Epidemiology

• Prevalence has been recorded at 17.1 per 100,000 for women and 10.8 for men in Sweden.^[2]
• A prospective study from Queen Square, examining the incidence and lifetime prevalence of neurological diseases based on a London population found that for MG the incidence rates, age and sex adjusted, per 100,000 population per year was 3 (95% CI = 0.8-7).^[3]
• Mean age at onset for women is 34.9 years and for men it is 48.5 years.^[2]
• Peak incidence is in the third decade for women and the sixth or seventh decade in men.
• The diagnosis is being made more often in the elderly in whom the sex ratio is roughly equal.
• The disease may have a bimodal distribution with an early peak with a female preponderance and a later peak with a male majority.

Aetiology

• About 10% of patients with MG have a thymoma and around half of patients with thymoma also have MG.
• The condition can sometimes be inherited although there is a predisposition for autoimmune diseases to run in families.
• Online Mendelian Inheritance in Man (OMIM) lists many entries under MG, although most are myasthenic syndromes. Just one is called myasthenia gravis. This suggests an association of MG with HLA B8 and DR3. In terms of underlying genetic abnormalities, work is ongoing.^[4]
• It can be aggravated by or induced by drug treatment, of which penicillamine is the best documented.^[5]
• Most cases are however idiopathic.

Presentation

50% of patients present with problems of the ocular muscles and 90% experience them at some stage.
Weakness can be highly variable and, despite a strong history, very little abnormal may be demonstrated at examination.

• Muscle fatigues more readily after exercise - a feature used in making the diagnosis. For example, getting the patient to count up to 50. As the patient nears 50 their voice becomes less audible as they are fatiguing. Alternatively, ask the patient to keep their head still and look at your finger, which is held above the forehead level. Thus, the patient has to look up and stay looking up. Patients with ocular muscle involvement are usually unable to do this for more than a few seconds.
• Droop of the upper eyelids is typical with weakness of external ocular muscles producing diplopia. Patients may tilt their head upwards to compensate.
• Weakness is more marked in proximal muscles and isolated weakness of limb muscles is the presenting feature in less than 10%.
• Weakness of the following muscles may also be seen:
  • Small muscles of the hands (finger extensors).
  • Deltoid and triceps muscles.
  • Bulbar muscles - common, causing a nasal sound to speech that is slurred.
  • Facial muscles - very common, producing an abnormal horizontal smile with a furrowed brow that compensates for ptosis.
  • Muscles involved in chewing - thus eating can become difficult and weak muscles may make the jaw drop so that the patient may sit with his chin on his hand to support it.
  • Flexors and extensors of the head - are often weak.
• Symmetrical weakness of a number of other muscles may produce difficulty with walking, sitting or even holding the head up.^[6]
• Seizures may occur and there is a case report of undiagnosed MG mistakenly thought to be eclampsia.^[7]

Progression

• The most typical pattern is for disease to spread from mild to moderate or severe over the course of weeks or months, although sometimes the disease can remain restricted to the external ocular muscles and eyelids for years.
• In severe and general weakness it is rare for the ocular muscles to be unaffected.
• Disease is confined to the ocular muscles in only around 15% of patients.
• Nearly 90% of patients develop general disease within a year from onset, and onset to maximal weakness is less than 36 years in over 80%.
• Intercurrent illness, medications, pregnancy, emotions and hypokalaemia can all exacerbate weakness and may swiftly precipitate a myasthenic crisis and respiratory inadequacy.
• Spontaneous remissions are rare. Full and prolonged remissions are even rarer. Most remissions from treatment occur in the first 3 years of the disease.
• Choking, drooling and difficulty with chewing or swallowing can produce aspiration pneumonia.

Respiratory compromise

• Monitoring arterial pO₂ or oxygen saturation is not enough, as vital capacity can decrease markedly before these parameters change.
• The best method is regularly to monitor vital capacity, tidal volume, negative inspiratory force and blood gases in such patients.

Potentially dangerous drugs

There are a number of drugs that can aggravate the condition and they should be used with caution if essential but are best avoided:

Differential diagnosis

Causes of generalised muscle weakness

• Multiple sclerosis - hyperreflexia and extensor plantar response can be seen, which help differentiate it from MG.
• Motor neurone disease (MND) - usually features of lower motor neurone (LMN) disease with wasting and fasciculation are present.
• Hyperthyroidism.
• Myalgic encephalomyelitis (ME) - 'chronic fatigue syndrome' - will have vague feelings of exhaustion made worse by any effort and no neurological signs to accompany it unless from disuse. The specific tests for MG will be negative.
• Other myopathies - may show fasciculation and elevated creatine kinase (CK).
• Toxins and drugs, eg botulin, organophosphate poisoning.
• Acute Guillain-Barré syndrome - the motor type will have LMN features.
• Eaton-Lambert syndrome - produces slight benefit from exercise before deterioration and typical autoantibody and electromyographic (EMG) findings and ocular weakness do not occur.^[9]

Causes of ocular symptoms

• Horner's syndrome - is usually unilateral. The eyelid may droop but the pupil is smaller than the other and sweating is reduced or absent on that side of the face.
• Oculopharyngeal muscular dystrophy.

Bulbar symptoms

• Amyotrophic lateral sclerosis/motor neurone disease.

Investigations

• Anti-acetylcholine-receptor antibodies are detectable in around 85% of patients with generalised myasthenia but in only about 50% of those with purely ocular myasthenia. False positives may occur with Lambert-Eaton syndrome, thymoma, small cell lung cancer, treatment with penicillamine and between 1 and 3% of all those aged over 70 years.
• Anti-striated muscle antibody (anti-SM Ab) is positive in 84% of those aged under 40 years with the disease but is less common without a thymoma. If it is positive in a patient aged under 40 it should prompt a search for a thymoma; however, at age over 40 years it more often occurs without one.
• Anti-MuSK antibodies - may be present in up to a third of patients.^[1]
• Thyroid abnormalities are common enough to justify routine thyroid function tests (TFTs).
• CXR may show a thymoma as a mediastinal mass but will miss smaller lesions and older smokers may have lung cancer.
• CT or MRI scanning is used to gain images of the thymus.
• EMG may also be helpful if there is diagnostic difficulty. Repetitive stimulation may show early fatigue and failure to respond.

The Tensilon® test

• In MG the number of acetylcholine receptors at the neuromuscular junction is reduced, resulting in less interaction between the transmitter and the substrate.
• Neostigmine and pyridostigmine are cholinesterase inhibitors that impede the breakdown of acetylcholine by cholinesterase and hence enhance the effect of the transmitter.
• For diagnostic purposes the shorter-acting edrophonium is preferred.
• The drug comes in an ampoule of 10 mg in 1 ml. A test dose of 0.1 ml is given and if there are no adverse effects the rest of the ampoule is given 1 minute later.
• Two syringes are set up, one with edrophonium and one with normal saline 0.9%. This improves the validity of the test, as neither the doctor nor the patients knows which contains edrophonium and which contains just water for injection (double-blind). Alternatively, an independent observer can be used to comment on the effects seen.
• A particular concern is excessive vagal tone inducing marked bradycardia and an ampoule of atropine should be at hand.
• A positive test is substantial improvement in muscular power but, as the drug is so brief in duration, this lasts only about 1-5 minutes.
• This drug can sometimes produce improvement in MND, poliomyelitis and some other forms of peripheral neuropathy.

Associated diseases

There is an association between MG and other autoimmune diseases in 25%.^[10] They include thyroid diseases, rheumatoid arthritis, pernicious anaemia and systemic lupus erythematosus (SLE) as well as thymoma or hyperplasia of thymus (as mentioned above). In terms of thyroid disorders this may include thyroid eye disease.^[1][11]

Management

Reports of vigorously tested trials of management are lacking but it is still regarded as a treatable neurological disorder.

Medical treatment

• In the early stage, especially when symptoms are confined to the ocular region, acetylcholinesterase inhibitors are the main treatment, eg pyridostigmine.
• They may cause gastrointestinal problems that can be partially opposed by drugs like propantheline.
• As the disease becomes more general it is necessary to use immunomodulatory agents like steroids, azathioprine, ciclosporin, and mycophenolate mofetil.
• A Cochrane review found that steroids do appear to be of short-term benefit but there was no difference between steroids, azathioprine and immunoglobulin. However, trials are few.^[12]
• A more recent study suggests that ciclosporin, either alone or in combination with corticosteroids, may be more beneficial in MG. However, further clinical trials are needed.^[13]
• There are some data regarding the use of monoclonal antibodies - however, results are disappointing due to the incidence of infections.^[14] Rituximab may prove promising.^[15]
• Plasmapheresis or plasma exchange may be beneficial especially during crises. Weakness improves within a few days but lasts only 6 to 8 weeks.
• It is claimed that long-term immunoglobulin therapy may be effective in selected patients but a Cochrane review was unimpressed by the quality of the evidence for or against immunoglobulin or plasma exchange, even in a myasthenic crisis.^[16][17][18]
• If there is difficulty with swallowing, the diet may need to be modified to aid nutrition and to prevent inhalation.

Thymectomy

• Thymectomy is important if a thymoma is present but may be beneficial even without one.
• It is often first-line treatment for general disease between the ages of 10 and 55 years.
• In young patients with a short duration of disease and high antibody titres, it may induce remission.
• 7 to 10 years after thymectomy the remission rate has reached 40 to 60% except in those with histologically proven thymoma.
• Factors associated with a good response are age less than 60 years, symptoms less than 2 years and low does of pyridostigmine required.
• Factors associated with poor prognosis are the opposite of these plus use of steroids and either thymoma or thymic atrophy on histology.^[19]

Myasthenic versus cholinergic crisis

It can be extremely difficult to distinguish between worsening of myasthenia or excessive anticholinergic medication when a patient with known MG presents with rapidly increasing muscular weakness, with or without respiratory difficulty.

Features suggestive of a cholinergic crisis (too much medication) include muscle fasciculation, pallor, sweating, hypersalivation and small pupils. If in doubt, perform an edrophonium test. Improvement suggests too little medication, ie myasthenic crisis, but aggravation suggests too much medication. Be prepared to stop all medication, ventilate and possibly arrange a plasmapheresis. This test should only be performed with the necessary skills and equipment ready for intubation and ventilation.

Complications

• Aspiration pneumonia due to throat muscle weakness.
• Acute respiratory failure during an exacerbation.
• Babies born to mothers with the disease may show transient signs due to antibodies crossing the placenta. Antibodies are present in nearly all babies but only 10 to 20% have symptoms. It may not present until 10 to 14 days after birth. Babies are also more likely to have arthrogryposis multiplex.

Prognosis

• A typical picture involves exacerbations and remissions.
• Without treatment there is a mortality of 25 to 30% but, with modern management of crises, this falls to about 4%.
• Most of the mortality occurs in the first 3 years or so, and it tends not to get any worse after this time.
• Onset after the age of 40 years, a rapid and progressive disease and thymoma are all bad prognostic signs.^[20]
• Intercurrent infection and hot weather can aggravate features.

Seronegative myasthenia gravis

• There is evidence to suggest that a subgroup of MG patients exists, who are seronegative to the usual tests but have muscle-specific tyrosine kinase (MuSK) autoantibodies (in up to 40%).^[21]
• They are predominantly female, tend to be aged under 40years, a third failing to respond to anticholinesterase drugs, but nearly half responding to immunosuppression with steroids.
• At the end of a period of observation, 6 (35%) patients were in remission, 5 (30%) improved, 4 (24%) were unchanged, and 2 (12%) had died.
• They concluded that patients with antibodies to MuSK have characteristic clinical features that are different from features of the remaining seronegative MG patients.

Myasthenic syndrome

• Causes include:
  • Eaton-Lambert syndrome - associated with small cell lung cancer; may occur many years before detectable lesion.^[22]
  • Autoimmune disorders.
• Underlying aetiology is antibodies directed towards presynaptic calcium channels.
• Tends not to affect the eyes but the proximal muscles of limbs.
• Repeated contraction of muscles can actually increase muscle strength.
• Autonomic dysfunction and hyporeflexia are also seen.
• No, or little, response in the Tensilon® test.
• Management includes 3,4-diaminopyridine which increases the release of acetylcholine from presynaptic nerve endings. There is no role for immunosuppression; however, treatment of the underlying cause can lead to much improvement.