Myasthenia Gravis

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Chapter 64 Myasthenia Gravis

Corey R. Fehnel, MD , Ala Nozari, MD, PhD , Lee H. Schwamm, MD, FAHA

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

image 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.

image 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.

image Thyrotoxicosis: Presents with transient weakness and ocular findings. Hence thyroid function tests are part of the initial evaluation of any patient with suspected MG.

image Botulism: Presents with blurred vision, midposition nonreactive pupils, dysphagia, and limb weakness.

image 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.

6 What is myasthenic crisis?

Myasthenic crisis is weakness from MG severe enough to necessitate intubation or to delay extubation after surgery. It can occur spontaneously or may be precipitated by surgery, infection, pregnancy, or a number of drugs including aminoglycosides, erythromycin, β-blockers, procainamide, quinidine, and magnesium. It should be distinguished from a cholinergic crisis in which weakness is due to inadvertent excess cholinergic medication.

7 How should a patient in myasthenic crisis be evaluated?

With increasing muscle weakness it is important to assess respiratory muscle strength and identify impending respiratory failure. Tachypnea is often the first sign of impending respiratory failure. Important respiratory parameters that should be monitored include vital capacity (VC) and maximum inspiratory force (MIF). Because neither measurement has been shown to be superior, the two are usually analyzed in combination. In a patient with progressive muscle weakness, a MIF <20 cm H2O or VC <5 mL/kg indicates the need for elective intubation and mechanical ventilation. These measurements can often be difficult to obtain and are spurious in a patient with severe facial weakness, which can prevent a tight seal around the lips. Therefore surrogate measures of VC such as having the patient count out loud as high as he or she can in one breath may be useful (approximately 100 mL for each number counted slowly). Hypercarbia usually develops before hypoxia. Both are late signs of neuromuscular respiratory failure and should not be used as a decision for intubation in MG. After respiratory status has been stabilized, focus should be shifted to determining the underlying trigger for the exacerbation. Infections are a common trigger, often of pulmonary or urinary source, with further evaluation of other sources as clinical suspicion dictates. Great care should be taken to avoid medications that could worsen neuromuscular transmission. An extensive list of medications that aggravate MG can be found at http://www.myasthenia.org. The list should be reviewed for every patient with MG in your care. Key offenders are aminoglycosides and quinolones.

8 How are intubation and airway management handled differently in patients with MG?

Patients with MG are sensitive to nondepolarizing neuromuscular blocking agents but relatively resistant to depolarizing agents. As an example, the dose required to produce 95% depression of twitch height (ED95) for atracurium and vecuronium (nondepolarizing) is estimated to be 40% to 60% that of normal individuals. Preferably, short- or intermediate-acting nondepolarizing neuromuscular blocking agents should be used. If muscle weakness is excessive, intubation of the trachea can also be performed without neuromuscular blocking agents (e.g., with remifentanil and propofol bolus only). If succinylcholine is used, a dose of 1.5 to 2.0 mg/kg should be adequate for rapid-sequence intubation in most patients with myasthenia, as the ED95 of succinylcholine is approximately 2.6 times that needed for patients without myasthenia (0.8 mg/kg vs. 0.3 mg/kg).

Patients with MG are more likely than normal patients to have a phase II block, and cholinesterase depletion with plasmapheresis or inhibition with pyridostigmine may prolong the blockade.

9 What are the medical treatments for MG?

Acetylcholinesterase inhibitors represent the mainstay of symptomatic treatment. Pyridostigmine (Mestinon) is most commonly used as it has few muscarinic side effects. Onset of action is within 15 to 30 minutes (oral administration) and peak effect within 1 to 2 hours. Usual daily doses are between 30 to 120 mg, divided into three to six administrations per day. Corticosteroids cause a reduction in the number of antibodies to the acetylcholine receptors and are often used to initiate or maintain a remission. Care should be taken with sudden dose escalations of corticosteroids as there may be an initial period of worsening before improvement. Azathioprine and cyclosporine are popular steroid-sparing agents employed in refractory or steroid-dependent cases. Acute exacerbations require ICU care and are treated with intravenous immunoglobulin (IVIG) or plasmapheresis. Cholinesterase inhibitors are often held in the critical care setting to avoid toxicity, and restarting them can be tricky especially if the patient has reduced ability to handle oral secretions, which increase with use of these drugs. The oral dose of pyridostigmine is approximately 30 times the intravenous dose.

10 Who should undergo thymectomy?

Hyperplasia of the thymus gland is seen in 65% of MG cases, whereas thymoma is seen in up to 15% of patients. Video-assisted thorascopic surgery–assisted thymectomy is often performed but is largely unproved. If a thymoma is present, then thymectomy appears to result in 35% remission rate if performed within 1 to 2 years of diagnosis. Thymectomy should be performed electively and not during a myasthenic crisis.

11 Name the clinical signs of pyridostigmine toxicity

Pyridostigmine toxicity (cholinergic crisis) can cause weakness and may be misdiagnosed as worsening of MG symptoms. Overstimulation of the nicotinic acetylcholine receptors results in involuntary twitching, fasciculations, and weakness (inability to coordinate muscle contraction and relaxation). Muscarinic side effects include excess salivation, lacrimation, urinary incontinence, diaphoresis, bronchorrhea, pulmonary edema, miosis, and blurred vision and are referred to as the “SLUDGE syndrome.”

12 What is the prognosis for patients with MG?

Prognosis for most patients is quite good. Most patients are able to return to their regular lifestyle. However, a wide spectrum of disease severity exists. Some patients respond well to minimal doses of pyridostigmine and do not require long-term immunosuppressive drugs. Others require long-term corticosteroids and powerful immunomodulatory agents and may still have frequent exacerbations. Time of diagnosis from symptom onset and age at onset are predictors of clinical remission. History of intubation from respiratory failure is a negative prognostic sign. Pregnancy has variable effects on the course of MG and can lead to exacerbation, remission, or no change in disease. The first trimester and immediate postpartum period are times of highest risk for exacerbation.

Key Points Myasthenia Gravisimage

1. MG is an autoimmune disorder with antibodies directed against the postsynaptic acetylcholine receptors.

2. In a majority of cases MG preferentially affects ocular and bulbar musculature followed later by muscles of the trunk and limbs.

3. Myasthenic crisis is weakness resulting in respiratory failure best measured by respiratory rate and serial measurement of MIF and VC. Hypoxia and hypercarbia develop very late in myasthenic crisis and should not be used as intubation criteria.

4. Plasmapheresis and IVIG are the mainstays of treatment of severe myasthenic exacerbations. A careful evaluation for infection and review of all potentially harmful medications (an extensive list) should occur for every patient with exacerbation of MG.

Bibliography

1 Drachman D.B. Myasthenia gravis. N Engl J Med. 1994;330:1797–1810.

2 Gomez A.M., Van Den Broeck J., Vrolix K., et al. Antibody effector mechanisms in myasthenia gravis-pathogenesis at the neuromuscular junction. Autoimmunity. 2010;43:353–370.

3 Jani-Acsadi A., Lisak R.P. Myasthenic crisis: guidelines for prevention and treatment. J Neurol Sci. 2007;261:127–133.

4 Mao Z.F., Mo X.A., Qin C., et al. Course and prognosis of myasthenia gravis: a systematic review. Eur J Neurol. 2010;17:913–921.

5 Scherer K., Bedlack R., Simel D. Does this patient have myasthenia gravis? JAMA. 2005;293:1906–1914.

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