Practice Easily Missed?

Myasthenia gravis

BMJ 2012; 345 doi: (Published 21 December 2012) Cite this as: BMJ 2012;345:e8497
  1. J Spillane, clinical research associate 1,
  2. E Higham, general practitioner partner2,
  3. D M Kullmann, professor of neurology1
  1. 1UCL Institute of Neurology, London WC1N3BG, UK
  2. 2Central Medical Centre, Morden SM4 5RT, UK
  1. Correspondence to: J Spillane jennifer.spillane.09{at}

A previously well 78 year old man presented to his general practitioner with a six month history of double vision that was more pronounced when he was tired. His wife had also noted drooping of his eyelids towards the end of the day. Examination showed restricted eye movements (ophthalmoplegia) and fatigable ptosis. He was referred to his local neurology centre and a diagnosis of myasthenia gravis was confirmed with antibody and electrophysiological tests. A computed tomography scan of his thorax was normal and he was prescribed oral pyridostigmine.

What is myasthenia gravis?

Myasthenia gravis is an autoimmune disorder of neuromuscular transmission characterised by fatigable muscle weakness. The disorder is typically mediated by antibodies against the postsynaptic acetylcholine receptor or by antibodies against muscle specific tyrosine kinase. About 10% of patients with myasthenia gravis have a thymoma.1 Any muscle group can be affected in myasthenia gravis, but typically patients present with ocular symptoms, namely diplopia and ptosis. Weakness then becomes generalised in about 80% of patients.2 The most serious complication is myasthenic crisis: acute respiratory failure resulting from myasthenia gravis that requires mechanical ventilation. Myasthenic crisis occurs in about 20% of patients with myasthenia gravis and is a neurological emergency requiring admission to an intensive care unit for respiratory support.3

How common is myasthenia gravis?

  • The prevalence of myasthenia gravis in the United Kingdom is estimated at about 15 per 100 000 population, although this figure has increased over time4 5

  • The incidence is bimodal, with a female:male ratio of 2:1 in younger adults and a reversed sex ratio in older people6

  • Both the incidence and the prevalence of myasthenia gravis in older patients are greater than previously thought7

Why is myasthenia gravis missed?

The fluctuating nature of the symptoms and the often subtle findings on clinical examination can make myasthenia gravis difficult to diagnose. In one study, diagnosis was delayed for more than five years in 13% of patients, and 26% of patients had had an inappropriate non-specific investigation before diagnosis.8 The symptoms of myasthenia gravis are confined to the eye in about 20% of patients with the condition, which can make diagnosis challenging.2

Evidence suggests that myasthenia gravis is under-recognised in elderly people, partly because symptoms such as dysphagia, fatigue, and slurred speech can have a broad differential diagnosis in that group.9 Myasthenia gravis has been reported to have been mistaken for stroke, Parkinson’s disease, and motor neurone disease in elderly people.9 10 11 Signs such as ptosis may also be attributed to aponeurotic (“age related”) ptosis (so called because of the stretching of the aponeurosis tendon, which generally occurs in older people).

A diagnosis of myasthenia gravis may be missed in primary and secondary care as some patients may have negative serology results (antibodies) and normal electrophysiology, particularly if they have only ocular myasthenia gravis.12 Thus a thorough history is central to the diagnosis.

Why does it matter?

Myasthenia gravis is eminently treatable. Untreated patients are at risk of having an acute deterioration of their symptoms and developing myasthenic crisis.

How is it diagnosed?



The clinical hallmark of myasthenia gravis is fatigable muscle weakness. The history should elicit the pattern and severity of the weakness and any fluctuation of symptoms. Symptoms are typically worse at the end of the day. They may also worsen with heat, infections, surgery, or emotional stress, menstruation, pregnancy, and the post-partum state. Diplopia and ptosis are the most common presenting features of myasthenia gravis, but about 80% of patients will subsequently develop more generalised weakness.2 Weakness is typically more noticeable in the upper limbs than the lower limbs and is often proximal. Bulbar weakness can manifest as difficulty in chewing or as slurred speech, particularly after a long conversation. Dysphagia, choking, or nasal regurgitation of liquids can herald more severe bulbar weakness. Neck weakness can lead to head drop and neck pain. Respiratory weakness may manifest with exertional dyspnoea or orthopnoea.


Cranial nerve examination may show ophthalmoplegia or weakness of forced eyelid or mouth closure. Bulbar weakness may be evident if the patient develops dysarthria or nasal speech after prolonged speaking, such as at the end of the consultation or after counting to 50. Fatigability can be elicited by watching for the development of ptosis during sustained upgaze. On examination of the peripheral nervous system, fatigability can be assessed by testing shoulder abduction before and after unilateral repetitive arm movement. There may be obvious weakness of neck flexion or extension, and if diaphragmatic weakness is present, there may be paradoxical abdominal movement during inspiration.


Ice test

If the diagnosis of myasthenia gravis is suspected, refer the patient to a neurology unit for further investigations. In patients with ptosis, the ice test is a simple first line test that can be done in the clinic while waiting for other investigations. This distinguishes myasthenia gravis from other causes of ptosis and involves application of crushed ice in a latex glove to the eye for three minutes. In myasthenia gravis this leads to improvement of ptosis and has a sensitivity and specificity of >90%.13

Laboratory investigations

The presence of antibodies to the acetylcholine receptor or to muscle specific tyrosine kinase is highly specific. About 85% of patients with generalised myasthenia gravis have antibodies to the acetylcholine receptor, and 40-70% of the rest are positive for antibodies to muscle specific tyrosine kinase.14 Repeating negative serological tests can be useful because a seroconversion rate of 15% over one year has been reported.14 Nevertheless, some patients will be persistently seronegative, especially those with only ocular myasthenia gravis.12

Levels of muscle specific enzymes such as creatine phosphokinase are usually normal in myasthenia gravis.


Routine electrophysiology generally yields normal results in myasthenia gravis, and the diagnosis may be missed if specific electrophysiological tests such as repetitive nerve stimulation and single fibre electromyography are not requested. Repetitive nerve stimulation is specific for myasthenia gravis, but the sensitivity is only 70% and is even lower in disease that is purely ocular.12 Single fibre electromyography is a selective recording technique that allows identification of action potentials from individual muscle fibres. It is more sensitive (92-100%) than repetitive nerve stimulation for myasthenia gravis but is not specific.15 Single fibre electromyography is a challenging technique that depends greatly on the skill of the operator and the muscles that are tested as often only affected muscles will show positive results.

Edrophonium test

The edrophonium (Tensilon) test involves intravenous administration of a short acting acetylcholinesterase inhibitor while watching for a transient improvement in muscle strength.16 The test should be done only when an objective improvement in muscle strength, such as resolution of ptosis, can be shown. Although it has a high sensitivity (95%) for generalised myasthenia gravis, it is now rarely done as it can result in life threatening bradycardia and requires immediate access to resuscitation facilities.


Although it does not form part of the diagnostic tests, computed tomography of the thorax is required in all patients in whom myasthenia gravis is diagnosed to exclude the presence of an underlying thymoma.

How is myasthenia gravis managed?

Acetylcholinesterase inhibitors, such as pyridostigmine, provide short lived symptomatic relief and are first line treatment, although they are less useful in myasthenia gravis when patients have antibodies to muscle specific tyrosine kinase.17 Most patients will require immunomodulatory therapy, started by secondary care.18 Oral steroids are generally first line immunosuppressive treatment, although side effects limit long term use.17 High initial doses of prednisolone can transiently exacerbate weakness, and patients may be admitted to hospital if rapid escalation of treatment is needed.18 Second line immunosuppressive agents used in myasthenia gravis include azathioprine, mycophenolate mofetil, methotrexate, tacrolimus, and ciclosporin.17 Rituximab has been used in severe treatment resistant myasthenia gravis.19 Intravenous immunoglobulin and plasma exchange are reserved for rapidly deteriorating myasthenia gravis and for the treatment of myasthenic crisis.18

Thymectomy is a well recognised treatment for myasthenia gravis and should always be performed if a thymoma is suspected.17 18 Thymectomy is also considered in non-thymomatous generalised myasthenia gravis in patients with antibodies to the acetylcholine receptor who are aged under 50. 18 Thymectomy is not generally carried out in myasthenia gravis when patients have antibodies to muscle specific tyrosine kinase, late onset myasthenia gravis, or purely ocular disease.18

Importantly, patients should not abruptly discontinue their treatment for myasthenia gravis. Patients who are dysphagic and cannot take oral medication should be admitted to hospital and other routes of administration, such as nasogastric tubes, should be sought. Moreover, patients who are septicaemic, having surgery, or experiencing some other stress require close monitoring because a change or escalation of their treatment may be needed to prevent myasthenic crisis. Some medications—such as aminoglycoside and quinolone antibiotics, quinine, and intravenous magnesium—are contraindicated in myasthenia gravis as they can impair neuromuscular transmission. A full list of medications that can affect myasthenia gravis is available from the Myasthenia Gravis Foundation of America (

Key points

  • Suspect myasthenia gravis in patients with fluctuating weakness, which initially is typically ocular, although weakness subsequently becomes more generalised in 80% of patients

  • If myasthenia gravis is suspected, refer the patient to a neurology centre for investigations, including testing for the presence of antibodies to the acetylcholine receptor and to muscle specific tyrosine kinase, and specific electrophysiological tests

  • The patient may still have myasthenia gravis even if the results of serology and electrophysiological investigations are normal; history is key to the diagnosis

  • Effective treatment (including acetylcholinesterase inhibitors and steroids) is available for this potentially fatal condition and should not be discontinued abruptly; patients having surgery or experiencing other stresses need close monitoring and possibly changes in treatment to prevent myasthenic crisis

Red flags for an imminent myasthenic crisis

  • Rapid worsening of primary myasthenic symptoms

  • Rapid progression of bulbar symptoms

  • Increasing dose of pyridostigmine

  • Tachypnoea

  • Tachycardia

  • Decreased forced vital capacity

  • Respiratory infection


Cite this as: BMJ 2012;345:e8497


  • This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Health Care, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at easilymissed{at}

  • Contributors: All authors were responsible for the design of the article, drafting it, and revising it critically for intellectual content. All authors approved the final manuscript. JS is the guarantor.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; the Myasthenia Gravis Association UK funds JS’s research post; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; externally peer reviewed.

  • Patient consent not required (patient anonymised, dead, or hypothetical).


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