How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action-complement and neonatal Fc receptor (FcRn) inhibition-were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials. At present, it is unclear when and in whom to initiate these therapeutic agents and how to integrate them into the current treatment paradigm. When selecting a newer therapeutic agent, we use a simple equation: Value = Clinical Improvement/(Cost + Side Effects + Treatment Burden), which guides our decision-making. We consider using these novel therapeutic agents in two specific clinical situations. Firstly, the newer agents are fast-acting, suggesting they can be used in clinically unstable patients as "bridge therapy," and secondly, they provide additional options for those patients considered treatment-refractory. There are downsides, however, including treatment cost, unique side effect profiles, and intravenous and subcutaneous drug administration (though for some, this may be an advantage). As additional drugs enter the marketplace with unique mechanisms of action, routes of administration, and dosing schedules, the placement of the novel therapeutic agents in the gMG treatment algorithm will likely evolve.

Measuring treatment adverse event burden in myasthenia gravis: Single-center prospective evaluation utilizing the Adverse Event Unit (AEU).

INTRODUCTION/AIMS: We developed a patient- and physician-weighted consensus unit called the adverse event unit (AEU) that quantifies and compares adverse event (AE) burden among any group of medications in neurological patients. In this study we evaluated preliminary validity and feasibility of measuring AE burden with the AEU in myasthenia gravis (MG). METHODS: This is a single-center, prospective, 1-year, observational study of adult MG patients presenting for routine care between April 1, 2021 and March 31, 2022. The MG Activities of Daily Living (MG-ADL), the 15-item MG Quality of Life revised (MG-QOL15r), MG-Composite, and AEU scores were obtained at all visits. A priori primary feasibility metric was AEU completion rate equal to (within 3.8%, one-sided 95% confidence interval [CI]) or better than MG-ADL completion rate. Time to administer AEU and MG-ADL/MG-QOL15r, correlation between AEU total score and MG-QOL15r, and median AEU scores for each MG medication were evaluated. RESULTS: Fifty-four patients completed 67 study visits; side effects were reported at 75% of the visits. The study met the primary feasibility endpoint; AEU and MG-ADL were recorded at all visits. Times to administer the AEU (median 5 minutes) and MG-ADL/MG-QOL15r were similar. We observed a weak correlation of 0.29 (95% CI 0.03 to 0.51, P = .032) between AEU and MG-QOL15r scores. Non-statistically significant differences in median AEU scores were observed among MG medications. DISCUSSION: Our data demonstrate preliminary feasibility and validity of using the AEU to measure AE burden in MG. Future studies will compare AE burden among MG treatments and evaluate clinically meaningful AEU scores in MG.

Validation of myasthenia gravis diagnosis in the older Medicare population.

INTRODUCTION/AIMS: Administrative health data has been increasingly used to study the epidemiology of myasthenia gravis (MG) but a case ascertainment algorithm is lacking. We aimed to develop a valid algorithm for identifying MG patients in the older population with Medicare coverage. METHODS: Local older patients (age ≥65) who received healthcare at the Cleveland Clinic and possessed Medicare coverage in 2014 and 2015 were selected. Potential MG patients were identified by using a combination of ICD9 or ICD10 codes for MG and MG-related text-word search. Diagnosis was categorized as "definite MG", "possible MG" or "non-MG" after review of clinical summaries by 5 neuromuscular specialists. Performances of various algorithms were tested by use of the definite MG cohort as a reference standard, and calculation of sensitivity, specificity, and predictive values. RESULTS: A total of 118 988 local older patients with Medicare coverage were identified. Usage of MG ICD codes and text-word search resulted in 125 patients with definite and 67 with possible MG. A total of 45 algorithms involving ICD usage, medication prescription, and specialty visit were tested. The best performing algorithm was identified as 2 office visits using MG ICD codes separated by at least 4 weeks or 1 hospital discharge and 1 office visit each using MG ICD codes separated by at least 4 weeks within the two-year period, resulting in a sensitivity and positive predictive value of 80% for identifying definite MG patients. DISCUSSION: Algorithms using ICD codes can reliably identify patients with MG with a high degree of accuracy.

The neuromuscular fellowship portal and match.

For many years, Neuromuscular Medicine programs lacked a standardized means of handling fellowship applications and offering positions. Programs interviewed applicants and made offers as early as the first half of Post Graduate Year 3 (PGY3), a suboptimal timeline for applicants who may have had little prior exposure to neuromuscular or electrodiagnostic medicine. In 2021, the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) developed the Neuromuscular Fellowship Portal to standardize a later timeline and establish a process for fellowship applications and offers. In its first year, the Neuromuscular Fellowship Portal used a unique one-way match, in which the portal released serial offers to applicants based on rank order lists submitted by programs. Fifty-two Neuromuscular Medicine programs and seven electromyography (EMG)-focused Clinical Neurophysiology programs participated. Sixty-eight positions were filled, a similar number to previous years. A survey of fellowship directors and applicants following this process showed overwhelming support for the standardized timeline and application portal, but all program directors and most applicants favored moving to a traditional match. To maintain the existing application timeline and minimize costs for all parties, the AANEM Neuromuscular Fellowship Portal will host a two-way match, based on existing commercial match algorithms, in 2022. A match will afford a fair and efficient process for all involved. Both Neuromuscular Medicine and EMG-focused Clinical Neurophysiology programs will be encouraged to participate. The process undertaken by the AANEM can stand as an example for other neurologic subspecialties who are interested in standardizing their application timeline.

Telemedicine visits in myasthenia gravis: Expert guidance and the Myasthenia Gravis Core Exam (MG-CE).

INTRODUCTION/AIMS: Telemedicine may be particularly well-suited for myasthenia gravis (MG) due to the disorder's need for specialized care, its hallmark fluctuating muscle weakness, and the potential for increased risk of virus exposure among patients with MG during the coronavirus disease 2019 (COVID-19) pandemic during in-person clinical visits. A disease-specific telemedicine physical examination to reflect myasthenic weakness does not currently exist. METHODS: This paper outlines step-by-step guidance on the fundamentals of a telemedicine assessment for MG. The Myasthenia Gravis Core Exam (MG-CE) is introduced as a MG-specific, telemedicine, physical examination, which contains eight components (ptosis, diplopia, facial strength, bulbar strength, dysarthria, single breath count, arm strength, and sit to stand) and takes approximately 10 minutes to complete. RESULTS: Pre-visit preparation, remote ascertainment of patient-reported outcome scales and visit documentation are also addressed. DISCUSSION: Additional knowledge gaps in telemedicine specific to MG care are identified for future investigation.

Myasthenia gravis patient and physician opinions about immunosuppressant reduction.

INTRODUCTION: To reduce myasthenia gravis (MG) patient risk of immunosuppressant (IS) exposure adverse events (AEs), such as infections and malignancies, and to reduce treatment burden, international guidelines recommend decreasing IS dose in stable MG patients. METHODS: Online surveys were conducted of self-identified MG patients and MG physician experts about the importance of IS dose reduction for MG patients who achieve prolonged periods of disease stability. RESULTS: Eighty-four percent of MG patients (n = 283) and 100% of physicians (n = 45) were concerned about long-term IS-associated AEs. Although both groups favored attempting IS reduction, they raised concerns including MG relapse, hospitalization, and uncertainty about the future. Presented with an estimated 12% significant relapse rate with IS dose reduction, 76% of patients would be willing to enroll in a randomized IS dose reduction trial. DISCUSSION: Patients and physicians favor considering IS dose reduction but are also concerned about potential negative sequelae.

Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis.

INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.

Rituximab treatment of myasthenia gravis: A systematic review.

Rituximab is a chimeric mouse/human anti-CD20 monoclonal immunoglobulin. We reviewed the efficacy and safety of rituximab in 169 myasthenia gravis (MG) patients from case reports and series. Antibodies to the acetylcholine receptor (AChR) were present in 59% and muscle-specific tyrosine kinase (MuSK) in 34%. Modified Myasthenia Gravis Foundation of America postintervention scale of minimal manifestations (MM) or better occurred in 44%, and combined pharmacologic and chronic stable remission in 27% overall; MM or better was achieved in 72% of MuSK MG and 30% of AChR MG (P < 0.001). Posttreatment relapses decreased more in MuSK MG (P = 0.05). Response predictors were MuSK MG, less severe disease, and younger age at treatment. Among a responder subset, 26% of AChR and 82% of MuSK MG patients showed decreased posttreatment antibody titers. Rituximab was generally well tolerated. Detectable serum rituximab and depleted CD20+ B-cells were observed up to 20 and 16 weeks, respectively, after 4 weekly infusions. Muscle Nerve 56: 185-196, 2017.

Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): A randomized, controlled trial.

INTRODUCTION: In this study we evaluated the safety, tolerability, and efficacy of prednisone in patients with ocular myasthenia gravis (OMG) concurrently treated with pyridostigmine. METHODS: This investigation was a randomized, double-blind, placebo-controlled trial. Participants whose symptoms failed to remit on pyridostigmine were randomized to receive placebo or prednisone, initiated at 10 mg every other day, and titrated to a maximum of 40 mg/day over 16 weeks. The primary outcome measure was treatment failure. RESULTS: Fewer subjects were randomized than the 88 planned. Of the 11 randomized, 9 completed 16 weeks of double-blind therapy. Treatment failure incidence was 100% (95% CI 48%-100%) in the placebo group (n = 5) vs. 17% (95% CI 0%-64%) in the prednisone group, P = 0.02 (n = 6). Median time to sustained minimal manifestation status (MMS) was 14 weeks, requiring an average prednisone dose of 15 mg/day. Adverse events were infrequent and generally mild in both groups. CONCLUSIONS: A strategy of low-dose prednisone with gradual escalation appears to be safe, well-tolerated, and effective in treating OMG.

Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument.

INTRODUCTION: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. METHODS: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. RESULTS: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. CONCLUSIONS: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016.

Can mycophenolate mofetil be tapered safely in myasthenia gravis? A retrospective, multicenter analysis.

INTRODUCTION: Mycophenolate mofetil (MMF) is frequently used to treat myasthenia gravis, but there is little information to guide clinicians on the safety of reducing the dose in well-controlled patients. METHODS: This retrospective chart review at 3 institutions identified 92 patients who had undergone MMF taper after achieving either pharmacologic remission or minimal manifestations status. Statistical analysis was performed to assess differences in patient characteristics between patients who had successfully tapered MMF and those who relapsed. RESULTS: Of 92 patients undergoing a taper, 30 relapsed. The relapses were mild, transient, and usually responded to increased MMF dose. MG crisis did not occur. The mean dose at time of relapse was 888 mg/day. Patients with relapses were tapered more quickly (8.4 vs. 62.4 months). CONCLUSIONS: Tapering MMF appears safe after years of disease stability. Reducing the dose at a dose of only 500 mg/day every 12 months is recommended.

Different mechanism of LPS-induced calcium increase in human lung epithelial cell and microvascular endothelial cell: a cell culture study in a model for ARDS.

Acute respiratory distress syndrome (ARDS) is a contemporary term incorporating the historic 'acute lung injury' and the colloquial term 'shock lung'. ARDS remains a serious and enigmatic human disease, causing significant mortality. The mechanisms involved at the alveolar cell/capillary endothelial interface have been explored but to date we lack clarity on the role of intracellular calcium ([Ca(2+)]i) fluxes across this interface. To explore the mechanisms of Ca(2+) induced inflammatory reaction in epithelial cells and pulmonary microvascular endothelial cells (HMVEC) located at the two sides of blood-air barrier, lung epithelial A549 and HMVEC cells were treated with LPS. Our results demonstrated that LPS evoked the increase of [Ca(2+)]i, TNF-α and IL-8 in both cells types. The [Ca(2+)]i increases involved intracellular but not extracellular Ca(2+) sources in A549, but both intracellular and extracellular Ca(2+) sources in HMVEC cells. The effects of LPS on both cells types were completely inhibited by the combination of LPS and CaSR-targeted siRNA. Furthermore, LPS-inhibited cell proliferations were significantly reversed by the combined treatment. Therefore, LPS induced different mechanisms of [Ca(2+)]i increase during the activation of CaSR in A549 and HMVEC cells, which translates into functional outputs related to ARDS.

The association of chemotherapy-induced peripheral neuropathy with reduced executive function in chemotherapy-treated cancer survivors: A cross-sectional study.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is common and disabling among cancer survivors. Little is known about the association of CIPN with other measures of the nervous system's integrity, such as executive dysfunction. We compared measures of executive function in older chemotherapy-treated cancer survivors with and without CIPN. MATERIALS AND METHODS: This cross-sectional study enrolled 50 chemotherapy-treated cancer survivors (65.6 ± 11.5 years, 88% female) post-chemotherapy treatment who were previously referred for outpatient rehabilitation at the request of the cancer survivor or a medical provider. Twenty-two participants (44%) had CIPN defined by patient-reported distal paresthesia or numbness, which began with chemotherapy and continued to the time of cognitive testing. Measures of executive function included Trails-B, Stroop, and rapid reaction accuracy (RRA) and were evaluated between cancer survivors with and without CIPN using t-tests. Multivariable models were then used to determine whether CIPN was an independent determinant of the measures of executive function (Trails-B, Stroop Incongruent, and RRA). Models were adjusted for age, sex, history of anxiety, and benzodiazepine use due to their known associations with CIPN and executive function. RESULTS: Cancer survivors with CIPN (CIPN+) had reduced executive function compared to survivors without CIPN (CIPN-) on Trails-B (CIPN+: 84.9 s ± 44.1 s, CIPN-: 59.1 s ± 22.5 s, p = 0.01), Stroop (CIPN+: 100.6 s ± 38.2 s, CIPN-: 82.1 s ± 17.3 s, p = 0.03), and RRA (CIPN+: 60.3% ± 12.9%, CIPN-: 70.6% ± 15.7%, p = 0.01). There were no differences in cancer stage severity or functional status by patient report or sit-to-stand function. The association between CIPN and reduced executive function was found in multivariable models after adjusting for age, sex, anxiety, and benzodiazepine use for Trails-B (ß:17.9, p = 0.046), Stroop (ß:16.9, p = 0.02), and RRA (ß:-0.072, p = 0.03). DISCUSSION: In this population, CIPN is associated with reduced executive function in older cancer survivors treated with chemotherapy. Future research is required to further understand this preliminary association, the causality, and the potential risk factors.

Rare ACTN2 Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation.

Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2 , have been shown to cause distal myopathy. ACTN2 , a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. New ACTN2 variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations in ACTN2 -related diseases, actininopathies, persists. Objective: The objective of the study is to characterize the pathomechanisms underlying actininopathies. Methods: Functional characterization in C2C12 cell models of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants. Results: The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates. Interpretation: The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

Executive function is associated with balance and falls in older cancer survivors treated with chemotherapy: A cross-sectional study.

INTRODUCTION: Balance decrements and increased fall risk in older cancer survivors have been attributed to chemotherapy-induced peripheral neuropathy (CIPN). Cognition is also affected by chemotherapy and may be an additional contributing factor to poor balance through changes in executive functioning. We examined the association of executive function with balance and falls in older cancer survivors who had been treated with chemotherapy. MATERIALS AND METHODS: Fifty cancer survivors (aged 65.6 ± 11.5 years; 88% female) who were all treated with chemotherapy were included in this cross-sectional study at a tertiary medical center. Executive function was measured by Trails-B, Stroop, and rapid reaction accuracy, a measure emphasizing rapid inhibitory function. Balance was measured by five sit-to-stand time (5STS), repetitions of sit-to-stand in thirty seconds (STS30), and unipedal stance time (UST), which was the primary balance outcome measure. Self-reported falls in the past year were also recorded and was a secondary outcome. Bivariate analyses were conducted between executive function measures and balance variables. Multivariable models were constructed for UST and falls outcomes and included covariates of age and chemotherapy induced peripheral neuropathy status. RESULTS: Pearson correlations demonstrated significant relationships between two executive function measures (rapid reaction accuracy, Trails-B) and all the balance measures assessed (UST, STS30, and 5STS). Rapid reaction accuracy correlations were stronger than Trails-B. The Stroop measure correlated solely with UST. In multivariable models, rapid reaction accuracy was associated with better UST (standardized regression coefficient: 64.1, p < 0.01), decreased any fall (odds ratio = 0.000901, p = 0.04), and decreased recurrent falls (odds ratio = 0.0000044, p = 0.01). The interaction of CIPN with the inhibitory measures in the prediction of balance was not significant. DISCUSSION: Measures of executive function were associated with balance, but among the executive function tests, rapid reaction accuracy had the strongest correlations to balance and was independently associated with falls. The findings suggest that executive function should be considered when assessing fall risk and developing interventions intended to reduce fall risk in older chemotherapy-treated cancer survivors.

Unexpected neuroimaging abnormalities in patients with apparent C8 radiculopathy: broadening the clinical spectrum.

INTRODUCTION: C8-root impingement by C7/T1 lesions on neuroimaging studies is not consistently observed in C8 radiculopathy. We hypothesized that C7 or T1 root lesions (with a pre- or postfixed plexus) or cervical myelopathy might explain some "C8 radiculopathies" without C8 root compression. METHODS: Retrospective analysis of cervical neuroimaging in 31 consecutive patients with EMG-confirmed C8 radiculopathy. RESULTS: Five patients (16%) had C8-root compression at C7/T1. Of those without C8-root compression, 5 (16%) had C7-root compression at C6/7, one (3%) had T1-root compression at T1/T2, 7 (23%) had cervical cord compression at or above the C6/7 level, 4 (13%) had intramedullary cervical lesions, and 9 (29%) had mild or nonspecific findings. CONCLUSIONS: C8 radiculopathy without C8-root compression may be due to C7-root compression in the setting of a "prefixed" brachial plexus, upper cervical cord compression with vascular compromise of the distal cervical spinal cord ("myelopathic hand"), or intramedullary cervical cord lesions.

Diagnosis and Management of Myasthenia Gravis.

PURPOSE OF REVIEW: This article reviews updated diagnostic procedures and currently available treatment modalities for myasthenia gravis (MG). RECENT FINDINGS: Patients with MG can be classified based on antibody status and their clinical presentation; treatment responses may differ based on disease subtypes. Improved diagnostic methods and recognition of new antigenic targets such as lipoprotein-related protein 4 have led to improved diagnostic efficiencies. Corticosteroids remain the first-line immunotherapy, but there is a trend toward minimizing their use at high doses and for long durations. Oral immunosuppressants such as mycophenolate mofetil, azathioprine, and tacrolimus remain useful. An international, multicenter randomized trial comparing thymectomy plus prednisone with prednisone alone demonstrated that thymectomy improves clinical outcomes in selected patients with nonthymomatous MG. Eculizumab, efgartigimod, and ravulizumab have recently been approved by the US Food and Drug Administration (FDA) for adult patients with generalized MG who are acetylcholine receptor-antibody positive. These drugs take advantage of novel mechanisms of action and expand treatment options for patients with MG. Data on rituximab suggest that it can be a good option, especially for patients with MG who are positive for antibodies against muscle-specific tyrosine kinase (MuSK). The number of clinical trials and drugs in development for MG is steadily increasing. SUMMARY: The diagnosis of MG can generally be made from the patient's history, a neurologic examination, and laboratory and electrodiagnostic testing. Carefully selected treatment improves outcomes in MG. Additional treatment options for MG will likely be available in the near future.

Neck Flexion Strength as a Predictor of Need for Intubation in Guillain-Barre Syndrome.

OBJECTIVES: Respiratory failure in Guillain-Barre syndrome (GBS) is common. Forced vital capacity (FVC) is the gold standard for monitoring respiratory muscle strength in GBS. In some clinical situations, FVC testing could be delayed or unavailable, thus there is a need for accurate, fast, and device-free bedside respiratory evaluation. METHODS: We examined neck flexion strength in 23 GBS patients as a possible predictor of the need for subsequent intubation and as a predictor of FVC change. RESULTS: Intubation was required by 100% of patients with neck flexion strength of Medical Research Council grade ≤3. A correlation between neck flexion strength and FVC could not be determined. CONCLUSIONS: Significant weakness of neck flexion (Medical Research Council grade ≤3) at the time of admission correlates with poor respiratory status as measured by the need for intubation in patients with GBS.