Myasthenia Gravis Flashcards
(29 cards)
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.
What is the main trigger of MC?
Most patients have a predisposing factor that triggers the crisis, often a respiratory tract infection. It may present as a postsurgical patient, in whom exacerbation of muscle weakness from MG causes a delay in extubation.
What is the main treatment of MC?
Immunoglobulins, plasma exchange and steroids are the cornerstones of immunotherapy. With modern intensive care, the mortality rate of MC is now less than 5%.
Which medication overdose mimics MC?
It can be extremely difficult to distinguish between worsening of myasthenia (MC) or excessive anticholinergic medication (cholinergic crisis) when a patient with known MG presents with rapidly increasing muscular weakness, with or without respiratory difficulty.
What are features of cholinergic crisis?
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 MC; however, 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.
What is lambert-Eaton myasthenic syndrome?
Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission caused by impaired presynaptic release of acetylcholine (ACh).
What is the pathogenesis of LEMS?
LEMS results from an autoimmune attack directed against the P/Q subtype of voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal.
These channels are also found in high numbers in the tumour cells associated with LEMS - small cell cancer of the lung (SCCL).
It is thought that antibodies are produced against the tumour VGCCs but are then also responsible for the resulting attack on non-cancerous cells and their sequelae. This is supported by animal studies.
What are the risk factors of LEMS?
Cancer- typically SCCL is present when weakness begins or is later found in approximately 50% of patients.
Smoking and age at onset are major risk factors for cancer in LEMS. All patients with associated SCCL have a hx of long-term smoking.
Only half of patients with autoimmune LEMS are long-term smokers- e.g., a patient aged < 50 years, who does not have a cancer discovered in the first two years after diagnosis, is unlikely to have an underlying cancer.
What is the presentation of LEMS?
LEMS causes proximal muscle weakness, depressed tendon reflexes, post-tetanic potentiation and autonomic changes.
Symptoms usually begin insidiously, with many patients undiagnosed for months or years.
Weakness is a major symptom - usually, in the proximal muscles of lower limb. Gait is affected.
Muscles may ache and be tender. Oropharyngeal and ocular muscles are mildly affected.
Bulbar and respiratory muscles are usually spared.
Autonomic symptoms - dry mouth, impotence in males and postural hypotension may be seen.
Reduced strength in the proximal muscles of the arms and legs, producing a waddling gait and difficulty with raising the arms.
Eyelid ptosis and mild diplopia have been reported (23% and 20.5% respectively in one study).
Occasionally there may be difficulty in chewing, speech or swallowing.
Strength may improve initially on exercise but then lessens as exercise is sustained.
Deep tendon reflexes are reduced or absent. Sensory examination is normal, unless there is a coincident peripheral neuropathy associated with an underlying cancer.
What are the differentials of LEMS?
Myasthenia gravis
Acute or chronic inflammatory demyelinating polyradiculopathy
Dermatomyositis
Spinal muscular atrophy
