Myasthenia gravis

8 October 2008

Contributed by Dr Stuart Viegas, neuromuscular clinical research fellow at the John Radcliffe Hospital, Oxford.

Section 1 Aetiology and epidemiology
Myasthenia gravis (MG) and the rare Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders in which patients develop circulating autoantibodies against molecules normally present at the neuromuscular junction, causing disruption of normal function.

The neuromuscular junction is a highly specialised synapse that allows efficient communication between the nerve terminal and the muscle membrane (see figure). When a nerve impulse reaches the presynaptic terminal, it causes a local depolarisation, which leads to opening of the voltage-gated calcium channels (VGCC). This influx of calcium leads to the release of acetylcholine (ACh).

Schematic representation of the neuromuscular junction

ACh diffuses across the synapse and binds to the ACh receptor (AChR). This results in a short-term opening of the AChR and a further local depolarisation of the post-synaptic muscle membrane. If this reaches a sufficient threshold then an action potential is generated, which is propagated through the muscle causing muscle contraction. To prevent the ongoing effects, the action of ACh is terminated by acetycholinesterase (AChE).

Classification
In MG, approximately 80 per cent of patients have antibodies directed against the AChR. More recently, antibodies directed against another postsynaptic target, muscle specific kinase (MuSK), have been detected in a further 8-10 per cent of cases.¹ The remaining cases are termed 'seronegative'. Although no antibodies can be detected, there is indirect evidence that antibodies are responsible.

In LEMS, the majority of patients have antibodies directed against the VGCCs.

Aetiology
There is often a co-existence with other autoimmune conditions, notably thyroid disease, vitiligo, rheumatoid arthritis and type-1 diabetes. In 10 per cent of patients there is an associated thymoma, while over 50 per cent of LEMS cases are associated with an underlying neoplasia.

Epidemiology
The prevalence of MG was reported to be 400 per million in a UK prospective study.2 MG can affect any age group. Early-onset disease (<40 years) has a female predominance. Late-onset disease (>40 years) has a slight male predominance. Interestingly (unlike early-onset disease) its incidence appears to be increasing. MG is at least 20 times more common than LEMS.

Section 2 Diagnosis
The hallmark of MG is fatiguable muscle weakness, meaning muscles become weaker after sustained use. Extra-ocular muscles are the most commonly affected, giving rise to ptosis and diplopia. Fatiguability is evidenced by evolving ptosis during prolonged upgaze.

Ocular MG involves only ocular muscles, whereas generalised MG involves any other muscles, including facial muscles.

Fatiguability in limb muscles can be demonstrated by examining for weakness of the appropriate limb after repeatedly abducting the shoulder or flexing the hip.

Decrement of action potentials in diagnosis of MG

The use of repetitive nerve stimulation in diagnosing myasthenia gravis. Note the decrement between the first and fifth compound muscle action potentials (both arrowed).

In severe cases, respiratory muscles can also be affected, causing a reduced vital capacity. If this approaches 1 litre/min in an adult this is defined as a myasthenic crisis. This is a medical emergency and needs urgent inpatient assessment.

LEMS mainly affects the proximal limb muscles. Unlike MG, there is autonomic involvement with dry mouth, impotence in males, impaired sweating and bladder and bowel dysfunction. Tendon reflexes are characteristically reduced, although they can be enhanced by sustained voluntary contraction (termed potentiation).

Investigations
An AChR or MuSK antibody assay may be carried out. AChR antibodies are detected in approximately 50 per cent of purely ocular cases and around 80 per cent of generalised cases.

Of those with generalised MG, MuSK antibodies may be detected in a further 8-10 per cent of MG cases that are AChR antibody negative.

The most widely used neurophysiological study is repetitive nerve stimulation at 3Hz with simultaneous recording of the compound muscle action potential in the appropriate muscle. In MG, an abnormal response is a reduction in amplitude of >10 per cent between the first and fifth responses, termed decrement (see figure).

Single fibre electromyography is more sensitive than repetitive nerve stimulation but is technically more challenging and best left to experienced neurophysiologists in specialised centres.

In the edrophonium test, this short-acting cholinesterase inhibitor is administered intravenously, which may transiently improve weakness. However, the test is limited by both false positive and false negative results. Resuscitation facilities should also be readily available.

Imaging of the thymus (either by CT or MRI) is essential in all patients with detectable AChR antibodies, since 10 per cent will have an associated thymoma. Thyroid function should also be assessed, as co-existing disordered thyroid function may exacerbate muscle weakness.

In LEMS, screening for an underlying neoplasia is mandatory and should be undertaken regularly for at least five years.

Section 3 Management
Once the diagnosis has been confirmed, treatment offered can be classified as symptomatic or disease modifying.

Symptomatic treatment
Pyridostigmine, an anticholinesterase, improves neurotransmission by reducing the breakdown of ACh; the dosage should not exceed 360mg daily. Common side-effects include abdominal cramps and diarrhoea. Propantheline can be used if these symptoms prove troublesome.

In LEMS, 3,4-diaminopyridine is used. It increases presynaptic release of ACh. It should only be prescribed by specialists and is available on a named-patient basis from specialist centres.

Disease modifying
Corticosteroids form the mainstay of treatment when MG is not adequately controlled with pyridostigmine. They are often administered on an alternate day regimen, which may reduce side-effects.

In generalised disease, it is often recommended that patients are admitted for initiation of treatment since there is a risk of excerbating myasthenic weakness initially. The dosage is incrementally increased until a target dose of 1.5mg/kg body weight or 100mg on alternate days (whichever is lower) is achieved. Lower doses are required in ocular disease.

Once remission of symptoms has been achieved, the neurologist will aim to reduce the dosage slowly over many months. The aim is to find the lowest dosage required for disease control.

Patient receiving intravenous immunoglobulin, which is used in treating myasthenic crisis

Before initiation of treatment, the patient should be counselled about potential side-effects (weight gain, hypertension, raised blood sugars, cataracts, mood disturbance, osteoporosis and gastric irritation).

Routine bone protection (bisphosphonates) and gastric protection (proton pump inhibitors) should be offered. All patients should carry a steroid card, and be warned not to cease treatment abruptly.

Other immunosuppressive drugs may be used as steroid sparing agents, but they may need more than a year to take effect.

Azathioprine is the most commonly used (aiming for dosage of 2.5mg/kg body weight). Common side-effects include nausea, vomiting and diarrhoea while potential liver dysfunction and bone marrow suppression mandates regular blood tests. Mild lymphopenia and red cell macrocytosis are commonly seen, and should not prompt concern if they remain stable.

Mycophenolate mofetil is often well tolerated (1g twice daily), but dyspepsia is common. Routine monitoring of the FBC is again necessary.

Methotrexate is given once weekly, at a dosage of 7.5-20mg (together with folic acid).

In addition to regular blood tests, a baseline chest X-ray is recommended since pulmonary fibrosis is a recognised complication. Aspirin and NSAIDs should be avoided.

Ciclosporin is used at lower dosages than in transplant medicine (typically 2.5mg/kg body weight in divided doses). Regular monitoring of blood count, liver and renal function is also necessary. Hypertension, hirsuitism, tremor and paraesthesia are common adverse effects.

Thymectomy
Thymectomy has two roles in the management of MG. In young-onset disease and where AChR antibodies are found, it increases the chance of disease improvement or remission. However its role here remains unclear, and is the focus of an ongoing trial.

It is also the treatment of choice where a co-existing thymoma is found. Adjuvant therapy may also be necessary.

IV immunoglobulin and plasma exchange
IV immunoglobulin (IVIG) and plasma exchange (PE) have a rapid but short-lived (typically 6-8 weeks) effect and are used in treating myasthenic crisis. They may also be used to give rapid early benefit while waiting for immunosuppressant therapy to become effective.

Both are likely to be equally effective, although IVIG is easier to administer and can be used in relapse precipitated by sepsis. PE is usually reserved for those intolerant of IVIG.

Section 4 Special circumstances

Pregnancy
It is especially important to try to plan potential pregnancies. Where the disease is well controlled pre-conception, pregnancies are usually uncomplicated.

The benefit of satisfactory disease control with corticosteroids, azathioprine and pyridostigmine outweighs any potential risks from the drugs. The teratogenicity of other immunosuppressive agents remains unknown and so they are best avoided.

Both PE and IVIG are considered safe in pregnancy although relapses, when they do arise, tend to be post-partum.³

Finally, transient myasthenia can occur in the newborn child due to transplacental transfer of maternal antibodies. These babies usually manifest with poor cry and with feeding difficulties.

Treatment is with cholinesterase inhibitors, with resolution of symptoms over weeks.

Surgery
Pre-surgery anaesthetic assessment with an experienced anaesthetist is essential, as patients are particularly sensitive to certain drugs which can cause prolonged paralysis and should be avoided. For those on corticosteroid therapy, additional hydrocortisone cover will be required during the peri- and post-operative period.

Relapses
Disease relapse may occur due to physiological stress (inter-current illness, surgery), early (or too rapid) withdrawal of disease modifying therapy or the introduction of other drugs.

Many drugs have been implicated, but notable culprits include beta-blockers, calcium-channel blockers and certain antibiotics (aminoglycosides, tetracyclines and quinolones). Concurrent events should be addressed while the corticosteroid dose is also increased. IVIG and PE are used in severe relapses.

Prognosis
With better recognition of the disorder and improved treatment, the prognosis for those with MG has improved steadily over the past decades. The major cause of mortality remains respiratory failure in severe myasthenia crises. However, the mortality related to severe crises has fallen from 80 per cent in the 1960s to under 5 per cent,⁴ mainly due to better respiratory support together with early use of immunomodulatory therapy.

References

1. Vincent A, Leite M I. Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. Curr Opin Neurol 2005; 18: 519-25.

2. McDonald B K, Cockerell O C, Sanders J W, Shorvon S D. The incidence and lifetime prevalence of neurological disorders in a prospective community based study in the UK. Brain 2000; 123: 665-76.

3. Cialfaloni E, Massey J M. The management of myasthenia gravis in pregnancy. Semin Neurol 2004; 24: 95-100.

4. Lacomis D. Myasthenic crisis. Neurocrit Care 2005; 3: 189-94.