This patient complains of drooping of the eyelids in the evenings; examine this patient.
· Weakness in muscles is more marked in the evening.
· Muscle weakness which increases with exercise (remember that./~ttigability is the hallmark of myasthenia gravis) and is
· Muscle weakness affects smiling, chewing, speaking, muscles of the neck, walking, breathing, movements at the elbow and
· Obtain history of thyrotoxicosis, diabetes mellitus, rheumatoid arthritis, SLE and thymoma.
· D-Penicillamine treatment for rheumatoid arthritis (myasthenia gravis is sometimes caused by D-penicillamine).
· The patient may have obvious ptosis.
· Check for worsening of ptosis after sustained upward gaze for at least 45 seconds. · Check extraorolar movements for diplopia and
variable squint. · Comment oa snarlin~ face when the patient attempts to smile.
· Weakness without loss of reflexes, or alteration of sensation or coordination. The weakness may be generalized; it may affect
the limb muscles, often proximal in distribution, as well as the diaphragm and neck extensors.
· Speech is nasal.
· Muscle wasting is rare and presents late in the disease.
Proceed as follows:
Tell the examiner that myasthenia is associated with thyrotoxicosis, diabetes mellitus, rheumatoid arthritis, SLE and thymoma.
This patient has diplopia at the end of each day with ptosis; the weakness is marked on repeated exertion of the muscle (lesion) and
is due to myasthenia gravis (aetiology).
Read classic review: N Engl J Med 1994; 330: 1797-810.
At what age is myasthenia common?
The incidence has two age peaks: one peak in the second and third decades affecting mostly women and a peak in the sixth and
seventh decades affecting mostly men.
What groups of muscles are commonly involved?
The muscles affected are as follows, in order of likelihood: extraocular, bulbar, neck, limb girdle, distal limbs and trunk.
What investigations would you like to perform in this patient?
· Edrophonium (Tensilon) test. · Vital capacity.
· Imaging of the mediastinum: chest radiography, CT or MRI of the chest.
* Serum acetylcholine receptor antibodies (present in more than 80% of cases) (J Neurol Neurosurg Psychiatry 1985; 48:
1246-52). Remember, the basic deficit is a deficiency of acetylcholine receptors at the neuromuscular junction (Science 1973;
· Plasma thyroxine (to rule out an associated thyroid disorder).
· Anti-striated muscle antibody (seen in association with thymoma).
· Antinuclear antibody, rheumatoid factor, antithyroid antibodies may be positive.
· Tuberculin test if immunosuppressive therapy is contemplated.
· EMG abnormalities include a decremental response to tetanic train stimulation at 5-10 Hz (Bull Johns Hopkins Hospital 1941;
68:81-93; Ann N Y Acad Sci 1976; 274: 203-22), and evidence of neuromuscular blockade is seen on single-fibre EMG in the
form of jitter and blocking of motor action potentials (Muscle Nerve 1992; 15: 7204).
What is the differential diagnosis?
· Eaton-Lambert syndrome.
What are the treatment modalities available?
· Symptomatic treatment entails administration of an anticholinesterase drug, e.g. pyridostigmine given up to five times per day.
· Definitive treatment entails immunosuppression, e.g. steroids, azathioprine, ciclosporin, plasmapheresis, thymectomy.
Mention a drug that can cause myasthenia.
o-Penicillamine therapy given for rheumatoid arthritis.
Why may a 'gin and tonic' exacerbate myasthenia?
The quinine in tonic water causes muscle weakness.
If this patient develops an infection, which group of antibiotics would you avoid?
Mention a few exacerbating features.
Fatigue, exercise, infection, emotion, change of climate, pregnancy, magnesium enemas, drugs (aminoglycosides, propranolol,
morphine, barbiturates, procainamide, quinidine).
What do you know about Eaton-Lambert syndrome?
Eaton-Lambert syndrome (JAMA 1957; 163: 1117) is a myasthenic disorder associated with malignancy (Brain 1988; 111: 577; a
review of 50 cases). It is associated with small cell carcinoma of the bronchus. Weakness of the truncal and proximal limb muscles
is common. The pelvic girdle and thighs are almost invariably involved. Transient improvement in muscle strength and deep tendon
reflexes may follow brief exercise. Unlike myasthenia, bulbar symptoms are rare. Antibodies to calcium channels may be detected.
EMG is diagnostic. In the rested muscle there is marked depression of neuromuscular transmission after a single submaximal
stimulus and marked facilitation of response during repetitive stimulation at rates greater than 10 per second.
What is myasthenic crisis?
Exacerbation of myasthenia. The need for artificial ventilation occurs in about 10% of patients with myasthenia. Those with bulbar
and respiratory involvement are prone to respiratory infection. The crisis can be precipitated by respiratory infection and surgery.
Such patients should be closely monitored for pulmonary function. Those with artificial ventilation are not given cholinergics as this
avoids stimulation of pulmonary secretions and uncertainties about overdosage.
How does a cholinergic crisis manifest?
Excessive salivation, confusion, lacrimation, miosis, pallor and collapse. It is important to avoid edrophonium in such patients.
Mention a few associated disorders.
Thyroid disorders (thyrotoxicosis, hypothyroidism), rheumatoid arthritis, diabetes mellitus, dermatomyositis, pernicious anaemia,
SLE, SjOgren's disease, sarcoidosis, pemphigus.
What is the role of thymectomy in such patients?
In the case of thymoma, thymectomy is necessary to prevent tumour spread, although most thymomas are benign. In the absence of
a tumour, thymectomy has been found to be beneficial in 85% of patients, and 35% go into drug-free remission. The impruvement is
noticed 1-10 years after surgery (Neurology 1990; 41}:
1828-9). The role of thymectomy in ocular myasthenia, in adults over 55 years of age (Acta Neurol Scand 1994; 12: 343-68) and in children is still
How is myasthenia graded clinically?
Osserman's grading of severity:
· Grade 1: ocular myasthenia.
· Grade IIA: mild generalized myasthenia with slow progression; no crises; drug responsive.
· Grade liB: moderate generalized myasthenia; severe skeletal and bulbar involve-ment, but no crises; drug response is less satisfactory.
· Grade III: acute fuhninating myasthenia: rapid progression of severe symptoms of respiratory crises and poor drug response; high incidence of
thymoma; high mortality rate.
· Grade IV: late severe myasthenia; same as grade III but takes two years to progress from Class I to II; crises; high mortality rate.
Newsom-Davies clinical subgroups include:
1. Patients with thymoma, equal sex incidence, peak age of onset 30-50 years, no HLA association and poor response to thymectomy.
2. Young onset (<40 years), typically female, thymic medullary germinal centres present, strong association with HLA-B8 and -DR3, and usually a
good response to thymectomy.
3. Older onset (>40 years), more common in males, thymic involution, an association with HLA-B7 and -DR9, and doubtful response to
What is the role of immunomodulation in myasthenia gravis? Intravenous immunoglobulin seems as efficacious as plasma exchange (Ann Neuro/
1997; 41:789 96).
L.M. Eaton (1905-1958), Professor of Neurology at the Mayo Clinic, Rochester, Minnesota.
E.H. Lambert (b. 1915), Professor of Physiology, University of Minnesota.
Sir Samuel Wilks (1824-1911), physician, Guy's Hospital, London. Myasthenia gravis was known as Wi~ks' syndrome.
Myasthenia gravis was first described by the physiologist Thomas Willis in 1672 and by Erb in 1878. It was also known as Hoppe-Goldflam disease
after H.H. Hoppe (1867-1919), a US neurologist (Berl Kiln Wochenschr 1892; 29: 332-6) and S.V. Goldflam (1852-1932), a Polish neurologist. In 1895
F. Jolly named the disease myasthenia gravis pseudoparalytica (Berl Kiln Wochenschr 1895; 32: 1-7).
John Newsom-Davies, FRS, contemporary Professor of Clinical Neurology, Oxford.
Alastair Composton, PhD, FRCP, contemporary Professor of Neurology, Cambridge.