Elsevier

The Lancet Neurology

Volume 8, Issue 5, May 2009, Pages 475-490
The Lancet Neurology

Review
Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity

https://doi.org/10.1016/S1474-4422(09)70063-8Get rights and content

Summary

Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which patients experience fluctuating skeletal muscle weakness that often affects selected muscle groups preferentially. The target of the autoimmune attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the neuromuscular junction, such as the muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological result is muscle endplate dysfunction and consequent fatigable muscle weakness. Clinical presentations vary substantially, both for anti-AChR positive and negative MG, and accurate diagnosis and selection of effective treatment depends on recognition of less typical as well as classic disease phenotypes. Accumulating evidence suggests that clinical MG subgroups might respond differently to treatment. In this Review, we provide current information about the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and treatment of MG, including emerging therapeutic strategies.

Introduction

Acquired myasthenia gravis (MG) is a prototypical, antibody-mediated autoimmune disorder of the neuromuscular junction (NMJ).1 In most cases, it is caused by pathogenic autoantibodies directed towards the skeletal muscle acetylcholine receptor (AChR).2 In others, non-AChR components of the postsynaptic muscle endplate, such as the muscle-specific receptor tyrosine kinase (MUSK), might serve as targets for the autoimmune attack.3 The precise origin of the autoimmune response in MG is not known, but abnormalities of the thymus gland (hyperplasia and neoplasia) almost certainly play a part in patients with anti-AChR antibodies,4, 5 and genetic predisposition is also likely to influence which patients develop the disorder.6 Fluctuating muscular weakness that increases with effort is the characteristic manifestation of MG. A wide range of clinical presentations and associated features allow classification of MG into subtypes based on disease distribution (ocular vs generalised), age at onset, thymic abnormalities, and autoantibody profiles. Appropriate recognition of these clinical subtypes helps to determine management strategies and prognosis.

In this Review, we address the latest concepts in the immunopathogenesis of MG relevant to the clinical subtypes, including the role of genetic factors that underlie individual susceptibility to the disease. We discuss the importance of clinical recognition of the various presentations of MG, and the available tests that help to confirm the diagnosis. Finally, we review the evidence that supports the various therapeutic modalities in MG, and develop a current, hierarchical approach to its treatment. Emerging treatment strategies are also delineated, including the prospect of antigen-specific therapy.

Section snippets

Epidemiology

MG is a relatively uncommon disease, although prevalence has increased over time with recent estimates approaching 20 per 100 000 in the US population.7 This increased prevalence is most likely to be due to improved diagnosis and treatment of MG, and an increasing longevity of the population in general. Incidence varies widely from 1·7 to 10·4 per million, depending on the location of study,8 and has been reported to be as high as 21 per million in Barcelona, Spain.9 The occurrence of MG is

Clinical presentation

The clinical hallmark of MG is fatigable weakness, usually involving specific susceptible muscle groups. Patients often note that their weakness fluctuates from day to day or even from hour to hour, worsens with activity, and improves with rest. Patients can have varying degrees of ptosis, diplopia, dysarthria, dysphagia, dyspnea, facial weakness, or fatigable limb or axial weakness (panel 1). Ocular weakness, presenting as fluctuating ptosis and/or diplopia, is the most common initial

MG subtypes

Differences in clinical presentation, age at onset, autoantibody profile, and the presence or absence of thymic pathology allow identification of several MG clinical subtypes (table 1). Patients with generalised MG can be divided into early-onset and late-onset disease, with early-onset MG usually defined as beginning before the age of 40 years.15 These patients are more often female, have anti-AChR antibodies, and enlarged, hyperplastic thymus glands. In addition to anti-AChR antibodies, other

The NMJ in MG

The NMJ has three basic components (figure 1): (1) the presynaptic motor nerve terminal, where acetylcholine is synthesised, stored, and released; (2) the synaptic space; and (3) the postsynaptic muscle membrane, which contains the AChRs and the enzyme acetylcholinesterase. Neuromuscular transmission begins when a nerve action potential enters the nerve terminal and triggers the release of acetylcholine. Exocytosis of synaptic vesicles containing acetylcholine requires calcium, which enters the

Diagnosis

The tests that are available to confirm the clinical diagnosis of MG include bedside tests, such as the edrophonium or ice-pack test, electrophysiological tests, and tests to measure the concentrations of serum autoantibodies (table 2).

Cholinesterase inhibitors

Oral cholinesterase inhibitors increase the amount of acetylcholine available for binding in the NMJ, and are the first-line treatment in patients with MG (table 4).1 Pyridostigmine bromide is the most commonly used cholinesterase inhibitor. The initial oral dose in adults is 15–30 mg every 4–6 h, which is increased and adjusted to maximise benefit and minimise side-effects (diarrhoea, stomach cramps). Pyridostigmine can be given 30–60 mins before meals in patients with bulbar symptoms.

Conclusions and future challenges

There are several emerging therapies for MG, including tacrolimus, rituximab, and antigen-specific apheresis, whereas other treatments await clarification of efficacy and their role in MG (thymectomy, mycophenolate mofetil). In addition, the soluble tumour-necrosis-factor-receptor blocker, etanercept, has been used with some success as a steroid-sparing agent in small numbers of patients with MG, but further study is needed because disease worsening was observed in some patients.159 Preliminary

Search strategy and criteria

References for this Review were identified through searches of Medline and PubMed for articles from 1966 to February, 2009, by use of the search terms “myasthenia gravis” and “autoimmune myasthenia”. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.

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