Immune dysregulation in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disorder of the peripheral nerves with an incompletely understood underlying pathophysiology. This investigation focused on defining B and T cell frequencies, T cell functional capacity and innate immune system analysis in patients with CIDP. METHODS: By using multi-parameter flow cytometry, we examined the phenotype and function of PBMCs in 25 CIDP patients who were relatively clinically stable on treatment who met EFNS/PNS criteria, 21 patients with genetically confirmed hereditary neuropathy and 25 healthy controls. We also evaluated the regulatory T cell (Treg) inhibitory capacity by co-culturing Treg and effector T cells. RESULTS: Proinflammatory CD4 T cells, especially type 1 helper T cell (Th1) and CD8 T cells in patients with CIDP were found to have an enhanced capacity to produce inflammatory cytokines. There was no difference in frequency of Th17 regulatory cells in CIDP patients versus healthy controls, however, Treg function was impaired in CIDP patients. There was no remarkable difference in innate immune system measures. Within B cell subsets, transitional cell frequency was decreased in CIDP patients. INTERPRETATION: Patients with CIDP clinically stable on treatment continued to show evidence of a proinflammatory state with impaired Treg function. This potentially implies an inadequate suppression of ongoing inflammation not addressed by standard of care therapies as well as persistent activity of disease while on treatment. Targeting T cells, especially inhibiting Th1 and polyfunctional CD8 T cells or improving Treg cell function could be potential targets for future therapeutic research.

Pregnancy in Seronegative Myasthenia Gravis: A Single-Center Case Series.

INTRODUCTION: The course of double-seronegative myasthenia gravis (DSNMG) during and after pregnancy has not been well described. OBJECTIVE: To assess the course of DSNMG during pregnancy and within 6 months postpartum. METHODS: A retrospective cohort study of women with DSNMG seen in the Duke Myasthenia gravis (MG) Clinic after 2003. RESULTS: Review of the Duke MG Clinic Registry and electronic medical record identified 8 patients who became pregnant after MG onset; the mean age at disease onset was 17.6 (SD = 10.0) years. Increased MG symptoms were observed in the first and third trimester and, most commonly, postpartum in 6 of 18 pregnancies. Except for 1 infant who developed respiratory distress that required neonatal intensive care admission, all the newborns were healthy at birth. CONCLUSIONS: As in seropositive MG, increased MG symptoms during pregnancy and within 6 months postpartum is also seen in women with DSNMG.

Pregnancy in MuSK-positive myasthenia gravis: A single-center case series.

INTRODUCTION/AIMS: Myasthenia gravis (MG) with muscle-specific tyrosine kinase (MuSK) antibodies (MMG) is predominantly seen in women of childbearing age. Our objective in this study was to describe the course of MMG during pregnancy and within 6 months postpartum, and to document any effect on fetal health. METHODS: A retrospective review was performed of medical records of patients with MMG seen in the Duke Myasthenia Gravis Clinic from 2003 to 2022. MMG patients with onset of MMG symptoms before or during pregnancy as well as within 6 months postpartum were reviewed. RESULTS: A total of 14 pregnancies in 10 patients were included in our study cohort. Initial MG symptoms developed during pregnancy or within 6 months postpartum in six patients. Four patients had two pregnancies, three of whom developed MG during their first pregnancy. In the patients diagnosed before pregnancy, MG symptoms increased in five of eight patients during pregnancy or postpartum. Four patients required rescue therapy with plasma exchange or intravenous immunoglobulin during pregnancy or postpartum. One patient had a cesarean section after prolonged labor due to failure of progression. There were no other complications of pregnancy or delivery, and all infants were healthy at delivery. DISCUSSION: As in non-MuSK MG, women with MMG may also have worsening or may develop initial MG symptoms during pregnancy or within 6 months postpartum. More aggressive medical therapy may be required for pregnant patients with MMG. Further study is needed to identify the mechanism and risk of worsening of MMG during pregnancy or postpartum.

Clinicoserological insights into patients with immune checkpoint inhibitor-induced myasthenia gravis.

To compare the immunopathology of immune checkpoint inhibitor-induced myasthenia gravis (ICI-MG) and idiopathic MG, we profiled the respective AChR autoantibody pathogenic properties. Of three ICI-MG patients with AChR autoantibodies, only one showed complement activation and modulation/blocking potency, resembling idiopathic MG. In contrast, AChR autoantibody-mediated effector functions were not detected in the other two patients, questioning the role of their AChR autoantibodies as key mediators of pathology. The contrasting properties of AChR autoantibodies in these cases challenge the accuracy of serological testing in establishing definite ICI-MG diagnoses and underscore the importance of a thorough clinical assessment when evaluating ICI-related adverse events.

The Duke Myasthenia Gravis Clinic Registry: II. Analysis of outcomes.

INTRODUCTION/AIMS: The Duke Myasthenia Gravis (MG) Clinic Registry contains comprehensive physician-derived data on patients with MG seen in the Duke MG Clinic since 1980. The aim of this study was to report outcomes in patients seen in the clinic and treated according to the International Consensus Guidance statements. METHODS: This is a retrospective cohort study of patients initially seen after 2000 and followed for at least 2 years in the clinic. Treatment goal (TG) was defined as achieving MGFA post-intervention status of "minimal manifestations" or better; PIS was determined by the treating neurologist. Time-to-event analysis, including Cox proportional hazards modeling, was performed to assess the effect of sex, acetylcholine receptor antibody (AChR-Ab) status, age at disease onset, distribution (ocular vs generalized), thymectomy, and thymoma on the time to achieve TG. RESULTS: Among the 367 cohort patients, 72% achieved TG (median time less than 2 years). A greater proportion of patients with AChR-Abs and thymectomy achieved TG and they did so sooner than patients without these antibodies or thymectomy. Otherwise, there were no significant differences in these findings within the tested subgroups. The disease duration at the first Duke Clinic visit was shorter in patients who achieved TG than in those who did not. DISCUSSION: These results demonstrate outcomes that can be achieved in patients with MG treated according to the current Consensus Guidance statements. Among other things, they can be used to determine the added value and potential role of new treatment modalities developed since 2018.

A Case of Probable Multifocal Motor Neuropathy With Clinical Stability for Ten Years After a Single Treatment of Rituximab.

ABSTRACT: Multifocal motor neuropathy is a rare, immune-mediated motor neuropathy with asymmetric, often debilitating progressive weakness. The efficacy of intravenous immunoglobulin in this disease is well established; however, the response typically wanes over time. No other agent has shown similar therapeutic efficacy. We describe a case of anti-ganglioside GM1 IgM-positive multifocal motor neuropathy with typical incomplete and diminishing response to intravenous immunoglobulin over time. Sixteen years after symptom onset, rituximab was administered at 2 g/m2 over 2 weeks. No significant progression of disease has occurred over the following 10 years despite no additional treatments, including intravenous immunoglobulin, being given. Only case reports and small, mostly uncontrolled studies have reported the use of rituximab in multifocal motor neuropathy with mixed results. However, given its potential benefits and lack of an established second-line agent, treatment with rituximab may be considered in select patients with refractory multifocal motor neuropathy.

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Reduced plasmablast frequency is associated with seronegative myasthenia gravis.

BACKGROUND: The immunopathology of autoimmune seronegative myasthenia gravis (SN MG) is poorly understood. Our objective was to determine immune profiles associated with a diagnosis of SN MG. METHODS: We performed high-dimensional flow cytometry on blood samples from SN MG patients (N = 68), healthy controls (N = 46), and acetylcholine receptor antibody (AChR+) MG patients (N = 27). We compared 12 immune cell subsets in SN MG to controls using logistic modeling via a discovery-replication design. An exploratory analysis fit a multinomial model comparing AChR+ MG and controls to SN MG. RESULTS: An increase in CD19+ CD20- CD38hi plasmablast frequencies was associated with lower odds of being a SN MG case in both the discovery and replication analyses (discovery P-value = .0003, replication P-value = .0021). Interleukin (IL) -21 producing helper T cell frequencies were associated with a diagnosis of AChR+ MG (P = .004). CONCLUSIONS: Reduced plasmablast frequencies are strongly associated with a SN MG diagnosis and may be a useful diagnostic biomarker in the future.

Knowledge and perceptions of the COVID-19 pandemic among patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis (MG) may be particularly vulnerable during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic due to risk of worsening disease during infection, potential adverse impacts of coronavirus disease 2019 (COVID-19) treatments on neuromuscular transmission, and a limited ability to fight off infection related to immunosuppressive treatments. Our goal is to understand how patients are experiencing the COVID-19 pandemic, including where they receive relevant information, how it has affected medical care, and what measures they use to protect themselves. METHODS: This is a prospective online survey study at large academic practice. All patients with a neuromuscular junction disorder diagnosis code in the Duke Health System were invited to participate. RESULTS: One thousand eight hundred and forty eight patients were approached to participate and 75 completed the survey between 16 April 2020 and 28 May 2020. The most frequently used information sources were non-presidential federal government (75%), state government (57%), local healthcare provider (37%), and television news (36%). Non-presidential federal government (80%), local healthcare providers (55%), state government (33%), and patient support organizations (29%) were considered the most trusted information sources. Thirty-three (44%) of survey responders had attended a telemedicine visit. Patients were taking recommended precautions during the pandemic and remained very concerned (69%) about COVID-19. Generalized Anxiety Disorder-7 scores were moderate-severe in 20% of responders. CONCLUSIONS: Healthcare providers, the government, and patient organizations play a critical role in communicating with the MG patient community. Use of targeted messaging strategies by these groups to convey accurate information may increase effectiveness and lead to more informed patients with reduced anxiety.

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. Design, Setting, and Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. Main Outcomes and Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001). Conclusions and Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.

The Duke myasthenia gravis clinic registry: I. Description and demographics.

INTRODUCTION: The Duke Myasthenia Gravis (MG) Clinic Registry is a disease-specific database containing physician-derived data from patients seen in the Duke MG Clinic since 1980. METHODS: Data from 1060 MG patients initially seen between 1980 and 2008 were reviewed. RESULTS: Fifty-four percent were male. Symptoms began after age 50 in 66% of males and 42% of females. Peak onset age in males was in their 60's; females had no predominant onset age. Onset age for both sexes increased from 1980 to 2008. Thymoma was present in 8.5%. Weakness was limited to ocular muscles for at least 2 y in 22% and became generalized later in 8.3% of these. Acetylcholine receptor antibodies were present in 78% overall, 82% with generalized MG and 52% with ocular MG (OMG). The distribution of MG disease class was similar in males and females, except that a greater proportion of women experienced myasthenic crisis and men were more likely to have OMG. DISCUSSION: Data in the Registry permit comprehensive and longitudinal analysis of a validated MG population. Analysis of Registry data shows that the frequency of AChR antibody negative MG, ocular MG, and thymoma are similar to other reports, but the onset age and proportion of males have progressively increased compared to studies published more than 20 y ago. These observations demonstrate the value of collecting comprehensive clinical information and comparing historic and contemporary populations. Other potential uses of Registry data include comparison of outcome measures in different disease subgroups and the response to specific treatments.

Imbalance in T follicular helper cells producing IL-17 promotes pro-inflammatory responses in MuSK antibody positive myasthenia gravis.

A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (MuSK-MG) is lacking. We characterized phenotype and function of Tfh cells in MuSK-MG patients and controls. We found similar overall Tfh and follicular regulatory (Tfr) T cell frequencies in MuSK-MG and healthy controls, but MuSK-MG patients exhibited higher frequencies of Tfh17 cells and a higher ratio of Tfh:Tfr cells. These results suggest imbalanced Tfh cell regulation, further supported by increased frequencies of CD4 T cells co-producing IL-21/IL-17 and IL-17/IFN-γ, and increased Tfh-supported IgG production. These results support a role for Tfh cell dysregulation in MuSK-MG immunopathology.

Inhibition of the transcription factor ROR-γ reduces pathogenic Th17 cells in acetylcholine receptor antibody positive myasthenia gravis.

IL-17 producing CD4 T cells (Th17) cells increase significantly with disease severity in myasthenia gravis (MG) patients. To suppress the generation of Th17 cells, we examined the effect of inhibiting retinoic acid receptor-related-orphan-receptor-C (RORγ), a Th17-specific transcription factor critical for differentiation. RORγ inhibition profoundly reduced Th17 cell frequencies, including IFN-γ and IL-17 co-producing pathogenic Th17 cells. Other T helper subsets were not affected. In parallel, CD8 T cell subsets producing IL-17 and IL-17/IFN-γ were increased in MG patients and inhibited by the RORγ inhibitor. These findings provide rationale for exploration of targeted Th17 therapies, including ROR-γ inhibitors, to treat MG patients.

Clinical outcome measures following plasma exchange for MG exacerbation.

Our objective is to report longitudinal results of the MG-ADL, MG-Composite, MG-MMT, and MG-QoL15 in an open-label trial of therapeutic plasma exchange in myasthenia gravis. Ten MG patients experiencing exacerbation had assessments prior to, immediately following, and at selected time points post-TPE. Changes from baseline to 2 weeks post-TPE were: MG-ADL median -5.0, P < 0.0033, MG-QoL15 median -13.0, P < 0.001, MG-MMT median -10.0, P < 0.0001, and MG-Composite median -10.0, P < 0.005. TPE produced a rapid, clinically significant change in all instruments, indicating these outcome measures are robust endpoints for clinical trials of rapidly efficacious MG therapies.

Clinical neurophysiology of neuromuscular junction disease.

The neuromuscular junction (NMJ) is a cholinergic synapse where quantal release of acetylcholine (ACh) from motor nerve terminals generates a local endplate potential (EPP) on the muscle fiber. EPPs that reach threshold depolarize the entire muscle fiber and initiate the process of excitation-contraction coupling. Deficits of neuromuscular transmission result in clinical weakness that is fatigable and may fluctuate. Repetitive nerve stimulation (RNS) testing can unmask the reduced safety factor common to all NMJ disorders via depletion of immediate ACh stores at the presynaptic motor nerve terminal with decremental responses to low-frequency RNS (LF-RNS). The facilitated responses characterizing presynaptic NMJ disorders can be revealed by brief exercise or high stimulation rates that augment presynaptic calcium levels. Activation with isometric exercise may increase the sensitivity of RNS testing. Attention to technical detail and reproducibility of findings are essential in generating valid results in RNS testing. Motor unit potential (MUP) instability or jiggle is the main finding seen in NMJ disorders on conventional needle EMG and reflects the moment-to-moment variability in the number and synchrony of muscle fiber action potentials (MFAPs) that compose a MUP. Single fiber EMG (SFEMG) is a highly selective technique that assesses jitter, the temporal variability in MFAPs generated in response to motor nerve action potentials.

Single fiber electromyography.

Single fiber electromyography (SFEMG) is a highly selective technique that permits assessment of individual muscle fiber action potentials (MFAPs). This selectivity is achieved with a specialized concentric needle electrode with a 25-µm diameter recording surface located in a side port 3mm from the needle tip. Additional selectivity is achieved with 500-Hz low-frequency filtering. An oscilloscope with a trigger and delay line enables identification of time-locked MFAPs within the same motor unit. SFEMG techniques allow assessment of two important features of the motor unit: jitter and fiber density (FD). Neuromuscular jitter is a direct measure of neuromuscular transmission and reflects the temporal variation in end-plate potentials reaching threshold to elicit a MFAP. SFEMG may be used to assess paired jitter with voluntary activation or by axonal stimulation of motor nerve branches to individual end plates. SFEMG is the most sensitive clinical test for neuromuscular junction disease and is often abnormal in clinically unaffected muscles in patients with myasthenia gravis (MG) and Lambert-Eaton myasthenia (LEM). Normal jitter findings in a clinically weak muscle exclude neuromuscular junction disease as a cause for weakness in that muscle. FD measurements assess the local concentration of muscle fibers within a motor unit and provide a sensitive in vivo assessment of reinnervation.

Validation of the triple timed up-and-go test in Lambert-Eaton myasthenia.

INTRODUCTION: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.