Elsevier

The Lancet Neurology

Volume 14, Issue 10, October 2015, Pages 1023-1036
The Lancet Neurology

Review
Myasthenia gravis: subgroup classification and therapeutic strategies

https://doi.org/10.1016/S1474-4422(15)00145-3Get rights and content

Summary

Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis.

Introduction

Dysfunction at the neuromuscular junction underlies several disorders that are characterised by skeletal muscle weakness usually involving some but not all muscle groups. Genetic forms of these disorders are termed congenital myasthenic syndromes. Some toxins, like botulinum toxin and curare, can cause neuromuscular dysfunction; acquired antibody-mediated forms include autoimmune and neonatal myasthenia gravis, Lambert–Eaton myasthenic syndrome, and neuromyotonia.

Myasthenia gravis forms the largest disease group of neuromuscular junction disorders and is caused by pathogenic autoantibodies to components of the postsynaptic muscle endplate (figure 1).1, 2, 3, 4 Fluctuations in severity of muscle weakness are typical. Some, but not all, muscles are affected and not necessarily symmetrically. Increased weakness with continued muscle activity represents a diagnostic clue for myasthenia gravis, but these clinical features can vary. Patients with myasthenia gravis should be classified into subgroups, with implications for diagnosis, optimum therapy, and prognosis. In myasthenia gravis guidelines and consensus reports, subgrouping is recommended,1, 2, 3, 4, 5 but exact definitions vary and new subgroups are emerging as a result of increased knowledge. As this subgrouping takes into account myasthenia gravis autoantibodies, epidemiology, clinical presentation, and comorbidities, the subgroups are discussed after these sections in this Review. For a few patients, subgrouping is not possible owing to insufficient precise information, including suboptimum autoantibody testing and pathological changes of the thymus below the detection threshold of imaging.

Autoantibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MUSK), and lipoprotein-related protein 4 (LRP4) are well established as sensitive and specific diagnostic markers and pathogenic factors, and these autoantibodies are instrumental for subgrouping patients with myasthenia gravis. A prerequisite for optimum diagnosis and treatment, therefore, is access to autoantibody testing.1, 2, 3, 4, 5

With modern immunosuppressive, symptomatic, and supportive treatments, the prognosis for patients with myasthenia gravis is good. Most patients with mild-to-moderate symptoms will obtain full remission or substantial improvement. Full remission is rare in severe cases, some variation over time is common, and steady progression is unusual. Daily life functions of individuals with myasthenia gravis are not, or only modestly, affected and life expectancy is not reduced.6 Long-term drug treatment is necessary for nearly all patients with myasthenia gravis.2, 7 In 10–15% of these patients, full control of the disease is not possible or is only at the cost of severe side-effects of immunosuppressive therapy.8

Treatment protocols at leading centres are not based purely on results from well controlled studies or guidelines based on such studies, because well controlled studies are sparse for this disease, and do not take into account the variation in therapeutic response among the diagnostic subgroups. Myasthenia gravis is a rare disease, and most patients do well on existing treatments, both aspects that are a challenge for new trials. We will combine information from controlled studies, consensus reports, and expert views with insights from theoretical and experimental studies relevant for myasthenia gravis subgroups, with the aim of assessing the evidence base for the use of treatments, including interventions directed at the pathophysiological process.

Section snippets

Autoantibodies in myasthenia gravis

AChR antibodies are highly specific for myasthenia gravis, and their presence combined with muscle weakness confirms the disease. Further diagnostic investigation is necessary only to define the subgroup and disease severity. The value of repeated AChR antibody testing in patients with this disorder is debated, but changes in antibody concentration might predict disease severity in patients given immunosuppressive drugs and therefore can support therapeutic decisions. No correlation has been

Epidemiology

Autoimmune myasthenia gravis has a reported worldwide prevalence of 40–180 per million people, and an annual incidence of 4–12 per million people.20, 21, 22, 23 Recently collected figures of prevalence and incidence tend to be higher than older ones, especially for late-onset myasthenia gravis, partly explained by increased case finding and more widespread autoantibody testing. Population demographics with an increased number of elderly people and reduced myasthenia gravis mortality affect

Clinical presentation

Muscle weakness is a major symptom and sign in myasthenia gravis. The combination of weakness localisation, variation in weakness over time, and exercise-induced weakness usually gives strong clues to the diagnosis of the disease for all subgroups. In older individuals with eye muscle weakness and bulbar symptoms, cerebrovascular disease of the brainstem is sometimes suspected. In younger individuals, unspecific fatigue disorders can be part of the differential diagnoses.1, 3, 7

Weakness in

Comorbidities

Patients with early-onset and ocular subgroups of myasthenia gravis have increased frequency of organ-specific and general autoimmune disorders, especially thyroiditis.29 Patients with thymoma-associated myasthenia gravis are at an increased risk of developing haematological autoimmune disorders. Thymectomies have not been shown to increase the risk of infections, autoimmune disease, or cancer. Myasthenia gravis muscle weakness might increase the risk of respiratory infections and osteoporosis,

Early-onset myasthenia gravis with AChR antibodies

Patients with early-onset myasthenia gravis have, by definition, onset of their first symptom before age 50 years (table 1).1, 7, 39 Serum AChR antibodies are detected by standard diagnostic testing. Patients with a thymoma detected on imaging or during surgery are excluded from this myasthenia gravis subgroup. Thymic follicular hyperplasia occurs often but is not a prerequisite, and this group responds to thymectomy. Female cases outnumber male cases by three to one.20, 22 Early-onset

Thymus pathological changes

Thymoma, but no other thymic tumours, is associated with myasthenia gravis. Thymic hyperplasia is reported in most patients with early-onset myasthenia gravis and in some patients with late-onset, ocular, and antibody-negative disease. CT scanning or MRI of the mediastinum should be undertaken in all patients with myasthenia gravis to assess for a thymoma.1, 2, 3, 4, 7 Both sensitivity and specificity are challenges for imaging.

Experimental and clinical evidence strongly suggests that

Neurophysiological testing

Neurophysiological tests are unnecessary in patients with typical myasthenia gravis symptoms because diagnosis can be confirmed by specific antibody tests; these tests are also not helpful for myasthenia gravis subgroup classification. However, they are important for correct diagnosis in patients with myasthenia gravis without detectable autoantibodies.

Repetitive nerve stimulation and single-fibre electromyography for an increased jitter are useful tests for patients with myasthenia gravis.

Symptomatic drug treatment

Drugs that increase the amount of acetylcholine at neuromuscular endplates after motor nerve stimulation improve muscle weakness in all myasthenia gravis subgroups; pyridostigmine is the preferred drug for symptomatic treatment.7 Other acetylcholinesterase inhibitors, such as neostigmine and ambenonium chloride, have different durations of action and can differ regarding side-effects. The improvement reported in patients with these drugs is so specific that it is used as a diagnostic clue in

Treatment of myasthenia gravis crisis

Crisis is defined as a need for intubation for respiratory support caused by muscle weakness related to the disease. Treatment includes intensive care with respiratory support, treatment of infections, and monitoring of vital functions and mobilisation (figure 5). Intravenous immunoglobulin and plasma exchange are specific immunosuppressive treatments with a rapid effect occurring after 2–5 days, and either one should be given to patients with severe myasthenia gravis exacerbations and always

Treatment of myasthenia gravis in pregnancy

Pregnancy does not affect myasthenia gravis in any consistent way, with no increased risk of severe deterioration or myasthenia gravis crisis.85, 104, 105 During the first weeks and few months post partum, the risk of symptom worsening is moderately increased, mainly because of stress and new demands.

Pyridostigmine and corticosteroids are regarded as safe treatments for pregnant women.85 These drugs do not increase the risk of fetal malformations or delayed fetal development. Plasma exchange

Treatment of neonatal myasthenia gravis

Neonatal myasthenia gravis occurs in 10–15% of babies of mothers with the disease. The cause of this transient muscular weakness in these babies is transfer of the mother's AChR or MUSK antibodies of the IgG class across the placenta. This weakness usually lasts for only days or a few weeks and is typically mild but can interfere with feeding and respiration. Mothers with myasthenia gravis should always give birth at hospitals experienced in respiratory support treatment for newborn babies. The

Conclusions and future directions

Most patients with myasthenia gravis do well and have well controlled disease. However, most need long-term and often life-long drug treatment with acetylcholinesterase inhibitors and usually low-dose immunosuppression. Pathogenic autoantibodies are well characterised and myasthenia gravis subgroups are defined accordingly. However, treatment is far from antibody specific and is not even specific to the disease subgroup. Many new and more traditional drugs that have not been tested properly in

Search strategy and selection criteria

We searched MEDLINE and the Cochrane Library with the terms “myasthenia gravis”, “myasthenic syndromes”, and “myasthenia” from January 1995, to April, 2015. Guideline and review papers were assessed in detail, and controlled studies sought for in particular. Papers were selected by title and abstract. Only papers in English were included. Randomised trials on established and emerging therapies for myasthenia gravis are often scarce, so our recommendations are based on the best available

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