Myasthenia Gravis and Thymectomy

Daniel Blech, James B Eisenkraft

Abstract

Myasthenia Gravis (MG) is an autoimmune disorder affecting the neuromuscular junction for which patients commonly undergo surgical thymectomy as definitive treatment. To care for these patients perioperatively, anesthesiologists must understand the diagnosis, clinical course, and treatment of the disorder. Understanding Appreciating the distinct surgical options available also informs the anesthetic plan. Due to their tenuous respiratory status and neuromuscular pathology, patients with MG require a thoughtful anesthetic that balances adequate surgical conditions with mitigation of post-operative respiratory insufficiency.

Keywords

thymectomy; myasthenia gravis; myasthenic crisis; cholinergic crisis; neuromuscular blocking drugs; postoperative ventilation

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.¹

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.¹^,² 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).³

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.⁴

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.⁵

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.⁶

Clinical Classification

The original clinical classification by Osserman and Genkins⁷ 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 47.1.⁸ Note that each class is defined by the most predominant or “severe” symptoms and may include symptoms from a “lesser” class.

Table 47.1

Clinical Classification of Myasthenia Gravis
Myasthenia Gravis Class	Symptoms
I	Isolated ocular muscle weakness
IIa	Mild weakness predominantly affecting limb/axial muscles
IIb	Mild weakness predominantly affecting oropharyngeal/respiratory muscles
IIIa	Moderate weakness predominantly affecting limb/axial muscles
IIIb	Moderate weakness predominantly affecting oropharyngeal/respiratory muscles
IVa	Severe weakness predominantly affecting limb/axial muscles
IVb	Severe weakness predominantly affecting oropharyngeal/respiratory muscles
V	Requiring intubation and/or mechanical respiratory support

From Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000;55(1):16–23. With permission.

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.⁹^,¹⁰

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.¹^,⁶

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.¹¹ 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.¹² 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 47.2.¹³

Table 47.2

Comparison of Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome
	Myasthenia Gravis	Lambert-Eaton Myasthenic Syndrome
Primary weakness	Ocular, bulbar, facial muscles	Proximal limbs
Response to exercise	Increased fatigue	Improved strength
Muscle pain	Unusual	Common
Reflexes	Normal	Diminished
Gender ratio	Female predominance	Male predominance
Associated pathology	Thymoma	Small cell lung cancer
Response to neuromuscular blockade	Resistant to depolarizing NMBDs, sensitive to nondepolarizing NMBDs	Sensitive to depolarizing and nondepolarizing NMBDs

NMBDs, Neuromuscular blocking drugs.

From Dierdorf SF, Walton JS, Stasic AF. Rare coexisting diseases. In: Barash PG, Cullen BF, Stoelting RK, Calahan MK, Stock MC, Ortega R, Eds. Clinical Anesthesia. 7th edn. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2013:612–640. With permission.

Medical Treatment

Mary Walker was the first physician to report the similarity in presentation between MG and curare poisoning and to use an anticholinesterase to treat MG.¹⁴ Anticholinesterases prolong the action of ACh at the postsynaptic membrane and may also exert their own agonist effect at the postsynaptic AChRs. They are the most commonly used therapy in MG. No randomized controlled trial has been conducted on the use of acetylcholinesterase inhibitors in patients with MG because the response in observational studies was such that a placebo group could not be justified. MG patients learn to regulate their acetylcholinesterase medication and titrate dose to optimum effect over time. If several muscle groups/functions are affected, the patient titrates therapy according to the most important group. Acetylcholinesterase overdose causes the muscarinic effects of ACh and may cause a cholinergic crisis. Excessive amounts of ACh at the neuromuscular junction cause persistent depolarization of the muscle membrane. In comparison, underdosing can lead to weakness or a myasthenic crisis. Distinction between myasthenic and cholinergic crisis may be made by titrating small doses of neostigmine, or by examining pupil size, which will be large (mydriatic) in a myasthenic crisis but small (miotic) in a cholinergic crisis. Muscarinic side effects (bradycardia, bronchospasm, oral and respiratory tract secretions, and gastrointestinal cramps) are treatable with atropine; however, many MG patients treated with anticholinesterases seem to develop a resistance to the muscarinic effects.¹⁵

Pyridostigmine (Mestinon) is the anticholinesterase drug most commonly used to treat MG and has fewer muscarinic side effects than neostigmine (Prostigmin). Its onset of action following oral administration is 15 to 30 minutes, effect peaks at 1 to 2 hours, and duration of action is 3 to 4 hours. Daily dosage is typically 30 to 120 mg orally given in divided doses. For patients who are weak upon awakening in the morning, a long-acting formulation of 180 mg is available and can be taken at bedtime. MG patients whose disease subtypes are characterized by identifiable non-AChR antibodies generally have a limited response to anticholinesterase medications.

The immunologic basis of MG has led to the use of short- and long-term immunosuppressive drugs. Patients who do not meet treatment goals typically require immunosuppressive therapy. First-line therapy is generally a steroid combined with an immunomodulatory agent. Prolonged use of steroids may produce unwanted effects, such as peptic ulcer disease and osteoporosis. Alternate day dosing of either prednisone or prednisolone is generally prescribed to reduce side effects. Steroids often produce initial deterioration before an improvement. For long-term effect, immunomodulatory agents, such as azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, rituximab, and tacrolimus have been used. Rapid short-term immunomodulation has been achieved in acute exacerbations or to improve muscle strength before surgery. Plasma exchange or plasmapheresis may produce dramatic but transient improvements in muscle strength with decreases in anti-AChR and anti-MuSK titers, as well as other inflammatory mediators. Intravenous immunoglobulin (IVIG) and plasma exchange is usually reserved for severe MG—both have been found to be equally effective therapies.¹⁶ Plasma exchange has been shown to improve respiratory function in both postoperative and nonoperative patients with MG. Plasmapheresis also causes a decrease in plasma cholinesterase levels, which may prolong the effect of drugs normally metabolized by this system, such as succinylcholine.

Thymectomy

Surgical thymectomy is always indicated in MG patients with thymoma and is now considered the treatment of choice in most patients with MG, excluding those with only ocular myasthenia. A recent randomized control trial has demonstrated a benefit of thymectomy in adults with AChR-antibody-positive, nonthymomatous MG with the addition of glucocorticoids, versus glucocorticoid therapy alone. Overall, these patients required less glucocorticoid over the 3-year study period, had an improvement in symptoms, and had fewer hospitalizations for management of MG symptoms. Patients who have non-AChR antibody-positive disease do not benefit from a thymectomy. Approximately 70% of MG patients demonstrate thymic hyperplasia; 10% have a thymoma.¹⁷

Table 47.3 delineates the current understanding of when thymectomy is indicated for MG.¹⁸ Regardless of disease subtype, the medical treatments discussed earlier in this chapter are typically tried and evaluated for their individual effectiveness as symptoms necessitate.

Table 47.3

Indications for Thymectomy by Myasthenia Gravis Disease Subtype
Myasthenia Gravis Type	Age of Onset	Thymus Findings	Antibodies	Thymectomy?
“Early-onset”	<50 years	Hyperplasia	AChR	Yes
“Late-onset”	>50 years	Atrophy	AChR	Unclear
Thymoma	Any	Thymoma	AChR	Yes
MuSK antibody	Any	Normal	MuSK	No
LRP4 antibody	Any	Normal	LRP4	No
Seronegative	Any	Variable	None detected	No
Ocular	Any	Variable	Variable	No