Section 1: Epidemiology and aetiology
Section 2: Making the diagnosis
Section 3: Managing the condition
Section 4: Prognosis
Section 5: Case study
Section 6: Evidence base
Section 1: Epidemiology and aetiology
Myasthenia gravis (MG) is an autoimmune disorder that affects communication between peripheral nerves and muscles.
The causative antibodies reduce efficiency of signal transmission across the neuromuscular junction (NMJ), leading to weakness of the innervated muscle.1 The condition is characterised by fatigable, painless muscle weakness that improves with rest.
By far the most common form of MG is the result of antibody production against the nicotinic acetylcholine receptor (AChR). Antibodies against the muscle specific (tyrosine) kinase (MuSK) receptor are much less frequent. Not all patients with MG have detectable antibodies.
Classification
MG may be generalised or purely ocular in its effects. Involvement may progress from ocular to generalised over time, although many patients only ever have ocular features. Clinical severity and symptom development varies and patients require close clinical supervision.
MG may be classified by both the causative antibody and by clinical effect (see table 1). Some patients, particularly older men, may have a thymoma present. Some patients have thymic hyperplasia and the rest have normal thymic appearances.
MG can occur at any age but is most common in young women and older men. Estimates of the prevalence of MG vary from 15 to 179 per million with a pooled prevalence estimate of 77.7 cases per million.2 More recent studies show a higher prevalence rate, probably because more elderly patients are diagnosed and diagnostic tests have improved.
Other myasthenic disorders
Other uncommon myasthenic disorders are Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes.
LEMS is caused by antibodies against the voltage-gated calcium channel. It produces muscle weakness that may get better after sustained muscle contraction, often with autonomic features too. Just over half of LEMS patients have an underlying malignancy, so management should be tailored accordingly.
Congenital myasthenic syndromes are a group of rare disorders. They are phenotypically similar to autoimmune MG but are purely genetic in origin. Diagnosis and treatment of congenital myasthenic syndromes is highly specialised.
| Table 1: Classification of myasthenic syndromes | |
|---|---|
| Type | Causation |
| Ocular MG | AChR antibodies in 50% |
| Anti-AChR antibody positive generalised MG | AChR antibodies in 85% |
| Anti-MuSK antibody positive generalised MG | MuSK antibodies in 100% |
| Seronegative MG | AChR and MuSK antibodies negative; ‘low affinity’ antibodies in 50% |
| Lambert-Eaton myasthenic syndrome | Voltage-gated calcium channel antibodies; small cell lung cancer in 60% |
| Congenital myasthenic syndromes | Mutations in variety of genes encoding proteins at the NMJ |
Section 2: Making the diagnosis
Diagnosis is made clinically. Key clinical features of MG are weakness without muscle pain, weakness that becomes worse the more a muscle or muscle group is used, and muscle weakness that usually improves with rest.
Clinical features
The classical history given by a patient with MG includes double vision and drooping of eyelids, difficulties with speech and swallowing, neck weakness and weakness of shoulder and hip muscles leading to difficulties with raising arms or getting up from a chair. This may be gradual over months with relative exacerbations and remissions or may develop over a matter of days. The latter is easier to diagnose due to the rapidity and severity.
There may be few obvious physical signs, particularly if the patient has been resting his/her muscles in the waiting room, so fatiguing the relevant muscle to bring out the weakness is helpful.
This can be done through sustained elevation of the eyes (see box 1) and/or through repeated shoulder abduction, for example. Wasting of muscles is unusual unless diagnosis is very delayed.
Severe weakness may progress to involve the respiratory muscles and consequent type 2 (hypercapnic) respiratory failure. Other features, such as muscle pain, fasciculations or very brisk tendon reflexes with extensor plantar responses, suggest other diagnoses.
Further investigations can be helpful (see table 2). MG is an autoimmune condition and patients may have other autoimmune disorders, such as diabetes and thyroid disorders, too.
| Table 2: Diagnostic tests in MG | |
|---|---|
| Outcome | |
| Repetitive active shoulder abduction or sustained elevation of eyes | Fatigability of muscle power |
| Edrophonium test | Temporary improvement of power in clinically affected muscle |
| Anti-acetylcholine antibody titre | Positive above a certain threshold and therefore confirmatory |
| Anti-MuSK antibody titre | Positive and thus confirmatory of MuSK myasthenia |
| Repetitive stimulation EMG | Positive if shows decrement with successive stimulation and thus confirmatory; if negative then proceed to stimulated single fibre EMG |
| Single fibre EMG | Positive if shows increased jitter indicating defect in neuromuscular transmission |
| CT chest imaging | May indicate thymoma, thymic hyperplasia or normal appearances |
Many patients have positive anti-AChR antibodies of which there is a very low false positive rate; however, negative AChR antibodies do not exclude the diagnosis. Creatine kinase, ESR, bone biochemistry and TFTs should be normal.
Neurophysiological tests may be extremely helpful.3 Demonstration of progressively reduced compound muscle action potentials on repeated electrical stimulation (repetitive stimulation electromyography - EMG) of a clinically affected muscle is diagnostic. If this is negative then a further test for the stability of single muscle fibres (single fibre EMG) can be done to confirm the diagnosis.
The edrophonium test is less commonly used as a diagnostic tool now but can be useful in certain clinical situations. For example, when a diagnosis must be reached quickly because of rapidly developing and severe symptoms, especially when there is weakness of respiratory muscles causing respiratory failure, or if there is diagnostic doubt in patients with less marked weakness. Care must be taken to remain objective.
Once the diagnosis is confirmed then a CT chest scan is indicated to detect the status of the thymus gland. In adults, this will usually be atrophic and not visible on the CT, but in MG patients the gland may be enlarged (thymic hyperplasia) or with a tumour (thymoma).
Section 3: Managing the condition
The treatment of MG is simple in principle but often complex in practice. Although not a curable condition, it is possible for patients to return to living a normal life. Symptoms may take weeks or months to improve and there may be complications so it is important that the treating neurologist, GP and patient work closely together.
Treatment
Initial treatment is with symptomatic agents. Anticholinesterases, such as pyridostigmine, reduce the destruction of the neurotransmitter acetylcholine in the NMJ, temporarily improving muscle power.
This treatment may be all that some patients need, especially with ocular MG. However, most patients require immunosuppression.4 The use of immunosuppression requires careful judgment. The quickest way to gain control of the disease is with corticosteroids.5
Traditionally, corticosteroids are introduced slowly with upward titration until symptoms are controlled, which may take several weeks. Pitfalls are to use too low a dose so symptoms are never completely controlled, or to use an unnecessarily high dose initially. The well-known potential side-effects can limit the use of corticosteroids in some patients. The aim is to control the symptoms, hold the dose at that level for a few weeks and then gradually reduce the steroid dose to the minimum level at which MG symptoms are controlled.
Slow reduction of the steroid dose down to zero may be possible, with reintroduction of steroids if symptom relapse occurs. But most patients, particularly with generalised MG, require ongoing immunosuppression. This is likely to be life-long so ideally an agent other than steroids would be used, to reduce side effects.
The choice of second-line agents is increasing but there is little randomised controlled trial evidence for their use, so the patient's neurologist usually makes the decision based on clinical experience. The exception is azathioprine for which there is clear evidence of efficacy but not until between 12 to 15 months of use.6
Should azathioprine be unsuitable then the next most commonly used agent is methotrexate. Mycophenolate mofetil became popular several years ago but its clinical efficacy is dubious and trials have not been helpful.7 Other agents such as cyclosporine are used less commonly. There is interest in using rituximab in those with severe, treatment-resistant MG but clinical experience is in the early stages.8
Surgery
Thymectomy in patients with thymoma is mandatory due to the risk of malignant extension from the gland.
In those with hyperplasia it may be useful to remove the gland to improve the disease status and need for immunosuppression in the medium term. Although used for decades, its true effectiveness has never been demonstrated until recently. The international MGTX trial (in press) compared the overall corticosteroid dose in those with non-thymomatous MG who either did or did not undergo thymectomy. The results showed that a lower dose was needed in those who had surgery.
Myasthenic crisis
In some patients, weakness becomes so severe that a myasthenic crisis develops and urgent treatment is required. The priority is for supportive measures for life-threatening aspects, such as neuromuscular respiratory and bulbar failure.
Patients should be managed in a critical care environment where there are facilities for endotracheal intubation and ventilation. Monitoring patients during the difficult phase when they have borderline neuromuscular (type 2) respiratory failure requires great care. Serial measurements of forced vital capacity (not peak expiratory flow rate) are needed to determine respiratory muscle strength. Other than optimisation of anticholinesterase dosing, treatment with immunomodulation is used during this phase.
Either plasma exchange or IV immunoglobulin can reverse the downward trend within a few days. Precipitating factors, such as infection, should also be treated.
Section 4: Prognosis
MG is usually a life-long condition, but most patients can expect their symptoms to be well-controlled on medication.
Occasional relapses may occur, often precipitated by infection, a change in drug treatment or introduction of a new drug that exacerbates myasthenic weakness. These may be brought under control with an escalation in dose or reintroduction of steroids, IV immunoglobulin or plasma exchange. Long-term complications of drug treatment may be a problem, particularly if it is not possible to reduce steroid doses.
In contrast, some patients, especially those who have a thymectomy for thymic hyperplasia early in their disease course, may need little or no treatment for the rest of their lives. Modern treatments, especially with monoclonal antibodies, offer the prospect of disease remission but their use is not yet sufficiently established to be sure of their role. A randomised controlled trial of the monoclonal antibody eculizumab is underway.
Care and support
Most patients with MG will need to be managed in conjunction with an experienced neurologist, preferably working in a large neuromuscular centre with critical care support. This is also important for special situations, such as pregnancy and delivery, as patients often relapse in the puerperium.
Myaware is the UK patient support group and has meetings throughout the country. It has also helped to establish posts for MG nurse specialists who support patients at diagnosis or at difficult times thereafter.
Section 5: Case study
A 60-year-old man was referred to an ophthalmology clinic for assessment of double vision. It had developed while he had been driving for three hours on the motorway on his return from holiday. It had also occurred occasionally when watching a film on television but otherwise had not been noticeable. On formal ophthalmological examination there was no abnormality. No further action was taken.
A few months later, he developed a chest infection and became aware of double vision when reading. On returning to the ophthalmology clinic, he was found to have a fourth nerve palsy.
The registrar requested AChR antibody levels and arranged review for six weeks' time. However, two weeks' later, the patient attended his GP practice with intermittent swallowing problems and feelings of weakness. Although he attributed these to getting older, he was referred to A&E and subsequently seen by the neurology team.
Clinical examination
Clinical examination showed a complex ophthalmoplegia, bilateral but asymmetrical ptosis, lower facial weakness and marked proximal weakness in his arms. He was admitted to hospital and underwent repetitive stimulation EMG which confirmed the clinical diagnosis of MG. He was started on pyridostigmine and a slow upward titration of prednisolone. CT chest scanning did not show an abnormality.
During the following days he became weaker in his neck, arms and then legs. Vital capacity monitoring demonstrated a value declining from 3 to 1.5 litres per minute. He was transferred to the high-dependency unit and given 1g/kg IV immunoglobulin. His vital capacity declined further and he required five days of endotracheal intubation, during which his prednisolone dose was increased to 60 mg/day. After this time, his ventilator requirements decreased and he could be weaned. After a further few days he was able to walk around the ward.
He was discharged from hospital with minimal symptoms after a further two weeks.
His AChR antibodies subsequently came back as strongly positive.
He was intolerant of azathioprine and so was started on methotrexate on which he remains. His prednisolone dose was slowly decreased over six months to zero. He was able to return to work as a general manager.
Section 6: Evidence base
Clinical trials
Unfortunately there are relatively few good drug treatment trials in MG.
Schneider-Gold C, Gajdos P, Toyka KV et al. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev 2005; 2:CD002828.
This was a review of the use of corticosteroids.
Palace J, Newsom-Davis J, Lecky B. A randomised double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 1998; 50(6): 1778-83.
This was the only trial to convincingly show an effect of a second-line agent.
Benatar M, Rowland LP. The muddle of mycophenolate mofetil in myasthenia. Neurology 2008; 71: 390-1.
This review stated that trials of mycophenolate mofetil produced unclear results.
Guidelines
There are no NICE or SIGN guidelines on myasthenia.
The Association of British Neurologists produced guidelines recently. Myasthenia gravis: Association of British Neurologists' management guidelines. Sussman J, Farrugia ME, Maddison P et al. Pract Neurol 2015; 15: 199-206.
Key text
There are many neurology textbooks on MG but the best source of further information is review articles from specialist centres, for example.
- Hilton-Jones D, Palace J. The management of myasthenia gravis. Pract Neurol 2005; 5: 18-27.
Online
- www.myaware.org
The myaware website has information for both patients and medical professionals.
Take a test and add notes to your CPD Organiser on MIMS Learning
- Contributed by Dr Fiona Norwood, consultant neurologist and honorary senior lecturer, King's College Hospital, south London.
This is an updated version of an article that was first published in May 2011.
References
- Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology 2003;61:1652-61.
- Carr AS, Cardwell CR, McCarron PO et al. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010; 10: 46.
- Benatar M, Burns T, Swan AV. Serological, pharmacological and electrophysiological tests for the diagnosis of myasthenia gravis (protocol). Cochrane Database Syst Rev 2010; 12: CD008904.
- Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev 2007; 4:CD005224.
- Schneider-Gold C, Gajdos P, Toyka KV, et al. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev 2005; 2:CD002828.
- Palace J, Newsom-Davis J, Lecky B. A randomised double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 1998;50(6):1778-83.
- Benatar M, Rowland LP. The muddle of mycophenolate mofetil in myasthenia. Neurology 2008;71:390-1.
- Benveniste O, Hilton-Jones D. The role of rituximab in the treatment of myasthenia gravis. Eur Neurol Rev 2010; 5(2): 95-100.
