Chapter 64 Myasthenia Gravis
1 What is myasthenia gravis (MG)?
MG is an autoimmune disorder affecting the neuromuscular junction characterized by a T-cell–mediated response targeting the postsynaptic acetylcholine receptor or receptor-associated proteins. Patients typically have the classic pattern of fatigable weakness, where repetitive stimulation of a muscle results in progressive weakness.
2 What are the classic patterns of weakness seen in patients with MG?
The disease is divided into ocular and generalized forms. Both forms can present similarly with extraocular, facial, and oropharyngeal muscles presenting early in the course of the disease. Weakness of these muscles is seen clinically as diplopia, ptosis, dysphagia, and hypophonia, respectively. The ocular form is restricted to these muscles, whereas the generalized form may present initially with, and/or progress to, weakness of flexors and extensors of the neck and proximal muscles of the trunk.
3 List and describe the differential diagnosis of bulbar weakness
Lambert-Eaton myasthenic syndrome (LEMS): LEMS presents in the opposite fashion of MG. Patients present with weakness that improves on repetitive stimulation of the muscle. Autoantibodies are directed presynaptically and prevent Ca++-mediated release of synaptic vesicles. LEMS is most often a paraneoplastic disorder.
Miller Fisher variant Guillain-Barré syndrome (GBS): Antibodies to GQ1b affect the bulbar musculature first resulting in the triad of ophthalmoplegia, ataxia, and areflexia. See Chapter 63 for description of classic GBS presentation.
Botulism: Presents with blurred vision, midposition nonreactive pupils, dysphagia, and limb weakness.
Amyotrophic lateral sclerosis (ALS): Though early stage ALS can have protean manifestations, key differences are the presence of upper motor neuron signs such as spasticity and hyperreflexia not seen in MG.
4 How is MG diagnosed?
The clinical syndrome of fatigable muscle weakness should raise clinical suspicion, often with better strength in the morning that progressively worsens throughout the day. Physical examination should include testing of sustained upgaze for > 30 seconds with observation for eyelid twitch, ptosis, or diplopia. With ocular symptoms such as ptosis, an ice pack applied to the eyelid can speed synaptic transmission, which supports the diagnosis of MG; the reliability and specificity of this test are, nevertheless, questionable.
Edrophonium (Tensilon) is no longer widely available. It is a very rapidly acting cholinesterase inhibitor and carries a small risk of heart block, warranting a small test dose and a monitored setting with access to external cardiac pacing pads when used. Reliable measurement of clinical symptoms is essential before considering the test, as improvement must be measured as objectively as possible.
Electromyography (EMG) is the current diagnostic test of choice in MG. The characteristic EMG pattern found in MG is progressively smaller action potentials with repetitive nerve stimulation (decrement). Single-fiber EMG can be a more sensitive method but requires great cooperation of the patient and hence rarely applies to the patient in the intensive care unit (ICU). Though often present, serum autoantibodies to the acetylcholine receptor are not required for the diagnosis of MG.
5 Describe the pathophysiology of MG
Autoantibodies producing symptoms of MG are directed against the acetylcholine receptor (AChR) on the postsynaptic membrane. AChR antibodies are found in 80% to 90% of patients with generalized MG and 60% with ocular MG. Autoantibodies against the muscle-specific tyrosine kinase are found in 70% of patients with MG without AChR antibodies. A remaining small fraction of patients without identified autoantibodies have what is termed seronegative MG. The antibodies produce a functional deficit of acetylcholine receptors, as well as morphologic change in the neuromuscular junction visible by electron microscopy. Consequently, the effect of acetylcholine on the postsynaptic membrane is reduced, and the probability that a nerve impulse will cause a muscle action potential is reduced.
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