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Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used., Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated., Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited., Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency., Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242)., Competing Interests: Declaration of interests MB reports grants from the NIH (U01NS107027, U54NS092091) and the ALS Association (16-TACL-242) in support of this work. He is also an unpaid member of the Board of Trustees for the ALS Association. He has served as a consultant to Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. EAM reports grants from the NIH (U01NS107027, U54NS092091). He also serves as a consultant to Annexon, Biogen, Bial Biotech, Cortexyme, Chase Therapeutics, Enterin, nQ Medical, Partner Therapeutics, Stoparkinson Healthcare, and UCB. He has served on DSMBs for NeuroSense Therapeutics, Novartis, and Sanofi. AM reports grants from the NIH (U01NS107027). He has also provided consulting services to Roche, Pfizer, and Accure Therapeutics. MLR reports support from grants from the NIH (U01NS107027, U54NS092091) and FightMND. EH has nothing to declare. VL has nothing to declare. DR has nothing to declare. SS has nothing to declare. IM has nothing to declare. YC has nothing to declare. VG currently is an employee of Biohaven Pharmaceutical Inc. JS receives research funding from the NIH < MDA, FSHD Society, Friends of FSH Research, and FSHD Canada. He also serves as a consultant or on scientific advisory boards for Avidity, Fulcrum, Dyne, Armatus, Epic Bio, Roche, Lupin, and Entrada. JH has nothing to declare. RR reports grants from the NIH (U54NS092091) in support of this work. She is also an unpaid member of the Medical Advisory Board of the Association for Frontotemporal Dementias (AFTD) and a paid member of the Scientific Advisory Board of the Kissick Family Foundation FTD Grant Program. CAM reports funding from the ALS Association and the NIH (U54NS092091). LP reports support from the Mayo Clinic Foundation and grants from the National Institute on Aging (5P30AG0062677, U19AG063911) the National Institute of Neurological Disorders and Stroke (U54NS123743, R35NS097273, P01NS084974) and Target ALS Foundation. CM reports grants from the NIH (AG066597, AG076411, AG066152, AG072979, NS109260, NS092091), Department of Defense, and support from the Penn Institute on Aging, Decrane Family PPA Fund, and Newhouse Fund.2. JW reports funding from the NIH (U01NS107027, U54NS092091) and the ALS Association (16-TACL-242) in support of this work. The CReATe Consortium (U54NS092091) is part of the NIH Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This Consortium is funded through a collaboration between NCATS and the NINDS. This work was also supported by a Clinical Trial Readiness grant (U01NS107027) from NINDS and by a grant from the ALS Association to support the CReATe Biorepository (grant ID 16-TACL-242)., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective : The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach's α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.

Background: Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells., Methods: MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051., Findings: We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score., Interpretation: In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases., Funding: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health., Competing Interests: Declaration of interests VG has received honoraria as a consultant or advisory board member from Alexion Phermaceuticals, argenx, Immunovant, and Amylyx Pharmaceuticals and is employed by Biohaven Pharmaceuticals. MB received trial support and consulting fees from Alexion, Cartesian, Horizon, Immunovant, Sanofi, Takeda, UCB, and Ra Pharma. MK, MSS, and MVK are employees of and have ownership interest in Cartesian Therapeutics. MDM and CMJ are employees of Cartesian Therapeutics. CMJ is appointed as an employee of the University of Maryland and VA Maryland Health Care System. The views in this paper do not reflect the views of the state of Maryland or the US Government. GS has received research support from Cartesian Therapeutic, Immunovant, and argenx, paid to his institution; received consulting fees from UCB Pharma and Immunovant; received honoraria from argenx and Alexion; received travel support from argenx and Immunovant; and holds unpaid positions at the Myasthenia Gravis Foundation of California and the American Association of Neuromuscular and Electrodiagnostic Medicine. MHF has received honoraria as a consultant or advisory board member from argenx. TV is the University of South Florida site principal investigator for myasthenia gravis clinical trials sponsored by Alexion (now part of AstraZeneca), argenx, (now part of UCB), Horizon (now part of Viela Bio), Janssen (now part of Momenta), Regeneron, and Cartesian Therapeutics, and receives speaking or consulting honoraria relating to myasthenia gravis from Alexion, argenx, and UCB. JFH has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Cartesian Therapeutics, the US Centers for Disease Control and Prevention, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), the Patient-Centered Outcomes Research Institute, Ra Pharmaceuticals (now UCB), and Takeda Pharmaceuticals; honoraria from Alexion Pharmaceuticals, argenx, Immunovant, NMD Pharma, Novartis Pharmaceuticals, Ra Pharmaceuticals (now UCB), Regeneron Pharmaceuticals, Sanofi US, and Viela Bio (now Horizon Therapeutics); he has also received non-financial support from Alexion Pharmaceuticals, argenx, Ra Pharmaceuticals (now UCB), and Toleranzia. TM has served in an advisory capacity for Alexion, Amicus, AnnJi, argenx, Arvinas, Ask Bio, Audentes, AvroBio, Horizon Therapeutics, Immunovant, Maze Therapeutics, Momenta (now Janssen), Sanofi-Genzyme, Spark Therapeutics, UCB, and Zogenix; serves on the speaker's bureau for argenx and Sanofi-Genzyme; serves on the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California, and Myasthenia Gravis Foundation of America; receives research funding from the Myositis Association, the Muscular Dystrophy Association, the National Institutes for Health, Alexion, Amicus, AnnJi, argenx, Audentes (now part of Astellas) Gene Therapy, Bristol-Myers-Squib, Cartesian Therapeutics, Grifols, ML-Bio, Momenta, Ra Pharmaceuticals, Sanofi-Genzyme, Spark Therapeutics, and Valerion; and serves on the data safety monitoring board for Acceleron, Avexis, Sarepta, and the National Institutes for Health. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objectives: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study., Methods: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/μL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%)., Results: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/μL in 1,005 patients (83%), 5-49 cells/μL in 200 patients (16%), and ≥50 cells/μL in 13 patients (1%)., Discussion: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/μL, is compatible with GBS after a thorough exclusion of alternative diagnoses., Classification of Evidence: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS., (© 2023 American Academy of Neurology.)

Introduction/aims: Factors associated with coronavirus disease 2019 (COVID-19) infection among the myasthenia gravis (MG) population are incompletely understood. This study aimed to characterize the behavior of MG patients during the pandemic and to examine risk factors associated with COVID-19 infection., Methods: A "COVID-19 Survey" was sent to MG Patient Registry participants in the summer of 2020 (CSS20) and winter of 2021 (CWS21). Survey results were summarized descriptively. Demographics, disease characteristics, medication use, and survey results were compared between those reporting COVID-19 diagnosis (COVID), COVID-19 like symptoms without diagnosis (COVID-Like), and asymptomatic participants., Results: A total of 454 and 665 participants completed the CSS20 and CWS21 surveys respectively; 326 participants completed both. Most continued follow-up visits and MG treatments. The frequency of COVID-like symptoms was similar between CSS20 and CWS21, while COVID-19 exposure (6% vs. 27%), COVID-19 testing among symptomatic individuals (35% vs. 78%), and COVID-19 diagnosis (0.2% vs. 6%) were higher in the CWS21. Cough, fever, fatigue, myalgia, anosmia/ageusia, and hospital and intensive care unit (ICU) admissions were more frequent in the COVID compared to the COVID-Like group. COVID-19 exposure (odds ratio [OR] 7.88), number of people in the household (OR 1.31), and report of MG exacerbation before the pandemic (OR 2.6) were independently associated with COVID-19 infection., Discussion: COVID-19 affected MG patients increasingly through the early pandemic. While face-to-face contact with a COVID-19 infected individual was an obvious risk factor, MG patients who had more people in the household and unstable disease were at elevated risk for COVID-19 infection., (© 2022 Wiley Periodicals LLC.)

Background: As novel therapeutic interventions are being developed and tested in the amyotrophic lateral sclerosis (ALS) population, there is a need to better understand the symptoms and issues that have the greatest impact on the lives of individuals with ALS. We aimed to determine the frequency and relative importance of symptoms experienced by adults in a national ALS sample and to identify factors that are associated with the greatest disease burden in this population., Methods: We conducted 15 qualitative interviews of individuals with varied ALS phenotypes and analyzed 732 quotes regarding the symptomatic disease burden of ALS between August 2018 and March 2019. We subsequently conducted a national, cross-sectional study of 497 participants with ALS and ALS variants through the Centers for Disease Control and Prevention's (CDC) National ALS Registry between July 2019 and December 2019. Participants reported on the prevalence and relative importance of 189 symptomatic questions representing 17 symptomatic themes that were previously identified through qualitative interviews. Analysis was performed to determine how age, sex, education, employment, time since onset of symptoms, location of symptom onset, feeding tube status, breathing status and speech status relate to symptom and symptomatic theme prevalence., Findings: Symptomatic themes with the highest prevalence in our sample were an inability to do activities (93.8%), fatigue (92.6%), problems with hands or fingers (87.7%), limitations with mobility or walking (86.7%), and a decreased performance in social situations (85.7%). Participants identified inability to do activities and limitations with mobility or walking as having the greatest overall effect on their lives., Interpretation: Individuals with ALS experience a variety of symptoms that affect their lives. The prevalence and importance of these symptoms differ among the ALS population. The most prevalent and important symptoms offer potential targets for improvements in future therapeutic interventions., Funding: Research funding was provided by ALS Association., Competing Interests: CZ has previously provided consultation to Recursion Pharmaceuticals and reports no other disclosures. RB receives grants or contracts from the 10.13039/100000971ALS Association, Medicinova, Healey Center, and Orion with payments through 10.13039/100006510Duke University for various ALS projects and ALS trials. He receives book royalities through Demos Publishing. He provides consultation to ALS Association, Alexion, Amylyx, Apellis, Black Swan, Corcept, Cytokinetics, GenieUS, Guidepoint, ITF Pharma, New Biotic, Shinkei, and Woolsey Pharma. He has received payments for speaking on ALS from Amylyx. He has received payments for developing education materials on ALS from Projects in Knowledge and Medscape. He has participated on Data Safety Monitoring Boards for AB Science, Biogen, Brainstorm, Neurosense, and PTC. He has served on the scientific advisory board at GenieUS. VG is an employee of Biohaven Pharmaceuticals (his contribution to this work was done as part of his role at the University of Miami). He has received consultation/advisory board fees from Amylyx Pharmacuticals. JS has received grants or contracts from 10.13039/100000065NINDS (U01 ReSolve U01NS101944), NINDS (R21 CAPN3 R21TR003184), FSHD Canada (MOVE + FSHD), FSHD Society (MOVE FSHD), 10.13039/100004952MDA (MD CRNG), 10.13039/100012644Friends of FSH Research (MOVE FSHD). He has provided consultation and served on SAB with Avidity, Dyne, Fulcrum, Arrowhead, ML Bio, and Sarepta. He has provided consultation to MT Pharma, He has provided consultation and served on the advisory board for Amylyx. He has served on the steering committee at Roche. MB reports grants from 10.13039/100000971ALS Association (16-TACL-242 and 17-LGCA-331), 10.13039/100000002NIH (U54-NS092091, R01-NS105479 and U01- NS107027), and 10.13039/100005202Muscular Dystrophy Association (645863). He has received consulting fees from Alector, Biogen, Novartis, Sanofi, UCB, UniQure. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study (UMIP142-A.) In addition, he has a provisional patent pending entitled ‘Determining Onset of Amyotrophic Lateral Sclerosis.’ He serves on the Board of Trustees for the ALS Association (unpaid). CH receives royalty payments through the University of Rochester for copyrighted patient reported outcome measures including one for ALS. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, Neurocrine Biosciences, and the Marigold Foundation. He is scheduled to have travel reimbursement to present at the upcoming Muscle Study Group Meeting. JS, SR, DA, EW, JSW, AV, ND, JH, JW, JC, and PM report no disclosures., (© 2022 The Authors.)

Objective : Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. We evaluate quantile regression (QR), that accounts for age and education, relative to a traditional two standard deviation (SD) cutoff for defining CI. Methods : QR of cross-sectional data from a multi-center North American Control (NAC) cohort of 269 healthy adults was used to model the 5 th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to traditional two SD cutoff approach using the same NAC cohort (2SD-NAC) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI in 182 ALS patients. Results : QR-NAC models revealed that age and education impact cognitive performance on the ECAS. Based on QR-NAC normative cutoffs, the frequency of CI in the 182 PENN ALS patients was 15.9% for ALS specific, 12.6% for ALS nonspecific, and 15.4% for ECAS total. This frequency of CI is substantially more conservative in comparison to the 2SD-UK (20.3%-34.6%) and modestly more conservative to the 2SD-NAC (14.3%-16.5%) approaches for estimating CI. Conclusions : The choice of normative cohort has a substantial impact and choice of statistical method a modest impact on defining CI in ALS. This report establishes normative ECAS thresholds to identify whether ALS patients in the North American population have CI.

Amyotrophic lateral sclerosis, when viewed as a biological entity rather than a clinical syndrome, probably evolves along a continuum, with the initial clinically silent phase eventually evolving into clinically manifest amyotrophic lateral sclerosis. Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1-3.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1-2 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting >4 years and ∼9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale., Methods: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni , hepatitis E virus, Mycoplasma pneumoniae , cytomegalovirus, and Epstein-Barr virus., Results: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni -positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir ( p = 0.004) and a longer time to regain the ability to walk independently ( p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni -positive patients ( p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients ( p = 0.004)., Discussion: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models., (© 2022 American Academy of Neurology.)

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The electronic health record (EHR) is designed principally to support the provision and documentation of clinical care, as well as billing and insurance claims. Broad implementation of the EHR, however, also yields an opportunity to use EHR data for other purposes, including research and quality improvement. Indeed, effective use of clinical data for research purposes has been a long-standing goal of physicians who provide care for patients with ALS, but the quality and completeness of clinical data, as well as the burden of double data entry into the EHR and into a research database, have been persistent barriers. These factors provided motivation for the development of the ALS Toolkit, a set of interactive digital forms within the EHR that enable easy, consistent, and structured capture of information relevant to ALS patient care (as well as research and quality improvement) during clinical encounters. Routine use of the ALS Toolkit within the context of the CReATe Consortium's institutional review board-approved Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study protocol, permits aggregation of structured ALS patient data, with the goals of empowering research and driving quality improvement. Widespread use of the ALS Toolkit through the CAPTURE-ALS protocol will help to ensure that ALS clinics become a driving force for collecting and aggregating clinical data in a way that reflects the true diversity of the populations affected by this disease, rather than the restricted subset of patients that currently participate in dedicated research studies., (© 2021 Wiley Periodicals LLC.)

Background and Objectives: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity., Methods: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors., Results: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort., Discussion: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America., Classification of Evidence: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS., Trial Registration Information: NCT01582763., (© 2021 American Academy of Neurology.)

Objective: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG)., Methods: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks., Results: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified., Conclusions: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG., Classification of Evidence: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year., Trial Registration: ClinicalTrials.gov Identifier: NCT02110706., (© 2021 American Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development., Methods: In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations., Results: For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were 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 for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (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., Conclusions: Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect., (© 2020 American Academy of Neurology.)

Although there are alternative methods and drugs for preventing venous thromboembolism (VTE), it is not clear which modality is most suitable and efficacious for patients with severe (stable or unstable) head/spinal injures. The aim of this study was to compare intermittent pneumatic compression devices (IPC) with low-molecular-weight heparin (LMWH) for preventing VTE. We prospectively randomized 120 head/spinal traumatized patients for comparison of IPC with LMWH as a prophylaxis modality against VTE. Venous duplex color-flow Doppler sonography of the lower extremities was performed each week of hospitalization and 1 week after discharge. When there was a suspicion of pulmonary embolism (PE), patients were evaluated with spiral computed tomography. Patients were analyzed for demographic features, injury severity scores, associated injuries, type of head/spinal trauma, complications, transfusion, and incidence of deep venous thrombosis (DVT) and PE. Two patients (3.33%) from the IPC group and 4 patients (6.66%) from the LMWH group died, with their deaths due to PE. Nine other patients also succumbed, unrelated to PE. DVT developed in 4 patients (6.66%) in the IPC group and in 3 patients (5%) in the LMWH group. There was no statistically significant difference regarding a reduction in DVT, PE, or mortality between groups ( p = 0.04, p > 0.05, p > 0.05, respectively). IPC can be used safely for prophylaxis of VTE in head/spinal trauma patients.

The use of thrombolytic agents to treat peripheral arterial occlusions is a new method. Despite its advantages, information about complications caused by the use of rt-PA and about its place in treatment is still incomplete. The aim of this study was to establish a dose range for rt-PA and to follow the patients with a protocol during and after thrombolysis. Between May 1999 to January 2000, 14 patients with symptoms of peripheral arterial occlusion came to Istanbul Medical Faculty Emergency Surgery Unit. The duration of ischaemia before their hospitalization took an average of 44 hours. (Range 3 hours-7 days). A pulse-spray catheter was directed to the thrombus under angiographic control. Bolus injection of 5 mg of rt-PA was followed by 15 minutes of interval. The extent of thrombolysis was checked by angiography and then bolus injection of 5 mg of rt- PA was repeated. After angiographic control, patients having insufficient thrombolysis, received 0.05 mg/kg/hour of infusion for 12 hours. At the end of 12 hours, thrombolytic treatment ended with a control angiography. A thromboembolectomy operation was made to patients still having an occlusion after thrombolysis. To avoid re-occlusions, all of the patients received 1.5 mg/kg/day low molecular weight heparin (enoxaparin) for 1 week. At the end of thrombolysis, 9 patients had complete lysis. A patient, having an occlusion in superior mesenteric artery had 60% recanalisation. 2 patients (14%) having 90% stenosis, needed a balloon angioplasty besides thrombolysis, and both of them had complete reperfusion. 2 patients (14%) needed a thromboembolectomy operation due to insufficient thrombolysis. 2 patients (14%) had a minor bleeding after thrombolytic treatment. After thrombolysis, 2 patients (14%) had a stroke. There were no amputations. 1 of the patients having a stroke, died 2 days after thrombolytic treatment 1 patient died due to myocardial infarction during thrombolysis. 1 patient (7%) died due to diabetic coma on the 20th day. Acute myocardial infarction was the cause of death in 1 patient on the 25th day. In conclusion pulse spray thrombolysis with rt-PA is safe and efficient. Moreover there is a reduction in complications and need for surgical procedure. The recent problem is to find the optimum dosages for the best thrombolysis and for least complications.