Myasthenia Gravis (MG)

Myasthenia Gravis (MG) was first described by Thomas Willis in 1672, although he is more famous for the circle of Willis. It is an acquired autoimmune disease with antibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction or muscle-specific tyrosine kinase (MuSK).¹ This leads to muscular weakness with easy fatiguability, which is worse on exercise and improves with rest.

• 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 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.

• About 10% of patients with myasthenia gravis have a thymoma and around half of patients with thymoma also have myasthenia gravis.
• The condition can sometimes be inherited although there is a predisposition for auto-immune diseases to run in families.
• OMIM lists many entries under myasthenia gravis 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.

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 myasthenia gravis mistakenly thought to be eclampsia.⁷

• 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%.
• 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.

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

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

Causes of generalised muscle weakness

• Multiple sclerosis - hyperreflexia and extensor plantar response can be seen which help differentiate it from MG.
• Motor neurone disease - usually features of LMN disease with wasting and fasciculation are present.
• Hyperthyroidism.
• Chronic fatigue syndrome (ME) - 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 CK.
• Toxins and drugs e.g. 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 EMG findings and ocular weakness do not occur.⁸

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.

• 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 over 70 years old.
• Anti-striated muscle antibody (anti-SM Ab) is positive in 84% of those under 40 with the disease but is less common without a thymoma. If it is positive in a patient under 40 it should prompt a search for a thymoma but over 40 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 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 are used to gain images of the thymus.
• Electromyography may also be helpful if there is diagnostic difficulty. Repetitive stimulation may show early fatigue and failure to respond.

• In MG the number of acetyl choline receptors at the neuromuscular junction is reduced resulting in less interaction between the transmitter and the substrate.
• Neostigmine and pyridostigmine are choline esterase inhibitors that impede the breakdown of acetyl choline by choline esterase 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 N. 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). Or 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 motor neurone disease, poliomyelitis and some other forms of peripheral neuropathy.

There is an association between MG and other autoimmune diseases in 25%.⁹ They include thyroid diseases, rheumatoid arthritis, pernicious anaemia and SLE as well as thymoma or hyperplasia of thymus (as mentioned above). In terms of thyroid disorders this may include thyroid eye disease.^1,10

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, acetycholinesterase inhibitors are the main treatment e.g. 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 but trials are few.¹¹
• 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.¹²
• There is some data regarding the use of monoclonal antibodies - however, results are disappointing due to the incidence of infections.¹³
• 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.^14,15,16
• 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.
• In young patients with a short duration of disease and high antibody titres, it may induce remission.
• 7 to 10 years after surgery the remission rate has reached 40 to 60% except in those with thymoma.
• Factors associated with a good response are age less than 60, 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.¹⁷

It can be extremely difficult to distinguish between worsening of Myasthenia or excessive anticholinergic medication when a patient with known myasthenia gravis 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 i.e. 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.

• 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.

• 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 40 years old, a rapid and progressive disease and thymoma are all bad prognostic signs.¹⁸
• Intercurrent infection and hot weather can aggravate features.

• There is evidence to suggest that a subgroup of MG patients exist who are seronegative to the usual tests but have muscle specific tyrosine kinase (MuSK) autoantibodies (in up to 40%).¹⁹
• They are predominantly female, tend to be under 40, a third fail to respond to anticholinesterase drugs but nearly half respond 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.

• Causes include:
  • Eaton-Lambert syndrome - associated with small cell lung cancer; may occur many years before detectable lesion²⁰
  • Autoimmune disorders
• Underlying aetiology is antibodies directed towards pre-synaptic calcium channels.
• Tends not to effect the eyes but 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 pre-synaptic nerve endings. There is no role for immunosuppression, however, treatment of the underlying cause can lead to much improvement.