Muscle Weakness In Myasthenia Gravis Research Articles

Personality factors in patients with myasthenia gravis: A prospective study.

In myasthenia gravis (MG), depression and anxiety have frequently been reported as comorbidities. However, little is known about personality characteristics in MG patients. We aimed to characterise personality traits in MG and to correlate them with disease severity and disease course. The Big Five Inventory data questionnaire was used to investigate personality traits in 44 MG patients and 45 healthy controls similar in age and gender. In 28 MG patients, a caregiver was also available for patient assessments to limit bias associated with social desirability in patients' responses. Patients were assessed with regard to premorbid personality (before manifestation of MG) and to present condition. In addition, anxiety and depression scales (Hospital Anxiety and Depression Scale and Beck Anxiety Inventory) were applied. Compared to controls, MG patients showed significantly higher levels of neuroticism, whereas openness and extraversion were significantly lower. Agreeableness and conscientiousness did not differ between groups. Neuroticism was influenced by disease severity such as generalization of weakness, presence of thymoma, and bulbar involvement as well as disease duration. Neuroticism correlated with premorbid level of neuroticism but also with depression and anxiety scores. A personality profile of increased neuroticism and lower openness and extraversion in MG patients may contribute considerably to the perception of disease severity. It may also be related to frequent comorbidities such as anxiety and depression. Although premorbid levels of neuroticism were increased, this characteristic may also increase considerably during the course of the disease. The data indicate that muscle weakness in MG is accompanied or even complicated by psychological aspects. Therefore, a psychological and behavioral intervention in addition to the specific pharmacological therapy might be of particular value.

Outcomes and characteristics of myasthenia gravis: A 10-year retrospective cross-sectional study at King Fahad Medical City.

To investigate the distribution of muscle weakness in Myasthenia gravis (MG) and the therapeutic response in each category. This is a retrospective cross-sectional study included all MG patients presented to our clinic between 2010 and 2020. The demographic, clinical, serological, electrophysiological, radiological, and histopathological data of the patients were recorded. The details of the treatment administered were also documented. Muscle weakness was divided into: ocular, bulbar, and generalized. The mean age of the 147 patients included in this study was 34.2±16.6 years. The most common presentation was ocular MG (57.1%). There was no significant association between the gender of the patients and the MG subgroups. Antibodies against AChR were reported in 95.2%, 75%, and 87% of the patients with ocular, bulbar, and generalized myasthenia, respectively. Anti-MuSK antibodies were detected in 20% of the patients with bulbar weakness. Most of the patients with ocular (91.7%) and bulbar (90%) presentation developed generalized weakness. At the end of the follow-up, 82.6%, 70.2%, and 57.5% of the patients with generalized, ocular, and bulbar presentations, respectively demonstrated well-controlled weakness. The most common initial presentation was ocular weakness. Most patients with ocular and bulbar presentation developed generalized weakness during the follow up period. The most frequently reported autoantibody was against AChR. Most patients with generalized, ocular, and bulbar presentation demonstrated well-controlled weakness at the end of the follow up period.

A population-based follow-up study of maximal muscle strength and mobility in patients with myasthenia gravis

It is uncertain whether residual muscle weakness in myasthenia gravis (MG) can improve, and whether it reflects deficits and disability. In a population-based follow-up study of 107 patients with MG and 50 healthy controls, maximal shoulder, knee and ankle strength was measured using isometric dynamometry and related to the quantitative MG (QMG), the MG Composite (MGC), the MG-activities of daily living (MG-ADL), the MG quality of life 15-items (QOL15) and a 400 m walk test (400MWT). During a mean follow-up of 4.6 (±0.04) years, patients improved 10.8% (P < 0.001) in isometric shoulder strength, whereas their isometric knee strength did not improve (3.2%, P = 0.151). Higher age, longer disease duration and greater baseline impairment had no negative impact. Change in isometric shoulder and knee strength did not correlate with changes in the QMG, the MG-ADL or the QOL15. Change in isometric knee strength correlated with change in the 400MWT (r = -0.357), and the 400MWT correlated with changes in the QMG (r = 0.439), the MG-ADL legs subitem (r = 0.419) and the QOL15 (r = 0.310). Overall, muscle strength improved over time, and the MG clinical scales were related to impaired mobility and muscle strength. Change in residual muscle weakness was unrelated to disability (MG-ADL) and quality of life (QOL15).

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 ± 17.5 vs. 44.0 ± 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.

S12-2. Excitation-contraction coupling in myasthenia gravis: Up to date

Although defective neuromuscular transmission is known to be a cause of muscle weakness in myasthenia gravis (MG), previous studies have shown the possible roles of other processes, the failure of which may also cause muscle weakness in MG. Especially, excitation-contraction (E-C) coupling may be defective in patients with MG. Some investigators have applied the post-tetanic potentiation and/or the staircase phenomenon to elucidate the impairment of E-C coupling in MG. Recently, we reported a new method to assess E-C coupling of masseter and abductor pollicis brevis muscles using an accelerometer. In this method, compound muscle action potentials (CMAP) in the belly-tendon fashion and movement-related potentials (MRP) of jaw and finger movements were simultaneously recorded following nerve stimulation. The E-C coupling time (ECCT) was obtained from the difference in onset latencies between CMAP and MRP. The impairment of E-C coupling was assessed by prolonged ECCT and/or low MRP amplitude. In this lecture, I will discuss our data in MG, (1) correlation of bite force with ECCT of the masseter, (2) correlation between anti-ryanodine receptor antibody and ECCT, (3) early effect of tacrolimus in improving ECCT, (4) impairment of post-tetanic potentiation of muscle twitch, (5) effect of local cooling on E-C coupling.

Increased skeletal muscle expression of the endoplasmic reticulum chaperone GRP78 in patients with myasthenia gravis

In myasthenia gravis (MG), damage to neuromuscular junctions may induce endoplasmic reticulum (ER) stress in skeletal muscles. In the current study, skeletal muscles obtained from patients with MG exhibited upregulation of glucose-regulated protein 78 (GRP78) mRNA that was activated by ER stress. Furthermore, GRP78 mRNA expression was higher in patients with MG and myositis than in patients with non-myopathy. We also observed a significant positive correlation between GRP78 mRNA expression and GRP78 protein levels and between GRP78 mRNA expression and age of MG onset. Our findings suggest that muscle weakness in MG might be caused by both neuromuscular junction disruption and ER stress.

22. Hemoglobin concentration changes induced by transcranial magnetic stimulation (TMS) over the primary motor area

The aim of this study was to elucidate the correlation between excitation–contraction coupling time (ECCT) of the masseter and the bite force in myasthenia gravis (MG). Compound muscle action potentials (CMAPs) of the masseter and movement-related potentials (MRPs) using an accelerometer placed on the chin were simultaneously recorded after trigeminal nerve stimulation by a monopolar needle electrode inserted into the mandibular notch. The ECCT was defined as the difference in onset latencies between CMAP and MRP. The repetitive nerve stimulation test (RNS) was also performed in the same masseter before the ECCT recording. The bite force was measured using a pressure-sensitive sheet immediately after the ECCT recording. Successive examinations of RNS/ECCT and the bite force measurements were performed in 18 patients with MG. We calculated percent difference of the bite force to estimate the inter-trial differences of the bite force in each subject. The ECCT was significantly correlated with the percent difference of the bite force (p = 0.02). On the other hand, the percent difference of the bite force did not show any significant relationship with either the decrement in RNS or CMAP amplitude of the masseter. Our results suggest that dysfunction of E–C coupling may contribute to the muscle weakness in MG.

Differentiation of internuclear ophthalmoplegia and myasthenic pseudo-internuclear ophthalmoplegia by subjective visual vertical

Objectives: Internuclear ophthalmoplegia (INO) is characterized by an adduction deficit on lateral gaze and a dissociated nystagmus of the abducting eye. In the majority of cases INO occurs with lesions of the medial longitudinal fascicle (MLF) caused by multiple sclerosis or ischemia. However, extraocular muscle weakness in myasthenia gravis (MG) can mimic this ocular motor pattern and has been referred to as pseudo-internuclear-ophthalmoplegia (pseudo-INO). Differentiation between these entities can be difficult but is crucial for choosing specific therapeutic strategies. We here report that measurement of the subjective visual vertical (SVV) reliably differentiates INO from pseudo-INO.

Ptosis in myasthenia gravis: Extended fatigue and recovery bedside test

Fluctuating double vision and ptosis are the hallmarks of extraocular muscle weakness in myasthenia gravis (MG). On sustained upward gaze, ptosis usually increases temporarily. The first description of using this fatigue sign has been attributed to the Scottish neurologist John Simpson. Cogan added his lid-twitch sign to the diagnostic bedside armamentarium.1 For many years, we have applied a fatigue-recovery test at the bedside, whereby the strength of the previously fatigued levator palpebrae muscle is improved shortly after voluntary …

Spontaneous thymoma rat as a model for myasthenic weakness caused by anti‐ryanodine receptor antibodies

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation–contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1655–1660, 1998

Spontaneous thymoma rat as a model for myasthenic weakness caused by anti-ryanodine receptor antibodies.

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation-contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle.

Diverse Fab specific for acetylcholine receptor epitopes from a myasthenia gravis thymus combinatorial library.

The muscle weakness in myasthenia gravis (MG) is caused by heterogeneous high-affinity IgG autoantibodies to the nicotinic acetylcholine receptor (AChR), a complex ion channel glycoprotein. These antibodies are clearly responsible for reducing AChR numbers at the neuromuscular junction in myasthenia; however, the origins, diversity, specificity and pathogenicity of individual antibodies have not yet been established. We have cloned and characterized four different AChR-specific Fab from an MG patient's thymus by screening an IgG1/kappa gene combinatorial lambda phage library with soluble human AChR labeled with [125I] alpha-bungarotoxin. Unlike most previously cloned human antibodies, all four Fab immunoprecipitated soluble human muscle AChR. Two Fab strongly inhibited binding of mAb to the main immunogenic region on the alpha subunits and one Fab bound to an epitope on the fetal-specific gamma subunit. In sensitivity and fine specificity, these Fab resembled the anti-AChR antibodies found in many MG patients, including the donor. The closest germline counterparts for their heavy chains were in VH families 1, 3 and 4; however, there were many differences consistent with an antigen-driven response of diverse B cell clones. The combinatorial approach holds promise for further analysis of human autoantibodies.

Passive transfer of seronegative myasthenia gravis to mice

Muscle weakness in myasthenia gravis is due to autoantibody-induced loss of functional acetylcholine receptors (AChR). About 15% of myasthenia gravis patients, however, do not have detectable anti-AChR antibodies. To investigate the effect of their plasma immunoglobulins on neuromuscular transmission, mice were injected with plasma (and in some cases purified immunoglobulin G (IgG)) from 7 "seronegative" myasthenia gravis (SMG) patients, and neuromuscular transmission parameters were examined. When injected for 15 days, all patients' plasma caused reductions in miniature endplate potential amplitudes, while endplate potential quantal content was significantly reduced by plasma from 4 of the 7 patients. There were no changes in ACh-induced depolarization or single channel properties, and 125I-alpha-bungarotoxin binding studies showed no effect on AChR number, except in 1 case. Purified IgG injected for 3 days had similar effects to plasma injected for 15 days. Our findings confirm that SMG is autoantibody mediated and that there are pathogenic IgG antibodies. SMG appears to be a heterogeneous disorder and the target(s) for the antibodies may be diverse.

Seronegative myasthenia gravis: a plasma factor inhibiting agonist-induced acetylcholine receptor function copurifies with IgM.

Anti-acetylcholine receptor antibodies cannot be detected by standard radioimmunoassay in 10 to 15% of patients with generalized myasthenia gravis (seronegative myasthenia gravis). We investigated the effect of seronegative myasthenia gravis plasma on 22Na+ flux through acetylcholine receptors and voltage-gated sodium channels in the human rhabdomyosarcoma cell line, TE671. Fourteen of 19 seronegative MG plasmas inhibited acetylcholine receptor 22Na+ flux; none inhibited voltage-gated sodium channel flux. The inhibitory activity was found in the IgG-depleted fraction, and copurified with IgM after gel-filtration chromatography. Inhibitory activity was absent from the plasma of 8 healthy control subjects and of 6 patients with the Lambert-Eaton myasthenic syndrome, but was present in the IgG-depleted plasma fraction of 4 of 6 seropositive patients with myasthenia gravis and all 5 patients with demyelinating polyneuropathy. We conclude that a low-affinity serum factor, probably an IgM antibody, found in a high proportion in patients with seronegative and those with seropositive myasthenia gravis may contribute to the muscle weakness in myasthenia gravis, but its role in these and other neuroimmunological disorders requires further investigation.

Isolation of germinal centre (GC) cells is greatly improved by using the protease dispase to prepare cell suspensions.

The characteristic muscle weakness in myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR) of the motor endplate. They can be measured in a very sensitive radio-immunoassay (using detergent extracts of muscle, labelled with l25I-a-bungarotoxin1). There appears to be a special relationship with the thymus in MG. About 10% of cases have thymoma, and, in about two thirds of the remainder, there is thymic hyperplasia with medullary germinal centres (GC, reviewed in 1). Cell suspensions prepared by chopping and sieving these thymi (THYconv) spontaneously synthesise anti-AChR antibodies in culture.1 That is greatly increased if the tissue is dispersed instead by using the proteases collagenase and, especially, dispase2 (THYC+D) Dispase is a neutral protease that is apparently essential for isolating mouse follicular dendritic (FD) cells.3 We now report experiments probing the histological and functional basis of this striking bonus.

Acetylcholine Receptor Protein

Rabbits injected with purified acetylcholine (ACh) receptor protein produce antibodies against the receptor and develop generalized muscle weakness. The compound muscle action potentials show a decremental fall in amplitude with repetitive nerve stimulation. Both the weakness and the decrement is counteracted by reversible cholinesterase inhibitors. Intracellular recordings from muscle endplates show that the amplitude of the miniature end-plate potentials is considerably reduced. A reduced binding of neurotoxin to muscles from immunized rabbits was observed. Nerve impulses release a normal number of ACh packages (quanta) from the motor nerve terminals. The muscle weakness in immunized rabbits thus has the same features as the muscle weakness in myasthenia gravis and may be a good animal model of myasthenia gravis.