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BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral neuropathy that is currently classified into several clinical subtypes, which are presumed to have different pathogenic mechanisms. Recently, studies identified a subgroup of patients with CIDP who were positive for IgG4 autoantibodies against paranodal proteins, such as neurofascin-155 and contactin-1, who respond poorly to first-line therapies for typical CIDP, including intravenous immunoglobulin therapy. ObjectiveThis study aims to evaluate the efficacy and safety of intravenous rituximab according to IgG4 autoantibody status in patients with refractory CIDP. MethodsThe Evaluation of the Efficacy and Safety of Rituximab in Refractory CIDP Patients with IgG4 Autoantibodies in the Exploratory Clinical (RECIPE) trial consists of 2 cohorts: a multicenter, placebo-controlled, randomized study cohort of 15 patients with IgG4 autoantibody-positive CIDP (rituximab:placebo = 2:1) and an open-label trial cohort of 10 patients with antibody-negative CIDP. The primary endpoint is improvement in functional outcome assessed using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Scale score at 26, 38, or 52 weeks after the start of treatment with rituximab in patients with CIDP and anti-paranodal protein antibodies. Secondary outcome measures include grip strength, manual muscle testing sum scores, results of nerve conduction studies, and other functional scales. ResultsWe plan to enroll 25 cases for the full analysis set. Recruitment is ongoing, with 14 patients enrolled as of January 2020. Enrollment will close in September 2020, and the study is planned to end in December 2021. ConclusionsThis randomized controlled trial will determine if rituximab is safe and effective in patients with anti-paranodal antibodies. An open-label study will provide additional data on the effects of rituximab in patients with antibody-negative CIDP. The results of the RECIPE trial are expected to provide evidence for the positioning of rituximab as a pathogenesis-based therapeutic for refractory CIDP. Trial RegistrationClinicalTrials.gov NCT03864185, https://clinicaltrials.gov/ct2/show/NCT03864185 ; The Japan Registry of Clinical Trials jRCT2041180037, https://jrct.niph.go.jp/en-latest-detail/jRCT2041180037 International Registered Report Identifier (IRRID)DERR1-10.2196/17117

Background and objectivesNeuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab.MethodsWe recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%).ResultsThe Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps.DiscussionAn established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

Background and purpose: Various electrodiagnostic criteria have been developed in Guillain–Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria. Methods: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally. Results: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%. Conclusions and discussion: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Interpretation Guillain‐Barré syndrome (GBS) is an acute, self‐limited, immune‐mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add‐on therapy to IVIg (standard‐of‐care treatment) in patients with severe GBS.This phase 3, multicenter, double‐blind, randomized, placebo‐controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow‐up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated.The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45–1.97; p = .89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow‐up period. No new safety signals for eculizumab were identified.Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS. [ABSTRACT FROM AUTHOR]

Background and purpose: Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non‐invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta‐analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS. Methods: A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls. Results: In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1–7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (−0.994, 95% confidence interval −1.12 to −0.873, p < 0.001; Q = 38.61, p < 0.05; I2 = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences. Conclusion: This large meta‐analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta‐analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis. [ABSTRACT FROM AUTHOR]