Myasthenia Gravis and Thymectomy

Introduction

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction for which patients commonly undergo surgical thymectomy as definitive treatment. It is therefore of great significance to the thoracic anesthesiologist. It is a chronic disorder characterized by fluctuating painless weakness and fatigability of voluntary muscles made worse on exertion with improvement following rest. The onset is usually slow and insidious; any skeletal muscle or muscle group may be affected. The most common onset is ocular, presenting with ptosis and diplopia. If the symptoms remain localized to the eyes for 2 years, the likelihood of progression to generalized disease is about 10%. In many cases, however, MG is generalized and may involve the bulbar musculature (muscles innervated by cranial nerves IX, X, XI, and XII), causing problems with breathing, speaking, mastication, and swallowing. Proximal muscles are more commonly involved than distal. Peripheral muscle weakness may manifest as clumsiness, difficulty holding up the head, or in ambulating. Respiratory muscle weakness may cause dyspnea, as well as a decrease in the ability to cough and clear secretions.

The annual incidence of MG is estimated at 7 to 23 new cases per 1,000,000 people per year; the prevalence is 150 to 250 per one million. ^, It occurs more commonly in women than men. The disease affects all ages, but the age of onset has a bimodal distribution displaying an early peak in the second and third decades (female predominance) and a late peak in the sixth to eighth decades (male predominance).

Etiology and Pathophysiology

In normal neuromuscular transmission, the acetylcholine (ACh) released from the motor nerve terminal stimulates postsynaptic nicotinic receptors at the motor end plate to generate an action potential leading to depolarization of the membrane and contraction of the motor unit. The normal neuromuscular junction has a very large number of postsynaptic acetylcholine receptors (AChRs) such that muscle weakness only becomes apparent when 75% or more of the receptors have been blocked. This excess of receptors has been termed the “margin of safety of neuromuscular transmission.” MG patients have a significant decrease in the number of postsynaptic AChRs at the end plates of affected muscles resulting in a decreased margin of safety of neuromuscular transmission.

MG is an autoimmune disorder, and about 80% of affected patients have detectable circulating antibodies to the nicotinic AChR. These anti-AChR antibodies may cause complement-mediated lysis of the postsynaptic membrane, directly block the receptors, or may modulate the receptor turnover such that the rate of degradation exceeds the rate of resynthesis. Studies of the motor end plate area show loss of synaptic folds and a widening of the synaptic cleft. Approximately 10% of MG patients who do not have anti-AChR antibodies have antibodies to muscle-specific tyrosine kinase (MuSK). The MuSK-antibody-positive MG patients often develop prominent oculobulbar muscle weakness, but the MG is not limited to the eyes. In MuSK-antibody-positive individuals cholinesterase inhibitors have no effect and may even exacerbate symptoms.

The cause of MG is unknown but appears to be related in some way to the thymus gland. It has been suggested that thymic T cells are stimulated to produce antibodies following sensitization by a protein similar to the AChR. MG patients also have a higher incidence of other autoimmune diseases including autoimmune thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus.

Clinical Classification

The original clinical classification by Osserman and Genkins outlined four classes and two subclasses according to the progressive involvement of different muscle groups and the severity of presentation. The classification now most commonly used is that of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, summarized in Table 47.1 . Note that each class is defined by the most predominant or “severe” symptoms and may include symptoms from a “lesser” class.

Clinical and Differential Diagnosis

The diagnosis of MG is suspected from the patient’s history and confirmed by clinical, electrophysiologic, pharmacologic, or immunologic testing. Typically, the patient cannot sustain or repeat muscular contraction. Clinical tests of fatigability include maintaining an upward gaze, holding out an affected limb, and respiratory function testing (vital capacity, maximum breathing capacity).

The electrical counterpart of fatigability is demonstrated by the repetitive nerve stimulation (RNS) test. The RNS involves the application of supramaximal stimulation to a peripheral nerve at 2 to 5 Hz. If a decrement of 10% or more is observed in the compound muscle action potential amplitude between the first and the fourth or fifth waveforms, this is considered diagnostic of MG. This is the most specific neurophysiologic test for MG, but it can be performed only on certain muscles, which may not be the ones affected in an individual patient. A more sensitive electrophysiologic test is single-fiber electromyography (EMG) which examines the variability in time interval or “jitter” between two single muscle fibers from the same motor unit. ^,

Historically, pharmacologic testing for MG was performed by administering the anticholinesterase edrophonium (Tensilon) and observing a rapid improvement in function; mechanical and electrical (e.g., EMG) decrements improve with 2 to 10 mg of intravenous edrophonium (Tensilon test). At time of writing, this medication is no longer available in the United States but an equivalent dose of neostigmine or pyridostigmine should produce a similar improvement.

Antibodies to the AChR are detectable in 80% of patients with MG. In equivocal cases, a positive result of a test for anti-AChR or MuSK antibodies is considered diagnostic.

A number of disorders can mimic MG and should be included in the initial differential diagnosis. Thyroiditis and resulting thyrotoxicosis can present with generalized weakness and abnormal thyroid function. Patients with neurasthenia characteristically have weakness, which disappears when individual muscle groups are tested. Progressive external ophthalmoplegia, restrictive cardiomyopathies, muscular dystrophies, brain tumors, amyotrophic lateral sclerosis, and myasthenic polymyopathy with hypersensitivity to neostigmine can all cause MG-like symptoms, as can drugs such as d -penicillamine, aminoglycosides, quinine, procainamide, and calcium channel blockers. ^,

Lambert-Eaton myasthenic syndrome (LEMS) is a very rare immune-mediated disorder of neuromuscular transmission, associated with antibodies to the presynaptic voltage-gated calcium channel. The prevalence is estimated to be about 3 to 4 per million. It is associated with small cell carcinoma of the lung in 50% to 60% of cases. Complaints of weakness may be mistaken for MG, but the symptoms of LEMS do not respond to administration of anticholinesterases or steroids, and activity improves strength. The defect in this condition is prejunctional, is associated with diminished release of ACh from motor nerve terminals, and is improved by “facilitating” agents, such as 4-aminopyridine or 2,3-diaminopyridine that potentiate the release of ACh. Affected patients are particularly sensitive to the effects of nondepolarizing muscle relaxants, which should be used with great caution or avoided entirely. The possibility of LEMS should be considered in all patients with known malignant disease and those patients undergoing diagnostic procedures for suspected carcinoma of the lung.

The major differences between MG and LEMS are specified in Table 47.2 .