Randomized Double-Blind Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Comparison of fixed cell-based assay to radioimmunoprecipitation assay for acetylcholine receptor antibody detection in myasthenia gravis.

OBJECTIVE: To compare specificity and sensitivity of a commercially available fixed cell-based assay (F-CBA) to radioimmunoprecipitation assay (RIPA) for acetylcholine receptor antibody (anti-AChR) detection in myasthenia gravis (MG). METHODS: In this retrospective diagnostic cohort study we reviewed the clinical information of suspected MG patients evaluated at the London Health Sciences Centre MG clinic who had anti-AChR RIPA and then F-CBA performed, in order to classify them as MG or non-MG. Classification of each patient as anti-AChR F-CBA-negative/positive, RIPA-negative/positive, and MG/non-MG permitted specificity and sensitivity calculations for each assay. RESULTS: Six-hundred-eighteen patients were included in study analysis. The median patient age at time of sample collection was 45.8 years (range: 7.5-87.5 years) and 312/618 (50.5%) were female. Of 618 patients, 395 (63.9%) were classified as MG. Specificity of both F-CBA and RIPA was excellent (99.6% vs. 100%, P > 0.99). One F-CBA-positive patient was classified as non-MG, although in retrospect ocular MG with functional overlay was challenging to exclude. Sensitivity of F-CBA was significantly higher than RIPA (76.7% vs. 72.7%, P = 0.002). Overall, 20/97 (21%) otherwise seronegative MG (SNMG) patients after RIPA evaluation had anti-AChR detected by F-CBA. CONCLUSIONS: In our study anti-AChR F-CBA and RIPA both had excellent specificity, while F-CBA had 4% higher sensitivity for MG and detected anti-AChR in 21% of SNMG patients. Our findings indicate that F-CBA is a viable alternative to RIPA for anti-AChR detection. Prospective studies comparing F-CBA, RIPA and L-CBA are needed to determine optimal anti-AChR testing algorithms in MG.

International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update.

OBJECTIVE: To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature. METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity. RESULTS: The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment. CONCLUSION: This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.

Classically Described, Paradoxically Underrecognized: A Case of Proximal Weakness, Hyporeflexia/Areflexia, and Dysautonomia.

ABSTRACT: We present a case of chronic, progressive proximal weakness with dysautonomia and hyporeflexia/areflexia ultimately diagnosed with Lambert-Eaton myasthenic syndrome. An approach to neuroanatomical localization is discussed leading to the appropriate selection of electrodiagnostic studies. The electrophysiologic triad of Lambert-Eaton myasthenic syndrome is demonstrated with diffusely reduced motor amplitudes, decrement with low-frequency repetitive nerve stimulation, and increment of motor amplitudes after maximum voluntary contraction. Subsequent serologic testing for P/Q-type voltage-gated calcium channel antibodies are markedly elevated. We highlight the clinical features and pitfalls of examining a patient with Lambert-Eaton myasthenic syndrome when suspecting this challenging diagnosis. The neurophysiological underpinning of the electrodiagnostic results is explained, and the diagnostic utility of single-fiber electromyography is briefly discussed.

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. METHODS: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). RESULTS: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. CONCLUSIONS: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations.

The Positive Predictive Value of Onconeural Antibody Testing: A Retrospective Review.

Paraneoplastic syndromes (PNS) are immune-mediated neurologic diseases that occur as an indirect effect of malignancy, and can be challenging to diagnose. Onconeural antibodies have a greater than 95% association with cancer, and their presence in a patient with neurologic symptoms is reportedly highly indicative of PNS. However, we performed a single-centre retrospective review to determine the positive predictive value of onconeural antibody testing, and found it to be concerningly low (39%). Recognising the limitations of onconeural antibody testing is critical to ensure accurate test interpretation, avoid unnecessary repeated malignancy screening and prevent the use of potentially hazardous immunotherapy.

Effect of Treating Acute Optic Neuritis With Bioequivalent Oral vs Intravenous Corticosteroids: A Randomized Clinical Trial.

Importance: Intravenous (IV) administration of corticosteroids is the standard of care in the treatment of acute optic neuritis. However, it is uncertain whether a bioequivalent dose of corticosteroid administered orally, which may be more cost-efficient and convenient for patients, is as effective as IV administration in the treatment of acute optic neuritis. Objective: To determine whether recovery of vision following treatment of acute optic neuritis with a high-dose IV corticosteroid is superior to that with a bioequivalent dose of an oral corticosteroid. Design, Setting, and Participants: This single-blind (participants unblinded) randomized clinical trial with 6-month follow-up was conducted at a single tertiary care center in London, Ontario, Canada. Participants were enrolled from March 2012 to May 2015, with the last participant's final visit occurring November 2015. Patients 18 to 64 years of age presenting within 14 days of acute optic neuritis onset, without any recovery at time of randomization and without history of optic neuritis in the same eye, were screened. Inclusion criteria included best-corrected visual acuity (BCVA) of 20/40 or worse and corticosteroids deemed required by treating physician. In total, 89 participants were screened; 64 were eligible, but 9 declined to participate. Thus, 55 participants were enrolled and randomized. Primary analysis was unadjusted and according to the intention-to-treat principle. Interventions: Participants were randomized 1:1 to the IV methylprednisolone sodium succinate (1000-mg) or oral prednisone (1250-mg) group. Main Outcomes and Measures: Primary outcome was recovery of the latency of the P100 component of the visual evoked potential at 6 months. Secondary outcomes were the P100 latency at 1 month and BCVA as assessed with Early Treatment Diabetic Retinopathy Study letter scores on the alphabet chart and scores on low-contrast letters at 1 and 6 months. Results: Of 55 randomized participants, the final analyzed cohort comprised 23 participants in the IV and 22 in the oral treatment groups. The mean (SD) age of the cohort was 34.6 (9.5) years, and there were 28 women (62.2%). At 6 months' recovery, P100 latency in the IV group improved by 62.9 milliseconds (from a mean [SD] of 181.9 [53.6] to 119.0 [16.5] milliseconds), and the oral group improved by 66.7 milliseconds (from a mean [SD] of 200.5 [67.2] to 133.8 [31.5] milliseconds), with no significant difference between groups (P = .07). Similarly, no significant group difference was found in the mean P100 latency recovery at 1 month. For BCVA, recovery between the groups did not reach statistical significance at 1 month or 6 months. In addition, improvements in low-contrast (1.25% and 2.5%) BCVA were not significantly different between treatment groups at 1 or 6 months' recovery. Conclusions and Relevance: This study finds that bioequivalent doses of oral corticosteroids may be used as an alternative to IV corticosteroids to treat acute optic neuritis. Trial Registration: clinicaltrials.gov Identifier: NCT01524250.

Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome.

PURPOSE OF REVIEW: This article discusses the pathogenesis, diagnosis, and management of autoimmune myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). RECENT FINDINGS: Recognition of new antigenic targets and improved diagnostic methods promise to improve the diagnosis of MG, although the clinical phenotypes associated with newer antibodies have not yet been defined. Future therapies might specifically target the aberrant immune response. The apparent increase in the prevalence of MG is not fully explained. Results of a long-awaited trial of thymectomy support the practice of performing a thymectomy under specific conditions. SUMMARY: The current treatment options are so effective in most patients with MG or LEMS that in patients with refractory disease the diagnosis should be reconsidered. The management of MG is individualized, and familiarity with mechanisms, adverse effects, and strategies to manage these commonly used treatments improves outcome. Patient education is important. LEMS, frequently associated with an underlying small cell lung cancer, is uncommon, and the mainstay of treatment is symptomatic in most patients.

A Review of Azathioprine-Associated Hepatotoxicity and Myelosuppression in Myasthenia Gravis.

OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disorder in which antibodies interfere with neuromuscular transmission. Azathioprine (AZA) is an immunosuppressant frequently used for treatment of various autoimmune conditions, including MG. The literature suggests that the rates of AZA-associated hepatotoxicity and myelosuppression in MG are highly variable. Published studies have not formally analyzed their pattern, severity, timing, and/or recovery. We assessed the prevalence, pattern and timing of AZA associated toxicity in a large group of MG patients. METHODS: We identified 113 patients with MG with AZA-associated toxicity among 571 managed with this immunosuppressant. The timing of when toxicities occurred as well as pattern of laboratory abnormalities was assessed. RESULTS: The overall prevalence of hepatotoxicity and myelosuppression was 15.2% and 9.1%, respectively. The most common pattern of hepatotoxicity seen was gamma-glutamyl transpeptidase (GGT) enzyme elevation in 67.8% of patients. Of note, 21.2% of patients with myelosuppression had normocytic anemia, 17.3% had pancytopenia, and another 17.3% developed macrocytic anemia. CONCLUSIONS: AZA-associated hepatotoxicity and myelosuppression in MG are not uncommon and may be underrecognized depending on the timing, frequency, and specific tests ordered for blood work monitoring.

International consensus guidance for management of myasthenia gravis: Executive summary.

OBJECTIVE: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. RESULTS: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. CONCLUSION: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.

Hope, Coping, and Quality of Life in Adults with Myasthenia Gravis.

UNLABELLED: Myasthenia gravis significantly impacts quality of life. However, the relationship between hope, coping, and quality of life (QOL)in myasthenia patients has not been studied (Kulkantrakorn & Jarungkiatkul, 2009; Raggi et al., 2010). OBJECTIVE: The aim of this study was to explore the relationship between hope, coping, and quality of life in adults with myasthenia gravis. DATA COLLECTION: Subjects with MG (n = 100) completed six questionnaires, including a demographic profile, the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL), Herth Hope Index (HHI), Jalowiec Coping Scale (JCS), Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), and Short Form Health Survey (SF-36v2). RESULTS: Mean hope scores indicated a high level of hope. An optimistic coping style was the most common and effective coping strategy identified by subjects. Positive thinking and humour were also frequently used strategies. Participants identified quality of life as good tolerability, above general population mental well-being, and below general populationphysical well-being. Participants who identified good quality of life had low scores on the MG-QOL15 scale and high scores on the SF36v2. Hope and independence for activities of daily living were found to correlate with improved quality of life and mental well-being(p < 0.001). Age and length of illness were not significant factors. There was no mediation by well-being or quality of life in the relationship between hope and coping. Hope and coping were not important factors for well-being or quality of life. CONCLUSION: Nurses caring for adults with myasthenia gravis should use interventions that continue to support hope, quality of life, and coping throughout the unpredictable and chronic course of MG.

Electrodiagnostic Testing and Treatment for Carpal Tunnel Syndrome in Canada.

OBJECTIVES: 1) Assess which electrodiagnostic studies Canadian clinicians use to aid in the diagnosis of carpal tunnel syndrome (CTS). 2) Assess whether Canadian clinicians follow the American Association of Neuromuscular & Electrodiagnostic Medicine/American Academy of Neurology/American Academy of Physical Medicine and Rehabilitation Practice Parameter for Electrodiagnostic Studies in CTS. 3) Assess how Canadian clinicians manage CTS once a diagnosis has been established. METHODS: In this prospective observational study, an electronic survey was sent to all members of the Canadian Neuromuscular Group (CNMG) and the Canadian Association of Physical Medicine and Rehabilitation (CAPM&R) Neuromuscular Special Interest Group. Questions addressed which electrodiagnostic tests were being routinely used for the diagnosis of carpal tunnel syndrome. Management recommendations for CTS was also explored. RESULTS: Of the 70 individuals who completed the survey, fourteen different nerve conduction study techniques were reported. Overall, 36/70 (51%) of participants followed the AANEM/AAN/AAPM&R Practice Parameter. The standard followed by the fewest of our respondents with 64% compliance (45/70) was the use of a standard distance of 13 to 14 cm with respect to the median sensory nerve conduction study. Regarding management, 99% would recommend splinting in the case of mild CTS. In moderate CTS, splinting was recommended by 91% of clinicians and 68% would also consider referral for surgery. In severe CTS, most recommended surgery (93%). CONCLUSIONS: There is considerable variability in terms of which electrodiagnostic tests Canadian clinicians perform for CTS. Canadian clinicians are encouraged to adhere to the AANEM/AAN/AAPM&R Practice Parameter for Electrodiagnostic Studies in CTS.

A genome-wide association study of myasthenia gravis.

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Development of Myasthenia Gravis in a Patient with Chronic Myeloid Leukemia during Treatment with Nilotinib.

We report on a patient diagnosed with chronic myeloid leukemia (CML) who developed myasthenia gravis while on treatment with nilotinib. Autoimmune disease, including the development of myasthenia gravis, has been described in association with CML as well as the use of tyrosine kinase inhibitors. Second generation tyrosine kinase inhibitors are highly effective in the treatment of CML, although can result in adverse effects related to off-target kinase inhibition, and longer term reporting of adverse effects is required.