Accuracy of patient-reported data for an online patient registry of autoimmune myasthenia gravis and Lambert-Eaton myasthenic syndrome.

Disorders of the neuromuscular junction (NMJ) comprise a spectrum of rare diseases causing muscle fatigability and weakness, leading to life-long effects on quality of life. We established the Dutch-Belgian registry for NMJ disorders, based on a unique combination of patient- and physician-reported information. Information on natural course, disease burden, prevalence of complications and comorbidity is collected through patient-reported standardized questionnaires and verified using medical documentation. Currently, the registry contains information of 565 Myasthenia Gravis (MG) patients and 38 Lambert-Eaton myasthenic syndrome (LEMS) patients, constituting approximately 25% (MG) and 80% (LEMS) of patients in the Netherlands. This is a very large registry, with the highest participation rate per capita. In addition to confirming many disease characteristics previously described in the literature, this registry provides several novel insights. The reported rate of potentially corticosteroid-related comorbidity, including hypertension, heart disease, osteoporosis and type 2 diabetes was high, emphasizing the need to commence corticosteroid-sparing immune suppressive treatment as soon as possible. The reported rate of other auto-immune diseases is far higher than previously expected: 27% of MG and 38% of LEMS patients, and a surprisingly high number of MG patients (47%) is unaware of their antibody status. In conclusion, this registry provides a valuable collection of information regarding MG and LEMS disease course. Continuous collection of annual follow-up data will provide further longitudinal insights in disease burden, course and treatment effect.

Myasthenia Gravis Impairment Index: Sensitivity for Change in Generalized Muscle Weakness.

INTRODUCTION: The recently developed Myasthenia Gravis Impairment Index (MGII) is a promising measure as it has less floor effects and a higher relative efficiency in its responsiveness to treatment effect compared to other MG measures. This study aimed at validating the MGII in a Dutch cohort of MG patients and analyzing the sensitivity of MGII compared to MG-ADL for changes in generalized weakness. METHODS: We analyzed (generalized items of; -gen) MGII, quantitative myasthenia gravis (QMG), Myasthenia Gravis Activities of Daily Living (MG-ADL), EQ-5D visual analog, Myasthenia Gravis Composite (MGC) and ACTIVLIM (an ADL questionnaire focusing on generalized weakness) scores in a prospective cohort of 99 MG patients. We investigated correlations between MGII and other outcome measures. We used a generalized linear model to assess whether MGIIgen had an additional sensitivity on top of MG-ADLgen for changes (Δ) in QMGgen in individual patients. RESULTS: MGII had a lower floor effect (4%) compared to QMG (6%), MG-ADL (11%) and MGC (16%). MGII correlated well with QMG (r = 0.68), MG-ADL (r = 0.83) and MGC (r = 0.74). As expected, the correlations with EQ visual analog and ACTIVLIM were lower (r = - 0.57 and - 0.48). ΔMGIIgen had an additional value on top of ΔMG-ADLgen in the prediction of ΔQMGgen (B = 0.54, p = 0.01). DISCUSSION: The MGII score was cross-culturally validated in a Dutch cohort of MG patients. MGII had a higher sensitivity for generalized weakness than MG-ADL.

Repetitive ocular vestibular evoked myogenic potentials in myasthenia gravis.

OBJECTIVE: To validate the repetitive ocular vestibular evoked myogenic potentials (RoVEMP) test for diagnostic use in myasthenia gravis (MG) and to investigate its value in diagnostically challenging subgroups. METHODS: The RoVEMP test was performed in 92 patients with MG, 22 healthy controls, 33 patients with a neuromuscular disease other than MG (neuromuscular controls), 4 patients with Lambert-Eaton myasthenic syndrome, and 2 patients with congenital myasthenic syndrome. RESULTS: Mean decrement was significantly higher in patients with MG (28.4% ± 32.2) than in healthy controls (3.2% ± 13.9; p < 0.001) or neuromuscular controls (3.8% ± 26.9; p < 0.001). With neuromuscular controls as reference, a cutoff of ≥14.3% resulted in a sensitivity of 67% and a specificity of 82%. The sensitivity of the RoVEMP test was 80% in ocular MG and 63% in generalized MG. The RoVEMP test was positive in 6 of 7 patients with seronegative MG (SNMG) with isolated ocular weakness. Of 10 patients with SNMG with negative repetitive nerve stimulation (RNS) results, 73% had an abnormal RoVEMP test. The magnitude of decrement was correlated with the time since the last intake of pyridostigmine (B = 5.40; p = 0.019). CONCLUSIONS: The RoVEMP test is a new neurophysiologic test that, in contrast to RNS and single-fiber EMG, is able to measure neuromuscular transmission of extraocular muscles, which are the most affected muscles in MG. Especially in diagnostically challenging patients with negative antibody tests, negative RNS results, and isolated ocular muscle weakness, the RoVEMP test has a clear added value in supporting the diagnosis of MG. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that RoVEMP distinguishes MG from other neuromuscular diseases.

Heterogeneity and shifts in distribution of muscle weakness in myasthenia gravis.

The distribution of muscle weakness in myasthenia gravis (MG) patients with acetylcholine receptor (AChR) antibodies is highly variable. As muscle groups respond differently to therapeutic interventions, it is important to acknowledge this variability. We analysed the distribution of muscle weakness in 225 AChR MG patients over time. On the basis of combinations of muscle weakness, seven phenotypes were defined: 'ocular' (O), 'bulbar' (B), 'neck/limbs/respiratory' (NLR), or a combination (O+B, O+NLR, B+NLR and O+B+NLR). MG remained restricted to ocular weakness in 5%, whereas 7% never had ocular weakness. At last follow-up, ocular or bulbar weakness had resolved more frequently than NLR weakness (40%, 38% and 25%; p = 0.003, respectively). Patients with O, B or OB phenotype at baseline had a higher age at onset and were more frequently male than patients with NLR, ONLR, BNLR or OBNLR phenotype (52.7 ±â€¯17.5 vs. 44.0 ±â€¯18.9; p = 0.007 and 64% vs. 37%; p = 0.002, respectively). MG patients have heterogeneous distributions of muscle weakness and frequently shift between phenotypes. The phenotypic variations found in AChR MG suggest that also other factors aside from the AChR antibody mediated immune response are of importance in determining the disease expression in MG.

Ocular Weakness in Myasthenia Gravis: Changes in Affected Muscles are a Distinct Clinical Feature.

INTRODUCTION: In this study we quantitatively describe ocular weakness patterns in myasthenia gravis (MG) to help neurologists in making the clinical diagnosis and to investigate how the current outcome measures reflect ocular weakness in MG. METHODS: We investigated ptosis and diplopia patterns in a retro- and prospective cohort of 306 MG patients. Diplopia was systematically examined by testing extra-ocular muscle (EOM) fatigability in two horizontal and four oblique directions for 60 seconds. RESULTS: Of patients with initial symmetric ptosis, 40% developed asymmetric ptosis at the second visit. Changes in form of ptosis occurred less often in seronegative MG patients (50%) than in patients with acetylcholine receptor (AChR) antibodies (70%) or muscle-specific kinase (MuSK) antibodies (69%) (p = 0.038). Of patients with diplopia on the first visit, double vision contained both a vertical and horizontal component in 95%. At the second visit, 83% manifested diplopia in other gaze directions. The mean time (in seconds) to diplopia was 11.6±14.0 and the mean time to ptosis was 27.6±19.8. Diplopia or ptosis manifested within 30 seconds in 87% and 58%, respectively. Patients who manifested diplopia after 30 seconds, reported no limitations due to diplopia. DISCUSSION: Changes in the gaze directions in which diplopia occurs or ptosis side occur frequently in MG. In diagnostically challenging cases, we recommend testing ptosis and diplopia in multiple gaze directions for 30-60 seconds during at least two follow-up visits to maximize the chance of observing changes in ocular weakness patterns.

A prospective, double-blind, randomized, placebo-controlled study on the efficacy and safety of influenza vaccination in myasthenia gravis.

OBJECTIVE: To investigate the efficacy and safety of an influenza vaccination in patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG). METHODS: An influenza vaccination or placebo was administered to 47 AChR MG patients. Before and 4 weeks after administration blood samples and clinical outcome scores were obtained. Antibodies to the vaccine strains A/California/7/2009 (H1N1)pdm09, A/Hong Kong/4801/14 (H3N2) and B/Brisbane/060/08 were measured using the hemagglutination-inhibition (HI) assay and disease-specific AChR antibody titers were measured with a radio-immunoprecipitation assay. Forty-seven healthy controls (HC) were vaccinated with the same influenza vaccine to compare antibody titers. RESULTS: A post-vaccination, seroprotective titer (HI ≥ 1:40) was achieved in 89.4% of MG patients vs. 93.6% in healthy controls for the H3N2 strain, 95.7% vs 97.9% for the H1N1 strain and 46.8 vs 51% for the B-strain. A seroprotective titer for all three strains of the seasonal influenza vaccine was reached in 40.4% (19/47) of the MG group and in 51% (24/47) of the HC group. Immunosuppressive medication did not significantly influence post geomean titers (GMT). The titers of disease-specific AChR antibodies were unchanged 4 weeks after vaccination. The clinical outcome scores showed no exacerbation of MG symptoms. CONCLUSION: The antibody response to an influenza vaccination in patients with AChR MG was not different from that in healthy subjects, even in AChR MG patients using immunosuppressive medication. Influenza vaccination does not induce an immunological or clinical exacerbation of AChR MG. CLINICAL TRIAL REGISTRY: The influenza trial is listed on clinicaltrialsregister.eu under 2016-003138-26.

Activity limitations in myasthenia gravis and relation to clinical variables.

INTRODUCTION: It is unknown how fluctuations in muscle weakness affect activity limitations in myasthenia gravis patients and how the severity of these limitations compares with published data on other neuromuscular disorders (NMD). METHODS: In this study we analyzed ACTIVLIM (acronym of "ACTIVity LIMitations") and quantitative myasthenia gravis (QMG) scores. We assessed the impact of QMG and other clinical variables on ACTIVLIM, using B coefficients. RESULTS: The mean ACTIVLIM score in 118 MG patients was 3.3. There was a correlation between QMG and ACTIVLIM (B coefficient = -0.206, P < 0.001) and between changes in both scores (B coefficient = -0.175, P = 0.002). Men and patients without another autoimmune disease had a better ACTIVLIM score (B coefficient = 0.785, P = 0.015 and B coefficient = 0.998, P = 0.008, respectively). CONCLUSIONS: The ACTIVLIM score in MG is higher than in other NMD. Fluctuations in QMG correlated significantly with changes in ACTIVLIM. Muscle Nerve 56: 64-70, 2017.

Prognostic factors for exacerbations and emergency treatments in myasthenia gravis.

BACKGROUND: Disease course in myasthenia gravis (MG) patients is highly variable. Prognostic factors that identify patients at risk for a more severe disease course would be helpful in clinical practice. METHODS: We investigated MG patients under treatment at our university medical center between 1993 and 2013. The impact of baseline characteristics on the occurrence of exacerbations and the necessity of emergency treatments were investigated using multiple logistic regression analysis and log-rank tests for our Kaplan-Meier survival curves. RESULTS: We included 96 MG patients. Late age at onset (LOMG, ≥ 50 years) was associated with a higher risk of an exacerbation (odds ratio [OR]=9.33, 95% confidence interval [CI] = 2.43-35.87; p = 0.001) and the necessity of an emergency treatment within 3 years (OR = 5.25, 95% CI = 1.21-22.80; p = 0.027). The presence of additional autoimmune diseases (AID) in the patient was associated with a higher risk of an exacerbation (OR = 4.03, 95% CI = 1.09-14.85; p = 0.036). Patients with both LOMG and an additional AID had a markedly higher risk of an exacerbation (OR = 47.00, 95% CI = 6.49-340.65; p < 0.001) and the necessity of an emergency treatment (OR = 26.11, 95% CI = 4.12-165.55; p = 0.001) compared to early-onset patients without additional autoimmune diseases. CONCLUSIONS: Late-onset MG and the presence of additional autoimmune diseases were associated with a higher risk of exacerbations of MG and the necessity of emergency treatments.