Journal of Neurology, Neurosurgery & Psychiatry

BackgroundAmyotrophic lateral sclerosis (ALS), also known as Lou Gehri[g]s disease, is a rare neurological disease and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics. Patients and MethodsThis prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB(R) (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB(R) administered. All evaluable patients were analysed in a modified intention-to-treat analysis. EudraCT number. 2018-000668-28 FindingsBetween 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB(R) and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB(R) treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB(R) injection. InterpretationLong-term weekly ILB(R) injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

ObjectiveIdentify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development. MethodsProspective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs) 1. Neurofilament assays were performed in a blinded manner by independent contract research organizations (CROs). ResultsFor serum NfL and pNfH measured using the Simoa assay, missing data (i.e. both technical replicates below the lower limit of detection (LLD) was not encountered. For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in [~]4% and [~]10% of serum samples respectively. Mean coefficients of variation (CVs) for pNfH in serum and CSF were [~]4-5% and [~]2-3% respectively in all assays. Baseline NfL concentration, but not pNfH, predicted the future ALSFRS-R slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of [~]8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, have potential utility as pharmacodynamic biomarkers of treatment effect.

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.

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.

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.

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 [≥]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.

ObjectiveTo study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barre syndrome (GBS). MethodsWe measured NfL using SiMoA in serum (98 samples) and CSF (24 samples) of GBS patients prospectively included in the International GBS Outcome Study (IGOS) in Spain and compared them with controls (HC). We performed multivariable regression to analyze the association between sNfL levels and functional outcome at one year. ResultsGBS patients had higher NfL levels than HC in serum (55.49pg/mL vs 9.13pg/mL, p<0,0001) and CSF (1308.5pg/mL vs 440.24pg/mL, p=0.034). Patients with preceding diarrhea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90pg/mL vs 47.86pg/mL vs 38.02pg/mL, p=0.016). sNfL levels correlated with GDS and R-ODS scales. Patients with pure motor variant and Miller- Fisher syndrome showed higher sNfL levels than patients with sensory-motor GBS (162.18pg/mL vs 95.50pg/mL vs 38.02pg/mL; p=0.025). AMAN patients had higher sNfL levels than other variants (190.55pg/mL vs 46.79pg/mL, p=0.013). sNfL returned to normal levels at one year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14-2.40, p=0.009) and lower R-ODS ({beta} -2.60, 95% {beta} -4.66-(-0.54), p=0.014) at one year. Cut-off points predicting clinically relevant outcomes at one year with high specificity were calculated: inability to walk independently (>319pg/mL), inability to run (>248pg/mL) and ability to run (<34pg/mL). ConclusionBaseline sNfL levels are increased in patients with GBS, they are associated with disease severity and axonal variants and they have an independent prognostic value in GBS patients.

ObjectiveOcrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval. MethodsInternet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600mg treatment cycles (week 0-72), followed by an 18 month treatment-free period. ResultsCD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events. ConclusionsOcrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression. Further studies are now clearly required to determine whether this data is robust, as few people seemed to complete the study.

Acute malignant catatonia with autonomic instability developed in a previously healthy man with PCR-verified SARS-CoV-2. CT and MRI were normal, EEG showed slowing and cerebrospinal fluid showed a subtle indication of inflammation. There were no signs of pathology in other organs. 18F-FDG-PET conveyed high bilateral uptake in the striatum. While commercial tests were negative, immunohistochemical staining of mouse brain revealed anti-neuronal IgG antibodies against neuronal targets in the hippocampus, thalamus, striatum and cortex. Early treatment with plasmapheresis and corticosteroid reversed disease progression and may have prevented large-scale neurological damage. We are not aware of other types of encephalitis with such distinct pyramidal tract symptoms and raise the possibility that this may be a novel form of autoimmune encephalitis induced by infection with SARS-CoV-2.

Background and ObjectivePeople with multiple sclerosis (pwMS) receiving B cell-depleting therapies have impaired antibody responses to vaccination. In a proportion of individuals, repeat vaccination against COVID-19 leads to seroconversion. We sought to describe the immune phenotype of pwMS on ocrelizumab, and identify clinical and immunological determinants of an effective vaccine response. MethodsThis was a single-centre, prospective cohort study. Peripheral blood samples were collected from pwMS receiving ocrelizumab (n = 38) pre and post administration of a third dose of mRNA COVID-19 vaccine. Immunogenicity was measured by T cell IFN{gamma} ELISpot, antibody titres, and live virus neutralisation. Humoral immunity was benchmarked against pwMS receiving natalizumab (n = 15), and against a correlate of real-world protection (50% reduction in incidence of infection) from SARS-CoV-2 ancestral and omicron BA.5 variants. The peripheral immune phenotype was comprehensively assessed by flow cytometry, and potential clinical and phenotypic determinants of response to vaccination identified. ResultsImmune cell populations relevant to disease and vaccine response were altered in pwMS receiving ocrelizumab versus natalizumab treatment, including depleted CD20-expressing B cell, T cell and NK cell populations, and elevated CD27+CD38+ T cell and NK8 cell frequencies. Following a third vaccine dose, 51% of pwMS on ocrelizumab were seropositive for SARS-CoV-2 receptor-binding-domain IgG, and 25% and 14% met the threshold for effective neutralisation of live SARS-CoV-2 ancestral and omicron BA.5 virus, respectively. B cell frequency at the time of vaccination, but not time since ocrelizumab infusion, was positively correlated with antibody response, while a strong negative correlation was observed between CD56bright NK cell frequency and antibody response in the ocrelizumab group. In this exploratory cohort, CD3-CD20+ B cells (% of lymphocytes; OR=3.92) and CD56bright NK cells (% of NK cells; OR=0.94) were predictive of an effective neutralising antibody response in second dose non-responders (AUC: 0.98). DiscussionOcrelizumab treatment was associated with an altered immune phenotype, including recently described T cell and NK populations with potential roles in disease pathogenesis. However, seroconversion was severely impaired by ocrelizumab, and less than half of those who seroconverted following a third vaccine dose demonstrated effective immunity against SARS-CoV-2 ancestral or omicron BA.5. B cell frequency was associated with an effective antibody response, while immunomodulatory CD56bright NK cells were identified as a potential negative determinant of response in those with inadequate B cell numbers. Immune phenotype rather than time since ocrelizumab infusion may help to stratify individuals for prophylaxis.

A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post mortem frozen and formalin-fixed paraffin embedded specimens from human sporadic ALS/MND and control cases using the nCounter(R) Neuroinflammation Panel. Archival data were re-analysed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord, motor cortex, and regions across the brain and validate changes found at during transcriptomic analyses. In the spinal cord, marked inflammation was observed while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted TREM2, TYROBP, APOE, and CD163 as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity, and involvement of TREM2, ApoE (encoded by APOE) and TYROBP was confirmed, suggesting the involvement of the disease-associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the APOE haplotype and ALS/MND risk, age of onset and survival. We confirm associations between APOE {varepsilon}4 and a more aggressive disease; and between {varepsilon}2 and a less severe disease phenotype. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.

ImportanceSeveral preclinical and clinical investigations have argued for nervous system involvement in SARS-CoV-2 infection. Some sparse case reports have described various forms of encephalitis in COVID-19 disease, but very few data have focused on clinical presentations, clinical course, response to treatment and outcomes yet. Objectiveto describe the clinical phenotype, laboratory and neuroimaging findings of encephalitis associated with SARS-CoV-2 infection, their relationship with respiratory function and inflammatory parameters and their clinical course and response to treatment. DesignThe ENCOVID multicentre study was carried out in 13 centres in northern Italy between February 20th and May 31st, 2020. Only patients with altered mental status and at least two supportive criteria for encephalitis with full infectious screening, CSF, EEG, MRI data and a confirmed diagnosis of SARS-CoV-2 infection were included. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment and outcomes were recorded. ResultsOut of 45 cases screened, twenty-five cases of encephalitis positive for SARS-CoV-2 infection with full available data were included. The most common symptoms at onset were delirium (68%), aphasia/dysarthria (24%) and seizures (24%). CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by RT-PCR resulted negative. Based on MRI, cases were classified as ADEM (n=3), limbic encephalitis (LE, n=2), encephalitis with normal imaging (n=13) and encephalitis with MRI alterations (n=7). ADEM and LE cases showed a delayed onset compared to the other encephalitis (p=0.001) and were associated with previous more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to other encephalitis. Conclusions and relevanceWe found a wide clinical spectrum of encephalitis associated with COVID19 infection, underlying different pathophysiological mechanisms. Response to treatment and final outcome strongly depended on specific CNS-manifestations. Questionwhat are the phenotypes of encephalitis associated to SARS-CoV-2 infection? Findings25 cases of encephalitis in SARS-CoV-2 infection were included in a prospective observational multi-centre study. Encephalitis cases in COVID-19 exhibited a wide heterogeneity in terms of clinical features, CSF, MRI findings, response to treatment and outcomes with 13 cases with normal MRI, 7 with heterogeneous MRI alterations and rarer ADEM/limbic encephalitis cases. Meaningheterogeneity of presentation, response to treatment and outcomes of encephalitis of COVID-19 underlines different pathophysiological mechanisms

Background and ObjectivesVarious peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown. ResultsIn an observational study, we studied 23 patients (92% female; median age 40years) reporting new neuropathic symptoms beginning within 1 month after SARS-CoV-2 vaccination. 100% reported sensory symptoms comprising severe face and/or limb paresthesias, and 61% had orthostasis, heat intolerance and palpitations. Autonomic testing in 12 identified seven with reduced distal sweat production and six with positional orthostatic tachycardia syndrome. Among 16 with lower-leg skin biopsies, 31% had diagnostic/subthreshold epidermal neurite densities ([&le;]5%), 13% were borderline (5.01-10%) and 19% showed abnormal axonal swelling. Biopsies from randomly selected five patients that were evaluated for immune complexes showed deposition of complement C4d in endothelial cells. Electrodiagnostic test results were normal in 94% (16/17). Together, 52% (12/23) of patients had objective evidence of small-fiber peripheral neuropathy. 58% patients (7/12) treated with oral corticosteroids had complete or near-complete improvement after two weeks as compared to 9% (1/11) of patients who did not receive immunotherapy having full recovery at 12 weeks. At 5-9 months post-symptom onset, 3 non-recovering patients received intravenous immunoglobulin with symptom resolution within two weeks. ConclusionsThis observational study suggests that a variety of neuropathic symptoms may manifest after SARS-CoV-2 vaccinations and in some patients might be an immune-mediated process.

BackgroundDisorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12-18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment. MethodsThis retrospective, multicenter, tertiary care cohort study conducted from 2014 to 2025 evaluated archived biofluids from patients with IM, known autoimmune myelitis, or other neurological diseases (ONDs). Proteome-wide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF). ResultsAutoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 out of 32 IM patients (56%) in a discovery cohort. Bioactive B12 concentration was decreased in the CSF of anti-CD320 positive patients compared to OND controls (P = 0.0273), indicative of autoimmune B12 central deficiency (ABCD). Compared to anti-CD320 negative IM cases, anti-CD320 positive IM cases demonstrated a higher frequency of subacute time course (56% vs 7%, P = 0.008), normal CSF profile (83% vs 50%, P = 0.044), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (MRI) (61% vs 7%, P = 0.003). In two independent validation cohorts comprising 94 and 25 patients with IM, anti-CD320 was detected in 43 (46%) and 12 (48%) patients, respectively. Comorbid anti-CD320 was detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five anti-CD320 positive IM patients received B12 supplementation with or without concurrent immunosuppression, and four out of five clinically improved. ConclusionsABCD is associated with a substantial proportion of IM. Screening for anti-CD320 followed by metabolic confirmation of a CNS-restricted B12 deficiency may be considered in the diagnostic evaluation of myelopathy.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregates in motor neurons. Present and earlier proteomic studies to characterize peptides in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target the low molecular weight proteins and peptides. We generated the hypothesis that specific changes in CSF peptides or low molecular weight proteins are significantly changed in ALS, and that these changes may support deciphering molecular pathophysiology and even guide approaches towards therapeutic interventions. MethodsCerebrospinal fluid (CSF) from 50 ALS patients and 50 non-ALS controls was collected, centrifuged immediately after collection, aliquoted into polypropylene test tubes, frozen within 30-40 min after the puncture and stored at -80{degrees}C until use. Peptides were sequenced using capillary electrophoresis or liquid chromatography / mass spectrometry (CE-MS/MS or LC-MS/MS) analyses. FindingsIn cerebrospinal CSF from 50 patients and 50 non-ALS controls 33 peptides were found, of which 14 could be sequenced using a non-lytic single pot proteomic detection method, CE/MS. ALS deregulated peptides vs. controls included Integral membrane protein 2B, Neurosecretory protein VGF, Osteopontin, Neuroendocrine protein 7B2 (Secretogranin-V), EGF-containing fibulin-like extracellular matrix protein 1, Xylosyltransferase 1 XT-1, Chromogranin-A, Superoxide dismutase SOD-1, Secretogranin-1 (Chromogranin B), NR2F2 Nuclear Receptor Subfamily 2 Group F Member 2 and Collagen alpha-1(VII) chain. InterpretationMost striking deregulations in CSF from ALS patients were found in VGF, Osteopontin, SOD-1 and EFEMP1 peptides. No associations of disease severity, duration and region of onset with sequenced peptides were found. Declarations of InterestS. Petri received honoraria as speaker/consultant from Biogen GmbH, Roche, Novartis, Teva, Cytokinetics Inc., Desitin, Italfarmaco, Ferrer, Amylyx, and Zambon; and grants from DGM e.V, Federal Ministry of Education and Research, German Israeli Foundation for Scientific Research and Development, EU Joint Program for Neurodegenerative Disease Research. J. Beige received funding from GSK and German Federal Ministries of Research and Health. FundingThere was no funding to the presented investigation Ethical ApprovalThis study was approved by the ethics committee of Hannover Medical School. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki. Key words: ALS, CSF, proteomics, biomarker, peptidomics, peptide deregulation

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

ObjectiveIn addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). We test the hypotheses that baseline in vivo assessments of regional neuroinflammation ([11C]PK11195 PET), tau pathology ([18F]AV-1451 PET), and atrophy (structural MRI) predict disease progression. MethodsSeventeen patients with PSP-Richardsons syndrome underwent a baseline multi-modal imaging assessment. Disease severity was measured at baseline and serially up to 4 years with the PSP-rating-scale (average interval 5 months). Regional grey-matter volumes and PET ligand binding potentials were summarised by three Principal Component Analyses (PCAs). A linear mixed effects model was applied to the longitudinal PSP-rating-scale scores. Single-modality imaging predictors were regressed against the individuals estimated rate of progression to identify the prognostic value of baseline imaging markers. ResultsThe PCA factors reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSP-rating-scale. PCA-derived PET markers of neuroinflammation and tau pathology correlated with brain atrophy in the same regions. However, MRI markers of brain atrophy alone did not predict clinical progression. ConclusionsMolecular imaging with PET can predict clinical progression in PSP. These data encourage the evaluation of immunomodulatory approaches to disease-modifying therapies in PSP, and the potential for PET to stratify patients for early phase clinical trials.

Background and ObjectivesBiomarkers that are informative with regards to the degree of demyelination associated with disease activity in multiple sclerosis may aid in prognostication and treatment considerations. Protein components of myelin, such as myelin oligodendrocyte glycoprotein (MOG), are potential biomarkers of demyelination, but questions remain about the significance and usefulness of blood MOG protein levels in multiple sclerosis. We examined blood MOG protein levels to determine the extent to which MOG levels are associated with the diagnosis and disease activity of multiple sclerosis. MethodsIn a case-control study, MOG protein levels were compared in serum samples from individuals with multiple sclerosis and controls. Cerebrospinal fluid (CSF) MOG protein levels were measured in a subset of the cases. Serum neurofilament light chain (NfL) levels were also measured for comparison. ResultsSerum MOG protein levels were higher in individuals with multiple sclerosis than those of healthy donors and non-inflammatory neurological controls. ROC curve analysis indicated good discrimination between multiple sclerosis and controls based on serum MOG protein levels. Correlation between serum and CSF MOG protein levels was moderate. Higher MOG protein levels were associated with clinical disease activity in multiple sclerosis and incrementally added to information provided by serum NfL levels. There was a moderate correlation between serum MOG and serum NfL levels. DiscussionMOG protein levels are elevated in the blood of individuals with multiple sclerosis and may be associated with disease activity.

BackgroundReports of Guillain-Barre Syndrome (GBS) have emerged during the Coronavirus Disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. MethodsThe epidemiology of GBS cases reported via the UK National Immunoglobulin Database were studied from 2016-2019 and compared to cases reported during the COVID-19 pandemic. For the cohort study, members of the British Peripheral Nerve Society reported all cases of GBS during the pandemic. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases were compared. ResultsThe UK GBS incidence from 2016-2019 was 1.65-1.88 per 100,000 people per year. GBS and COVID-19 incidence varied between regions and did not correlate (r = 0.06, 95% CI -0.56 to 0.63, p=0.86). GBS incidence fell between March and May 2020 compared to the same months of 2016-2019. Forty-seven GBS cases were included in the cohort study (13 definite, 12 probable COVID-19 and 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome. Intubation was more frequent in the COVID-19+ve cohort (7/13, 54% vs 5/22, 23% in COVID negative) thought to be related directly to COVID-19 pulmonary involvement. ConclusionsThis study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

ObjectiveInformative biomarkers are an urgent need in management and therapy development of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in most amyotrophic lateral sclerosis patients and not correlated with neurofilaments. We sought to delineate the functional implications and the informative value of serum troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis. MethodsWe analyzed two independent hospital-based amyotrophic lateral sclerosis cohorts (d=discovery cohort; v= validation cohort) with data available on serum cardiac troponin T levels (nd=297; nv=49), serum neurofilament light chain levels (nd=116; nv=17), and routine respiratory test results (nd=86; nv=49). ResultsSerum cardiac troponin T levels, unlike serum neurofilaments, were strongly associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating score (rd = - 0.29, pd = 0.001; rv= - 0.48, pv = 0.007) and with relevant pulmonary function parameters (nd), namely SVC% (r = - 0.45; p = 0.001), FVC% (r = - 0.43; p = 0.001), FEV1% (r = -0.37, p = 0.007), and PEF (r = - 0.34, p = 0.027). Serum cardiac Troponin T reliably discriminated benchmarks of SVC% < 80%: (AUC 0.75, p = 0.003), FVC % < 80%: (AUC 0.72, p = 0.011) and PEF% <75%: (AUC 0.72, p = 0.015). InterpretationOur findings confirm cardiac Troponin T as an informative serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments. Serum Troponin T can flag compromised respiratory function in amyotrophic lateral sclerosis and might prove useful as a proxy of respiratory impairment with prognostic implications.