Guidelines for the treatment of autoimmune neuromuscular transmission disorders

Important progress has been made in our understanding of the cellular and molecular processes underlying the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus guidelines for the treatment of the autoimmune NMT disorders. References retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts and a patient representative. The proposed practical treatment guidelines are agreed upon by the Task Force: (i) Anticholinesterase drugs should be the first drug to be given in the management of MG (good practice point). (ii) Plasma exchange is recommended as a short‐term treatment in MG, especially in severe cases to induce remission and in preparation for surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and plasma exchange are equally effective for the treatment of MG exacerbations (level A Recommendation). (iv) For patients with non‐thymomatous autoimmune MG, thymectomy (TE) is recommended as an option to increase the probability of remission or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is indicated irrespective of the severity of MG (level A recommendation). (vi) Oral corticosteroids is a first choice drug when immunosuppressive drugs are necessary in MG (good practice point). (vii) In patients where long‐term immunosuppression is necessary, azathioprine is recommended together with steroids to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (level A recommendation). (viii) 3,4‐diaminopyridine is recommended as symptomatic treatment and IvIg has a positive short‐term effect in LEMS (good practice point). (ix) All neuromyotonia patients should be treated symptomatically with an anti‐epileptic drug that reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive management of paraneoplastic neuromyotonia and LEMS is treatment of the underlying tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and NMT it is reasonable to adopt treatment procedures by analogy with MG (good practice point).     

Guidelines for treatment of autoimmune neuromuscular transmission disorders

Background: Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs’ syndrome). Methods: To prepare consensus guidelines for the treatment of the autoimmune NMT disorders, references retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts. Conclusions: Anticholinesterase drugs should be given first in the management of MG, but with some caution in patients with MuSK antibodies (good practice point). Plasma exchange is recommended in severe cases to induce remission and in preparation for surgery (recommendation level B). IvIg and plasma exchange are effective for the treatment of MG exacerbations (recommendation level A). For patients with non‐thymomatous MG, thymectomy is recommended as an option to increase the probability of remission or improvement (recommendation level B). Once thymoma is diagnosed, thymectomy is indicated irrespective of MG severity (recommendation level A). Oral corticosteroids are first choice drugs when immunosuppressive drugs are necessary (good practice point). When long‐term immunosuppression is necessary, azathioprine is recommended to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (recommendation level A). 3,4‐Diaminopyridine is recommended as symptomatic treatment and IvIG has a positive short‐term effect in LEMS (good practice point). Neuromyotonia patients should be treated with an antiepileptic drug that reduces peripheral nerve hyperexcitability (good practice point). For paraneoplastic LEMS and neuromyotonia optimal treatment of the underlying tumour is essential (good practice point). Immunosuppressive treatment of LEMS and neuromyotonia should be similar to MG (good practice point).     

M wave changes with temperature in amyotrophic lateral sclerosis and disorders of neuromuscular transmission

Local cooling of the muscle resulted in significant increases in M wave surface areas in patients with ALS, myasthenia gravis, the Lambert-Eaton myasthenic syndrome, and also in controls. The most striking increases were seen in patients with early ALS who had minimal lower motor neuron involvement and/or little defect on neuromuscular transmission and patients with the myasthenic syndrome. Patients with myasthenia gravis had intermediate increases between these groups and the controls; there was a larger increase in M wave surface area in myasthenia gravis compared with controls but this could be accounted for by improvement in neuromuscular transmission. The large increase in M wave surface area in early ALS could be the result of temporal summation of individual muscle fibers in motor units with increased fiber densities. The increase in both ALS and the myasthenic syndrome could result also from the loss of a trophic factor causing changes at the muscle membrane.     

Paradoxical lid elevation with sustained upgaze: a sign of Lambert-Eaton syndrome

Myasthenia gravis and Lambert-Eaton myasthenic syndrome are causes of acquired extraocular muscle weakness and ptosis. Exacerbation of ptosis after sustained upgaze is a clinically useful sign in the diagnosis of myasthenia gravis. A 54-year-old woman with established Lambert-Eaton myasthenic syndrome exhibited transient improvement of her ptosis after sustained upgaze. We suggest that paradoxical lid elevation after sustained upgaze may be a clinically useful sign in distinguishing Lambert-Eaton myasthenic syndrome from myasthenia gravis.     

Evaluation of neuromuscular junction disorders in the electromyography laboratory

Neuromuscular junction (NMJ) disorders may be demonstrated using repetitive nerve stimulation (RNS) testing and single-fiber electromyography (SFEMG). RNS testing with low frequency stimulation reduces the safety factor of neuromuscular transmission (NMT) and may elicit decrementing compound muscle action potential (CMAP) responses. Exercise or tetanic nerve stimulation may potentiate acetylcholine release in presynaptic NMT disorders with CMAP facilitation. SFEMG is a selective recording technique assessing MFAPs within the same motor unit. Jitter is increased in NMJ disorders, and is the temporal variability between these MFAPs. Impulse blocking reflects failure of NMT. RNS and SFEMG findings in NMJ disorders are reviewed.     

Stimulated single-fiber electromyography in Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission. Electrodiagnosis is confirmed by an increase in compound muscle action potential amplitude during high-frequency repetitive nerve stimulation or following brief exercise. We describe the results of stimulated single-fiber electromyography in 4 patients with disorders of neuromuscular transmission: LEMS (2), LEMS/myasthenia gravis (MG) overlap (1), and MG (1). Stimulated SFEMG was performed in the extensor digitorum communis muscle with axonal intramuscular suprathreshold stimulation at low and high rates. In all 4 patients, a rate dependence of jitter was found. In LEMS and LEMS/MG, jitter and blocking improved with high stimulation rates, as compared with the opposite effect in MG. We conclude that stimulated SFEMG is a valuable technique in the diagnosis of LEMS.     

A Patient with Coexisting Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome

Background

The coexistence of myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) is very rare and remains controversial.

Case Report

A 48-year-old woman initially presented with noticeable right ptosis and intermittent diplopia. She then developed fluctuating proximal limb weakness and difficulty in swallowing. The serum titer of anti-acetylcholine-receptor antibody was elevated and the edrophonium (Tensilon) test was positive. However, repetitive nerve stimulation revealed abnormalities typical of LEMS. The patient exhibited a good response to treatment with anticholinesterase inhibitors and steroids, and long-term evaluation disclosed that she presented with the clinical, electrophysiological, and immunological characteristics of both diseases.

Conclusions

The reported clinical and electrophysiological features suggest that this patient was a very rare case of combined MG and LEMS.     

The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction.

The increasing understanding of the structural complexity of the neuromuscular junction (NMJ), and the processes that are important in its development, suggests many possible new disease targets. Here, we summarize briefly the genetic and autoimmune disorders that affect neuromuscular transmission, and the identified targets, including new evidence that antibodies to muscle-specific receptor tyrosine kinase (MuSK) are involved in the pathogenesis of acetylcholine receptor (AChR) antibody-negative myasthenia gravis. We then review the development of the NMJ, focusing on the important roles of nerve-derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ.     

Late presentations of congenital myasthenic syndromes: How many do we miss?

Introduction: Congenital myasthenic syndromes (CMS) usually present neonatally or in early childhood. When they present later, they may be mistaken for seronegative autoimmune myasthenia, and unnecessary immunosuppressive treatment may be administered. Methods: Patients who met criteria for seronegative generalized myasthenia without congenital or early childhood onset, but with an affected sibling were tested for CMS associated genes using exome and Sanger sequencing. Results: Four sibling pairs from nonconsanguineous families were identified. Three had mutations in the RAPSN gene, and 1 had a mutation in CHRNA1. One sibling of a pair with symptoms of fatigue but no convincing features of neuromuscular dysfunction tested negative on genetic studies. The definite CMS cases comprised 7 of 25 seronegative patients with definite generalized myasthenia in the clinic, and over half had been treated for autoimmune myasthenia. Conclusions: CMS is probably underdiagnosed in seronegative myasthenic disorders and should be considered in the differential diagnosis. Muscle Nerve 54 : 721–727, 2016     

Muscle-Specific Receptor Tyrosine Kinase Antibody Positive Myasthenia Gravis Current Status

Muscle-specific tyrosine-kinase-antibody-positive myasthenia gravis (MuSK-MG) has emerged as a distinct entity since 2001. This disease has been reported worldwide, but with varying rates among patients with generalized acetylcholine-receptor-antibody-negative MG. MuSK-MG was detected in approximately 37% of generalized acetylcholine receptor antibody-negative MG. MuSK-MG patients were predominantly female with more prominent facial and bulbar involvement and more frequent crises. Disease onset tended to be earlier. Patients tended to have a relatively poor edrophonium response but showed prominent decrement in the repetitive nerve stimulation test in the facial muscles. Patients were more likely to display poor tolerance of, or a lack of improvement with, anticholinesterase agents. Somewhat better response was observed with steroids and plasma exchange. Most were managed successfully with aggressive immunomodulatory therapies, although a higher proportion of MuSK-MG patients had a refractory course when compared with other forms of generalized MG. I present here an up-to-date overview on MuSK-MG based on our experience at the University of Alabama at Birmingham and the existing literature.     

MuSK-positive myasthenia gravis is rare in the Polish population

Background and purpose:  MuSK-positive myasthenia gravis (MG) is diagnosed in 0–48% of cases with generalized seronegative MG in different populations. The presence of anti-MuSK antibodies generally relates to a severe course and lack of response to thymectomy. We analyzed for the first time the serology and clinical characteristics of MuSK-positive MG in the Polish population.
Methods:  One hundred and fifty-one patients were tested for the presence of anti-AChR and anti-MuSK antibodies: 62 with seronegative MG, including 14 with ocular seronegative MG, 48 age-matched patients with seropositive MG and 41 controls.
Results: All patients with seropositive MG and the disease controls were MuSK-negative. Anti-MuSK antibodies were detected only in four patients with seronegative MG (8.7% of generalized seronegative cases): three women and one man. All four had predominantly bulbar involvement, and underwent thymectomy, with no apparent benefit. All of them improved clinically after immunosuppressive treatment with remissions lasting up to 7 years.
Conclusion: MuSK-positive MG is rare in Polish population accounting for only 8.7% of seronegative cases with generalized MG. This is consistent with emerging evidence for lower MuSK antibodies at more northerly latitudes.     

Single motor end-plates in myasthenia gravis and LEMS at different firing rates.

The jitter and frequency of blocking was studied at single motor end-plates in 10 patients with myasthenia gravis (MG) and in a patient with Lambert-Eaton myasthenic syndrome (LEMS), using single fiber EMG (SFEMG) with axonal microstimulation at rates varying from 0.5 Hz to 20 Hz. While some myasthenic motor end-plates showed lowest degrees of transmission disturbance at the lowest rates and most pronounced abnormality at the highest rates of stimulation, over one-half were most abnormal at intermediate rates and improved at higher rates. In 1 patient, all end-plates behaved in this way. On the other hand, all end-plates in the LEMS patient showed the expected improvement of the abnormal jitter and blocking on increasing the stimulation rate. It is argued that improvement of jitter and blocking at higher rates, unless dramatic, does not necessarily suggest a presynaptic abnormality.     

AAEE Minimonograph #33: electrodiagnostic approach to defects of neuromuscular transmission

Clinical testing for neuromuscular dysfunction is supported by an extensive amount of excellent basic information about normal and abnormal subcellular physiology and ultrastructure. This information provides an essential frame of reference for describing the rationale of single-fiber electromyography (SFEMG). SFEMG in turn helps to explain the more conventional clinical testing of neuromuscular function by repetitive nerve stimulation (RNS). Electrical findings in myasthenia gravis, Lambert-Eaton myasthenic syndrome, and botulinum intoxication are discussed from the subcellular level via the cellular level (SFEMG) to the integrated responses of whole muscle (RNS) as a rational means of understanding the technique of clinical repetitive nerve stimulation.     

Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients

Introduction: Myasthenia gravis (MG) is an autoimmune disease. Patients without detectable antibodies against the nicotinic acetylcholine receptor or the muscle‐specific tyrosine kinase are referred to as seronegative MG (SNMG). Because late‐onset congenital myasthenic syndromes (CMSs) due to RAPSN or DOK7 mutations may be mistaken for SNMG, we investigated their frequency in a nationwide SNMG cohort. Methods: We performed sequencing of RAPSN and DOK7 in all Norwegian SNMG patients (n = 74) and 37 healthy controls, examining for the N88K and c.1124_1127dupTGCC mutations, respectively. Results: We found 1 patient homozygous for N88K and 2 carriers of the N88K mutation. Sequencing of DOK7 revealed no mutations. Conclusions: This study confirms that rapsn CMS can be mistaken for SNMG. In addition, the frequency of rapsn CMS in our nationwide SNMG cohort was found to be low. SNMG patients with an atypical clinical presentation and pediatric cases should be tested for the N88K mutation before initiation of immunosuppressive drug treatment or thymectomy. Muscle Nerve, 2011     

Autoantibodies in neuromuscular transmission disorders

It is a great pleasure to be asked to honour the memory of Dr. Baldev Singh by reviewing the field of autoantibodies in myasthenia gravis and other neurotransmission disorders. The neuromuscular junction (NMJ) is the site of a number of different autoimmune and genetic disorders, and it is also the target of many neurotoxins from venomous snakes, spiders, scorpions and other species. The molecular organization of the NMJ is graphically represented in Figure 1A, where different ion channels, receptors and other proteins are shown. Four of the ion channels or receptors are directly involved in autoimmune diseases. This brief review will not only concentrate on these conditions but also illustrate how their study is helping us to understand the etiology of rare but treatable neurological syndromes of the central nervous system.Open in a separate windowFigure 1(A) The neuromuscular junction showing the targets for antibodies in disease. Rapsyn is the cytoskeletal protein that clusters the acetylcholine receptors. (B) The neuromuscular junction in myasthenia gravis with AChR antibodies. The AChRs are reduced in number and there is morphological damage to the postsynaptic membrane. (C) The AChR viewed from above the membrane consists of five subunits, two alphas, one beta, one delta and either a gamma (fetal type) or epsilon (adult type). Bungarotoxin and acetylcholine bind to sites on the interfaces between the alpha subunit and adjacent subunits. Many, but not all, antibodies bind to a region known as the main immunogenic region on the alpha subunits. Mothers with babies who are born with arthrogryposis may have antibodies that bind to a gamma-subunit specific site     

Myasthenia gravis Lambert‐Eaton overlap syndrome

Introduction: To assess whether a myasthenia gravis (MG) Lambert‐Eaton overlap syndrome (MLOS) exists. Methods: Case reports that met the universally accepted diagnostic criteria for MG and Lambert‐Eaton myasthenic syndrome (LEMS) were sought through a PubMed search. Fifty‐five possible cases of MLOS were identified. Results: Thirty‐nine cases met the diagnostic criteria for MG and LEMS. Analysis of clinical features showed that these patients have common MG and LEMS symptoms: oculo‐bulbar paresis and good response to anti‐cholinesterase for MG and limb weakness and decreased or absent reflexes for LEMS. All had the classical LEMS pattern in the repetitive nerve stimulation test: low compound muscle action potential amplitude and incremental response > 60% with brief exercise or at high rate of stimulation. Eight patients had combined positive acetylcholine receptor antibody (AChR‐ab) or muscle‐specific kinase‐ab and voltage‐gated calcium channel‐ ab tests. Conclusions: A myasthenia gravis Lambert‐Eaton overlap syndrome (MLOS) does exist. Muscle Nerve 53 : 20–26, 2016     

Molecular architecture of the neuromuscular junction

The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined.