Myasthenia Gravis Flashcards
What is myasthenia gravis?
Myasthenia gravis (MG) is a chronic autoimmune disorder of the post-synaptic membrane at the neuromuscular junction (NMJ) in skeletal muscle.
Circulating antibodies against the nicotinic acetylcholine receptor (AChR) and associated proteins impair neuromuscular transmission.
Patients present with muscle weakness, which typically worsens with continued activity (fatigue) and improves on rest.
Severity varies from isolated eye muscle weakness to generalised muscle weakness and respiratory failure requiring mechanical ventilation.
What is the aetiology of myasthenia gravis?
In most patients, IgG1-dominant antibodies to acetylcholine receptors cause fatigable weakness of skeletal muscles. In the rest, a variable proportion possesses antibodies to MuSK.
About 15% of patients with MG have a thymoma and 30-50% 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
Muscle-specific tyrosine kinase (MuSK) is an agrin-dependent protein on muscle membrane with an essential role in anchoring AChR at the tips of the postsynaptic folds.
What is the pathophysiology of myasthenia gravis?
In myasthenia gravis (MG) with antibodies to acetylcholine receptors (AChRs), an autoimmune attack against AChRs results in destruction of the post-synaptic membrane.
The reduced number of available binding sites for acetylcholine leads to inconsistent generation of muscle fibre action potentials, which manifests as skeletal muscle weakness.
What is the presentation of myasthenia gravis?
Almost all MG patients will have ocular manifestations at some point during the course of their disease.
Although ocular symptoms are often the first to appear, most patients progress to generalised MG and only 15% continue to have isolated ocular complaints for the entire course of the disease
The clinical presentation varies from mild weakness of limited muscle groups (class I, or ocular, MG) to severe weakness of multiple muscle groups (class V, or severe generalised, MG).
Muscle fatigues more readily after exercise:
o This is a feature used in making the diagnosis.
o For example, getting the patient to count up to 50. As the patient nears 50 their voice becomes less audible as they are fatiguing.
Symmetrical weakness of a number of other muscles may produce difficulty with walking, sitting or even holding the head up.
There is no muscle wasting or fasciculation. Tone is normal. Sensation is unimpaired and tendon reflexes are normal.
Seizures may occur.
People with MG are resistant to suxamethonium (used to provide short-duration neuromuscular blockade for surgery) but can develop dual block resulting in delayed recovery
What is the progression of myasthenia gravis?
In the majority of patients, disease progression will take place within the first year after onset and within two years in up to 80% of cases.
If patients have restricted ocular disease for two years without developing generalised MG, they are not likely to develop it later.
When weakness is limited to the extrinsic ocular muscles and levator palpebrae superioris, the disease is called ocular myasthenia.
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.
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 three years of the disease.
What is the most serious complication of myasthenia gravis?
Weakness of the muscles of ventilation can cause acute respiratory failure. This is an acute neurological emergency that requires ventilation. Weak pharyngeal muscles can also lead to compromise of the airway.
The best method is regularly to monitor vital capacity, tidal volume, negative inspiratory force and blood gases in such patients.
What are the potential drugs that can aggravate myasthenia gravis?
Antibiotics such as gentamicin, ciprofloxacin, macrolides, tetracyclines and ampicillin.
Beta blockers
Verapamil
Atracurium
Vecuronium
Lithium
D-penicillamine
Opiates - eg, pethidine
Phenytoin
Statins
Magnesium
Chloroquine
Prednisolone
What are the differentials of myasthenia gravis?
Causes of generalised muscle weakness:
- Myasthenic syndromes: diseases of neuromuscular junction result from immune, toxic, genetic pathologies, including:
- Lambert-Eaton myasthenic syndrome - associated with small-cell lung cancer; may occur many years before detectable lesion.
- Autoimmune disorders.
- Congenital myasthenic syndromes.
- Multiple sclerosis (MS) - 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 - e.g., botulinum, organophosphate poisoning.
- Acute Guillain-Barré syndrome - the motor type will have LMN features.
Causes of ocular symptoms:
- Horner’s syndrome- 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.
- ALS/MND
What are the investigations for myasthenia gravis?
The diagnosis is based on clinical features, the benefit of cholinesterase inhibitors, the detection of specific autoantibodies (anti-AChR, anti-MuSK or anti-LRP4), and electrophysiological tests.
If the diagnosis of MG 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 while waiting for other investigations.
Serum anti-acetylcholine receptor (ACh-R) antibody testing is the first-line investigation for non-urgent patients.
Thyroid function for all patients.
Serum MuSK antibody testing for all patients negative for ACh-R antibodies.
Neurophysiological testing on symptomatic muscles may help to establish the diagnosis in seronegative patients with suspected MG. Repetitive nerve stimulation is the initial test. If this is negative then single-fibre electromyography should be considered.
MR scan of brain: patients with negative serology and neurophysiology, and with symptoms compatible with ocular myasthenia, may have structural brain disease.
Thymus CT or MRI scanning for all patients with suspected myasthenia, irrespective of distribution (ocular/generalised) or serology (seropositive/negative).
Edrophonium (Tensilon®) test if there is diagnostic doubt
What is the ice test?
This distinguishes MG from other causes of ptosis. Crushed ice in a latex glove is applied to the eye for three minutes. In MG this leads to improvement of ptosis and it has a sensitivity and specificity of over 90%.
What is the Tensilon test?
The edrophonium (Tensilon®) test involves intravenous administration of a short-acting acetylcholinesterase inhibitor while watching for a transient improvement in muscle strength. Although it has a high sensitivity (95%) for generalised MG, it is now rarely done, as it can result in life-threatening bradycardia and requires immediate access to resuscitation facilities
What are the associated diseases of myasthenia gravis?
There is an association between MG and other autoimmune diseases in 25%.
They include thyroid disease, dermatomyositis, polymyositis, systemic lupus erythematosus, Addison’s disease, Guillain-Barré syndrome and juvenile rheumatoid arthritis.
What is the management of myasthenia gravis?
Symptomatic treatment with acetylcholinesterase inhibition is usually combined with immunosuppression. Pyridostigmine is the preferred symptomatic treatment. For patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine and thymectomy are first-line immunosuppressive treatments.
Alternative immunosuppressive options to azathioprine include ciclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus.
Rituximab is a promising new drug for severe generalised MG. Emerging therapy options include belimumab, eculizumab and the granulocyte-macrophage colony-stimulating factor.
If there is difficulty with swallowing, the diet may need to be modified to aid nutrition and to prevent inhalation.
Newborn babies born to myasthenic mothers are at risk of transient myasthenic weakness (even if the mother’s myasthenia is well controlled) and should have rapid access to neonatal high-dependency support
Thymectomy is important if a thymoma is present but may be beneficial even without one.
What are the complications of myasthenia gravis?
Aspiration pneumonia due to throat muscle weakness.
Acute respiratory failure during an exacerbation.
Severe restrictions on activities of daily living.
What is myasthenic crisis?
Myasthenic crisis (MC) is a complication of MG characterised by worsening muscle weakness resulting in respiratory failure that requires intubation and mechanical ventilation.
MC is a very important, serious and reversible neurological emergency that affects 20-30% of myasthenic patients, usually within the first year of illness; it may be the first indication of the disease.
