, age and gender to generate risk scores of disability worsening (i.e., the time to confirmed disability worsening). Based on SunRiSe risk scores, high-, medium-, and low-risk subpopulations were defined at study entry. We assessed whether selecting patients at high risk of disability worsening reduces sample size compared to when all risk groups were sampled together. In both the training and external validation data sets, SunRiSe-stratified patients in three groups associated with different levels of risk of disability worsening. In the external validation data set, patients at high risk were mainly progressive MS and had more disability events compared to those at medium-risk (hazard ratio [HR]=1.34, p<0.0001) and low-risk (HR=1.51, p<0.0001). At study entry, male gender, older age, higher lesion load, higher disability, lower lobar cortical grey matter, lower normal-appearing white matter T1/T2 ratio and lower deep grey matter volumes, were the most important variables in defining the SunRiSe risk score. The inclusion of patients predicted to be at high risk, reduced (i) duration of an event-driven trial by an average of 4.5 months ({+/-}2.1 months); (ii) the number of participants in a randomised trial by approximately 200, with 80% statistical power to detect a 30% treatment effect. Machine learning provides a personalised risk score that can identify patients who have the greatest risk of disability worsening and therefore should be treated with the most effective medications and monitored more closely. Risk stratification allows the enrichment of clinical trials with patients more likely to worsen, and thereby reduces trial duration and sample size.

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

ObjectiveMotor neuron disease (MND) is a debilitating neurodegenerative disease with profound unmet need. In pre-symptomatic mutation carriers, elevations in neurofilament light (NfL) precede symptom onset, however, the presence and timing of elevation is much more difficult to study in sporadic cases. MethodsUsing the UK Biobank cohort, we tested whether plasma NfL predicted risk of diagnosis of sporadic MND using survival analysis. ResultsWe identified 241 MND patients with pre-diagnosis NfL data, of which 203 (84%) lacked predicted loss of function or deleterious missense variants in established ALS genes. A total of 42,752 controls without MND were obtained from a random sample of UK Biobank participants. At two years pre-diagnosis, we found that NfL levels in patients exceeded the 95th percentile of controls and that patients could be discriminated from controls at high accuracy (AUC = 0.95 (95% CI 0.89-1.01)). In participants with hospital record follow-up after study enrollment, a 2-fold increase in NfL levels was associated with a 3.4 fold risk of receiving an MND diagnosis per year (95% CI 2.9-3.9, P = 4 x 10-64)). DiscussionOur findings show that NfL can identify sporadic MND as early as 2 years prior to diagnosis.

Background: Neurofilament light chain (NfL) gained FDA recognition in amyotrophic lateral sclerosis (ALS) through SIMOA-based validation, where baseline serum NfL predicts ALSFRS-R slope and survival, and through the 2023 tofersen approval for SOD1-ALS. The commercial Roche Elecsys electrochemiluminescence immunoassay (ECLIA) reads 6- to 8-fold lower than SIMOA, and its clinical utility in ALS is uncharacterized. We assessed whether ECLIA NfL retains this correlation in routine care and whether GFAP or S-100B helps. Methods: Retrospective analysis of 58 chart-confirmed ALS patients at Georgetown University Hospital (2022-2026), biomarkers on the LabCorp Roche Elecsys ECLIA. The NfL-ALSFRS-R correlation was assessed where both measures fell within matching windows; serial NfL, in patients with repeat draws. Results: First-per-patient NfL median was 7.06 pg/mL (IQR 4.06-17.30; CV 99%). Among 31 patients with matched NfL and ALSFRS-R decline rates, Spearman r = 0.704; within 90 days (n = 17), r = 0.809 (both p < 0.0001). Fast progressors (n = 8) had mean NfL 17.10 pg/mL versus 4.64 in slow progressors (n = 21), a 3.7-fold separation. Serial NfL captured rising trajectories and stable low values. GFAP rose within patients but tracked neither progression rate, disease stage, nor motor-neuron predominance; S-100B added no value. Conclusions: Commercial ECLIA brings NfL into routine ALS care; its prognostic correlation with progression rate survives real-world fragmentation. The actionable unit is the longitudinal trajectory, not the single value, read against platform-specific reference ranges and clinical context (genotype, onset, stage). GFAP and S-100B add little. Keywords: amyotrophic lateral sclerosis, neurofilament light chain, biomarkers, implementation science, ECLIA, GFAP, monitoring, tofersen, real-world data