Electrophysiological profile of the patients with MuSK positive myasthenia gravis

Abstract

Objectives:

To determine the electrophysiological profile of our cohort of patients with muscle-specific tyrosine kinase (MuSK) positive myasthenia gravis (MG).

Methods:

Repetitive nerve stimulation test (RNS) and jitter analysis using concentric needle electrode were performed in 31 MuSK and in 28 acetylcholine receptor (AChR) positive MG patients.

Results:

Pathological RNS was verified in 16 (51·6%) MuSK and 26 (92·9%) AChR MG patients (P < 0·01). Pathological jitter analysis was registered in 28 (90·3%) MuSK and 26 (92·9%) AChR MG patients (P > 0·05). Increased jitter was present in extensor digitorum communis (EDC) in 23 (74·2%) MuSK and in 25 (89·3%) AChR MG patients (P > 0·05) as well as in orbicularis oculi (OO) muscle in 24 (85·7%) MuSK and 22 (81·5%) AChR MG patients (P > 0·05). Lower mean value of mean consecutive difference (MCD) and fewer potential pairs with increased jitter were registered in MuSK MG compared to AChR MG patients only in EDC muscle (P < 0·05). In MuSK MG patients, increased jitter was observed to be more frequent in patients with longer disease duration (P < 0·05) and also in those patients exhibiting more severe disease forms (P < 0·01) only in EDC muscle.

Discussion:

Repetitive nerve stimulation test has low sensitivity in MuSK MG patients, while jitter analysis shows high sensitivity, especially in facial muscles. The EDC muscle in MuSK MG patients usually shows increased jitter in more severe disease forms and later in the course of the disease.     

Association of muscle strength and electrophysiological measures of reinnervation in diabetic neuropathy

Motor function was assessed in 34 non-insulin-dependent and 19 insulin-dependent diabetic patients with macroelectromyography and isokinetic dynamometry. Fiber density (FD) and the amplitude of the macro motor unit potential (macro MUP) of the anterior tibial and lateral vastus muscles were obtained and maximal isokinetic strength of the ankle and knee extensors were determined. All patients underwent standardized clinical examination including a neurological disability score (NDS), quantitative sensory examination, and conventional motor nerve conduction studies. The amplitude of the macro MUP and FD of the anterior tibial muscle were increased in neuropathic patients without weakness (P < 0.05) and further increased in neuropathic patients with weakness (P < 0.05). The NDS was related to the FD and the amplitude of the macro MUP for the anterior tibial and lateral vastus muscle [r = 0.55–0.75 (P < 0.005)]. Muscle strength of ankle and knee extensors correlated with the FD [r = −0.69 (P < 0.0001) and r = −0.58 (P < 0.001), respectively] and with the amplitude of the macro MUP of the two muscles [r = −0.63 (P < 0.0001) and r = −0.37 (P < 0.05), respectively]. Our findings support the hypothesis that loss of muscle strength in diabetic patients is due to incomplete reinnervation following axonal loss. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1647–1654, 1998     

Anti-AChR antibodies, thymic histology, and T cell subsets in myasthenia gravis

The relationship between the titers of antibody against acetylcholine receptor (AChR) and T helper/suppressor balance (assessed by the OKT4/OKT8 ratio) were investigated in 74 patients with myasthenia gravis (MG). All patients with elevated AChR antibody titers (greater than 100 nM) had hyperplastic thymuses, while most patients with low or negative antibody titers (less than 1 nM) had involuted thymuses. All patients with thymoma had positive, though not very high, antibody titers. No correlation was found between anti-AChR antibody levels and OKT4/OKT8 ratios except for patients with thymoma. Thus, it appears that AChR antibody titers are more closely related to thymic pathology than to peripheral T cell imbalance. These results are consistent with the hypothesis giving a central role to thymic lymphocytes in the AChR antibody production, either as antibody producer B cells or helper T cells.     

Acetylcholine receptor and calcium leakage activity in nondystrophic and dystrophic myotubes (MDX)

To determine whether the lack of dystrophin alters the occurrence of calcium leakage activity (CLA) and acetylcholine receptor (AChR) activity, the frequency of each event class was determined from several cell attached patches on nondystrophic and dystrophic (mdx) myotubes. The frequency of CLA observed in the presence of ACh was significantly (P < 0.05) elevated in mdx myotubes, an effect which was partly due to a significant (P < 0.05) increase in the proportion of cell attached patches that exhibited 100% CLA with no AChR activity. Areas of mdx and nondystrophic membrane that exhibited reduced or absent AChR activity had significantly (P < 0.01) and substantially elevated calcium leakage event frequencies. This inverse and discontinuous relationship between CLA and AChR activity provides further evidence that some CLA in dystrophic muscle is produced by clusters of AChRs that form unusual physical associations with the dystrophic cytoskeleton during the processes associated with receptor localization and stabilization. © 1996 John Wiley & Sons, Inc.     

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     

Concentric and single fiber needle electrodes yield comparable jitter results in myasthenia gravis

The single fiber needle electrode (SFNE), which is designed to isolate single muscle fiber action potentials, has played an important role in the diagnosis of myasthenia gravis (MG). However, the concentric needle electrode (CNE) has been recently adopted by some workers to study neuromuscular instability in MG, and reference data have also been obtained in healthy subjects. In this study we wanted to establish whether data acquired using the SFNE is comparable to that obtained using the CNE when studying patients with MG. We established reference data for our laboratory using the CNE for orbicularis oculi (OO) and extensor digitorum communis (EDC). We compared data from 24 MG patients using both SFNE and CNE and found no significant differences in mean jitter values for either muscles. We correlated the neurophysiological data obtained by either electrode with various clinical assessments, the ice pack test, OO and EDC strength measurement, and MGFA classification of disease, and we found no significant relation. We compared discomfort scores for the two needle electrodes for each muscle and found that the discomfort scores for CNE are significantly lower (P = 0.0004). We conclude that the CNE is a useful alternative electrode for studying single fiber potentials, but more reference data from normal control subjects is desirable. Muscle Nerve, 2008     

B‐cell–activating factor is elevated in serum of patients with myasthenia gravis

Introduction: Myasthenia gravis (MG) is a B‐cell–mediated autoimmune disease. B‐cell–activating factor (BAFF) is a major factor in B‐cell development and activation. In this study we investigated serum BAFF levels in MG patients. Methods: We compared the serum BAFF levels of 20 MG patients with gender‐matched healthy controls. We assayed serum concentrations of BAFF and anti‐acetylcholine receptor antibody (AChR) titers. Results: Serum BAFF levels of MG patients with AChR antibodies were significantly higher than those of healthy controls. A significant positive correlation was observed between serum BAFF levels and anti‐AChR antibody titers. BAFF values did not correlate with disease severity. Conclusions: BAFF may play a major role in the pathogenesis of MG, and it may provide a potential target for therapy in patients with MG. Muscle Nerve 54 : 1030–1033, 2016     

Single fiber EMG as a prognostic tool in myasthenia gravis

Introduction: Single fiber electromyography (SFEMG) is the most sensitive diagnostic tool for diagnosis of myasthenia gravis (MG). Its prognostic value is not known. Methods: We retrospectively analyzed the clinical course of 232 MG patients who presented with only mild symptoms and had SFEMG of the orbicularis oculi muscle. We correlated their SFEMG results with the severity of their later clinical course. Results: During the observation period 39 patients (17%) developed severe disease exacerbations, and 193 (83%) remained stable. Patients with severe disease exacerbation had a significantly higher mean jitter value (P < 0.0001), a greater percentage of fibers with increased jitter (P < 0.0001), and/or impulse blocking (P < 0.0001) on SFEMG. Conclusions: The extent of the SFEMG abnormalities in this study correlated with the later clinical course of MG. Muscle Nerve 54 : 1034–1040, 2016     

Diffusion tensor imaging reveals changes in non-fat infiltrated muscles in late onset Pompe disease

MRI is a helpful tool for monitoring disease progression in late-onset Pompe disease (LOPD). Our study aimed to evaluate if muscle diffusion tensor imaging (mDTI) shows alterations in muscles of LOPD patients with <10% fat-fraction. We evaluated 6 thigh and 7 calf muscles (both legs) of 18 LOPD and 29 healthy controls (HC) with muscle diffusion tensor imaging (mDTI), T1w, and mDixonquant sequences in a 3T MRI scanner. The quantitative mDTI-values axial diffusivity (λ₁), mean diffusivity (MD), radial diffusivity (RD), and fractional anisotropy (FA) as well as fat-fraction were analyzed. 6-Minute Walk Test (6-MWT) data were correlated to diffusion metrics. We found that mDTI showed significant differences between LOPD and HC in diffusion parameters (P < .05). Thigh muscles with <10% fat-fraction showed significant differences in MD, RD, and λ_1-3. MD positively correlated with 6-MWT (P = .06). To conclude, mDTI reveals diffusion restrictions in muscles of LOPD with and without fat-infiltration and reflects structural changes prior to fatty degeneration.     

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptor flt-1 in microcystic meningiomas

We investigated the immunohistochemical expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and of its endothelial cell receptor flt-1 in relationship to microcyst formation in meningiomas. Expression of VPF/VEGF was studied in 60 meningiomas (6 microcystic, 38 partially microcystic and 16 with no microcystic areas) and 30 meningiomas from these three subgroups were evaluated for flt-1 expression. VPF/VEGF immunoreactivity was mainly observed in vessel endothelium. Positive vessels were present in 75% (33/44) of meningiomas with any amount of microcystic pattern and in 38% (6/16) of the solid meningiomas (P < 0.02). Densities and percentages of both VPF/VEGF-positive and flt-1-positive vessels were higher in meningiomas with microcystic areas than in solid meningiomas (P≤ 0.002). The 6 microcystic meningiomas showed the highest densities and percentages of both VPF/VEGF-positive (P≤ 0.0002) and flt-1-positive vessels (P≤ 0.01). Vessel expression of VPF/VEGF and flt-1 were positively correlated (r≥ 0.75, P < 0.0001). A strong positive correlation between VPF/VEGF-positive vessel density and proportion of microcystic pattern in all 60 specimens was found (r = 0.75, P < 0.0001). We conclude that accumulation of flt-1-bound VPF/VEGF on endothelial cells of meningiomas is associated with microcyst formation that leads to the histologic appearance of microcystic meningiomas. Received: 18 January 1999 / Revised, accepted: 31 March 1999     

Relationship between apoptosis and proliferation in secondary tumors of the brain

A correlation between apoptosis and proliferation in astrocytomas and oligodendrogliomas, but not in glioblastomas, has been previously reported. An index for apoptosis and proliferation was established for each tumor in a series of 20 brain metastases, and its correlation was studied using the Spearman rank correlation test. Apoptosis index (AI) ranged between 1 and 78% (mean ± SD: 11.48 ± 16.4). Proliferation index (PI) ranged between 2.4 and 21% (mean ± SD: 8.23 ± 4.8). When the relationship between AI and PI was studied, a clear correlation was found (r: 0.8965, 95% CI: 0.74–0.95; P < 0.0001). Therefore, it is concluded that a clear correlation exists between proliferation and apoptosis in secondary tumors of the brain.     

Cerebrospinal fluid and serum antibodies against neurofilaments in patients with amyotrophic lateral sclerosis

Background: The aim of the study was to assess autoimmune involvement in amyotrophic lateral sclerosis (ALS). Methods: We measured IgG antibodies against light (NFL) and medium (NFM) subunits of neurofilaments using ELISA in paired cerebrospinal fluid (CSF) and serum samples from 38 ALS patients and 20 controls. Results: Serum levels of anti‐NFL were higher in ALS patients than in controls (P < 0.005). Serum anti‐NFL antibodies and intrathecal anti‐NFM antibodies were related to patient disability (serum anti‐NFL: P < 0.05; intrathecal anti‐NFM: P < 0.05). Anti‐NFL levels were significantly correlated with anti‐NFM levels in ALS (P < 0.001) and the control group (P < 0.0001) in the CSF, but not in serum. Anti‐NFL and anti‐NFM antibodies significantly correlated between serum and CSF in the ALS group (anti‐NFL: P < 0.0001; anti‐NFM: P < 0.001) and in the control group (anti‐NFL: P < 0.05; anti‐NFM: P < 0.05). Conclusions: Autoimmune humoral response to neurocytoskeletal proteins is associated with ALS.     

A modified multiple point stimulation method for motor unit number estimation of the hypothenar muscles

Introduction: The goal of this study is to test the hypothesis that single motor unit action potentials (SMUPs) originating from other ulnar nerve–innervated intrinsic hand muscles can inflate the motor unit number estimation (MUNE) of the hypothenar muscles. Methods: Using the multiple point stimulation method, SMUPs recorded over the hypothenar muscles from distant origins were characterized through multichannel recordings. The MUNE calculated using only the hypothenar SMUPs was compared with estimations based on the whole ensemble. Results: Of the 41 studies performed, distant SMUPs represented 17 ± 9.5% (mean ± SD) of the overall sample. MUNE calculated using only hypothenar SMUPs was 423 ± 204, compared with 537 ± 290 if all SMUPs were included (P < 0.05). The extent of increase in MUNE was highly correlated with the proportion of distant SMUPs found (r = 0.89, P < 0.05). Discussion: Erroneous inclusion of SMUPs from distant muscles can significantly distort the MUNE results. Muscle Nerve 59 :337–341, 2019     

Cough peak flow decline rate predicts survival in patients with amyotrophic lateral sclerosis

Introduction: In this study we investigated the prognostic significance of cough peak flow (CPF) decline rate in patients with amyotrophic lateral sclerosis (ALS). Methods: Thirty-four patients with ALS participated in our investigation. We examined CPF, forced vital capacity (FVC), body mass index, and the revised ALS Functional Rating Scale (ALSFRS-R), and followed patients to death, tracheostomy, or non-invasive ventilator dependency. We analyzed the relationship between the rate of decline of each parameter and survival prognosis. Results: The CPF decline rate significantly correlated with the decline rates of the ALSFRS-R bulbar score (P < 0.0001) and FVC (P < 0.0001). Patients with a CPF decline rate ≥25% had shorter overall survival (P < 0.0001). Cox model multivariate analyses showed that the CPF decline rate was an independent prognostic factor for survival (P = 0.021). Discussion: The CPF decline rate reflects the progression of bulbar and respiratory dysfunction and predicts survival. Muscle Nerve 59 :168–173, 2019     

Fatigue is a relevant outcome in patients with myasthenia gravis

Introduction: Patients with myasthenia gravis often experience fatigue, but its effect on quality of life (QoL) is underestimated, and fatigue is rarely measured in clinical trials. Methods: Two hundred fifty‐seven myasthenic patients completed the Neuro‐QoL‐Fatigue and measures of disease severity and QoL. We studied the relationship between fatigue and clinical and demographic variables. Finally, we studied the responsiveness of the Neuro‐QoL‐Fatigue in 95 patients receiving treatments for myasthenia and estimated the minimal important difference (MID). Results: Fatigue correlated with greater disease severity (r = 0.52–0.69, P < 0.0001) and worse QoL (r = 0.65–0.75, P < 0.0001). Patients in remission, with minimal manifestations, and pure ocular symptoms reported minimal fatigue. Regression modeling showed that, in addition to its relationship with disease severity, fatigue was worse in females, patients with generalized disease, and those with anxiety/depression. Fatigue improved after immunomodulation (P < 0.0001), and the MID was 5.3 points. Discussion: Fatigue in myasthenia correlates with disease severity, affects QoL, and can improve after treatment. Muscle Nerve 58 : 197–203, 2018     

Bedside screening for aphasia: a comparison of two methods

A prospective study was carried out in 50 consecutive patients referred with suspected aphasia in order to compare the Frenchay Aphasia Screening Test (FAST) with the Sheffield Screening Test for Acquired Language Disorders (SST). The study included 32 men and 18 women with a mean (SEM) age 53.9 (2) years. The comprehension scores on the FAST were correlated with receptive skills on the SSTr=0.74 (P<0.001). For expression, the correlation coefficient wasr=0.92 (P<0.001) and the total scores of the two tests correlated closelyr=0.89 (P<0.001). There was a positive correlation between total score on the FAST and the Short Orientation, Memory and Concentration test (SOMC)r=0.86 (P<0.001), and the total scores on the SST and SOMCr=0.91 (P<0.001). The Barthel index also correlated positively with the FASTr=0.59 (P<0.001) and SSTr=0.63 (P<0.001). The study demonstrated that the two tests are simple, short and similar in their predictive value for the screening and diagnosis of aphasia. The SST was found to have additional advantages, as it does not require any special equipment or stimulus cards, and it was not affected by visual neglect.     

Motor ‘surround inhibition’ is not correlated with activity in surround muscles

Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle‐specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross‐correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non‐voluntary activity, generated in cortical and subcortical structures, respectively.     

Age-related susceptibility to experimental autoimmune myasthenia gravis: Immunological and electrophysiological aspects

Susceptibility to experimental autoimmune myasthenia gravis (EAMG) was found to decrease with aging in both Lewis and Brown Norway (BN) rats. In this study, the difference in susceptibility between young and aged Lewis and BN rats was used to analyze factors determining the clinical severity of EAMG. The incidence and severity of muscular weakness did not correlate with acetylcholine receptor (AChR) loss nor with the ability of antibodies to interfere with AChR function. Aged rats showed significantly lower anti-rat AChR antibody titers than young rats and developed less severe or no clinical signs of disease. In individual young or aged rats, however, no significant correlation was found between the clinical signs of disease and anti-rat AChR titer. Neuromuscular transmission was found to change with aging as measured by single-fiber electromyography (SFEMG). In aged BN rats, increased jitter and blockings were found even before EAMG induction. Despite this disturbed neuromuscular transmission, these aged BN rats were clinically resistant against induction of EAMG. The results of this study indicate that the age-related susceptibility to EAMG is influenced by factors determined by the immune attack as well as mechanisms at the level of the neuromuscular junction. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1091–1101, 1997     

Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation

Despite the beneficial effects of Globus Pallidus internus (GPi) deep brain stimulation (DBS) in patients with primary generalized dystonia (PGD), the degree of improvement varies from one patient to another. The objective of this study was to examine the effects of clinical, anatomical (volume of the GPi), and electrical variables on the postoperative Burke‐Fahn‐Marsden Dystonia rating scale (BFMDRS) motor score to identify which factors may be predictive of the degree of improvement. We reviewed retrospectively the clinical records of 40 steady‐state patients with PGD who had been treated by bilateral GPi lead implantation. The follow‐up period was 2 to 8 years. The correlation between the electrical parameters (voltage, impedance, and current) and the clinical outcome was studied. An analysis of covariance was performed to identify factors predictive of the magnitude of improvement. The most influential factors according to the model are as follows: the preoperative BFMDRS score (P < 0.0001); age at surgery (P < 0.0001); the right GPi volume (P = 0.002); the left stimulated GPi volume (P = 0.005). No significant correlation was found between the electrical parameters used and the mean motor scores in steady state. © 2009 Movement Disorder Society     

Lipid peroxides production after strenuous exercise and in relation to muscle morphology and capillarization

The antioxidative capacity of slow twitch muscle fibers has been reported to be higher than that of fast twitch ones. The purpose of this study was to relate the production of lipid peroxides during exercise to the morphology and capillarization of human muscles. Twenty-seven healthy volunteers performed a strenuous 90-min exercise. The content of malonyldialdehyde (MDA) in the middle portion of vastus lateralis muscle was found positively correlated with percentage and the relative cross-sectional area of the type I of muscle fibers (r = 0.46, P < 0.05, r = 0.43, P < 0.05, respectively) but negatively with type II muscle fibers (r = -0.46, P < 0.05, r = -0.43, P < 0.05, respectively), especially type IIB. The content of MDA in the vastus lateralis muscle correlated positively with the number of capillaries around type II muscle fibers (r = 0.71, P < 0.001). It is suggested that the production of lipid peroxides parallels the exercise-induced increase of oxygen uptake in the muscle, being highest in more oxidative and better perfused, oxygen-consuming muscle fibers. © 1996 John Wiley & Sons, Inc.