Myasthenic Disorders - Clinical Tree

Case Synopsis

A 22-year-old woman, 154 cm tall and weighing 44.2 kg, presents with a 4-month history of myasthenia gravis and mild generalized weakness (Myasthenia Gravis Foundation of America’s class IIA). The diagnosis is confirmed by the patient’s rapid improvement after the administration of intravenous edrophonium chloride and by the presence of antibodies to acetylcholine receptors (12.3 nmol/L; reference value <0.25 nmol/L). Nerve conductions and electromyography studies were normal, but the repetitive stimulation of a nerve demonstrated decrements of the muscle action potential. Magnetic resonance imaging identified an abnormal thymus gland. The patient is scheduled for transcervical-sternal thymectomy. Preoperatively, she took pyridostigmine 60 mg orally three times a day and had plasmapheresis. Results of her preoperative pulmonary function tests were as follows: forced vital capacity (FVC), 2.79 L/second (79% of predicted); maximum expiratory flow at 50% of FVC, 3.2 L/second (68% of predicted); and forced midexpiratory flow between 25% and 75% of FVC, 3.03 L/second (77% of predicted). Anesthesia was induced with fentanyl and propofol and maintained with a thoracic epidural block supplemented with propofol and 70% nitrous oxide in oxygen. Tracheal intubation was performed under topical laryngotracheal anesthesia (4 mL 4% lidocaine). No neuromuscular blockers were used. She required mechanical ventilation for 12 hours postoperatively.

Problem Analysis

Definition

The plasticity of the neuromuscular transmission is dependent on a coordinated mechanism involving (1) synthesis, storage, and release of acetylcholine from the presynaptic motor nerve endings at the neuromuscular junction; (2) binding of acetylcholine to nicotinic receptors on the postsynaptic region of the muscle membrane, with consequent generation of the action potential; and (3) rapid hydrolysis of acetylcholine by acetylcholinesterase enzyme present in the synaptic cleft.

Autoimmune or genetic defects at the presynaptic region, synaptic basal lamina, or postsynaptic structure of the neuromuscular junction can compromise the safety margin of neuromuscular transmission. This can result in a diverse array of myasthenic disorders ( Fig. 14.1 ). Fluctuating muscle weakness and fatigability are the main characteristics of myasthenic disorders ( mys, meaning “muscle”; aesthenia, meaning “weakness”). Myasthenic disorders affect the motor system only. Sensory and autonomic functions are not impaired. The exception is Lambert-Eaton syndrome, a myasthenic syndrome in which a significant minority of patients have autonomic dysfunction. Myasthenic disorders can be classified into three main categories: myasthenia gravis, congenital myasthenic syndromes, and Lambert-Eaton myasthenic syndrome ( Tables 14.1 and 14.2 ).

TABLE 14.1

Myasthenic Disorders

Site	Disorder	Type	Cause	Morphology	Clinical Features	Management
Presynaptic	Lambert-Eaton myasthenic syndrome	Autoimmune	Antibodies target voltage-gated calcium (Ca ²⁺ ) channels at motor nerve terminal and possibly another presynaptic component (synaptotagmin), leading to reduction in ACh release	Normal ACh contents and NMJ architecture	Approximately 60% of patients have paraneoplastic response, often in association with small cell lung carcinoma Weakness and fatigability	With malignancy, successful treatment can lead to marked improvement in symptoms 3,4-Diaminopyridine blocks prejunctional potassium (K) channels to (1) prevent K efflux, (2) increase action potential duration, (3) prolong activation of voltage-gated Ca ²⁺ channels, and (4) increase intracellular Ca ²⁺ stores and ACh release Pyridostigmine potentiates response to 3,4-diaminopyridine Often, plasmapheresis or IV immunoglobulin provides transient improvement
	Choline acetyltransferase deficiency	Genetic	Choline acetyltransferase mutations cause insufficient ACh resynthesis	Number of nAChRs and end-plate structure are normal	Autosomal recessive inheritance Characteristic apneic attacks along with myasthenic symptoms	AChE inhibitors
Synaptic	AChE deficiency	Genetic	Mutations in the gene encoding the collagenic tail subunit of the enzyme anchoring AChE in the synaptic cleft decrease the expression or the catalytic efficacy of the enzyme	Absent or reduced AChE activity (by histochemical staining) Secondary loss of nAChR and postsynaptic region degeneration	Autosomal recessive disease with variable phenotypic expression Moderately severe, generalized weakness and scoliosis with restrictive lung disease are common	Due to deficiency of AChE enzyme, patients do not benefit from anticholinesterase therapy
	Laminin β ₂ deficiency	Genetic	Mutations in the gene encoding laminin β ₂ subunit	Immature hypoplastic nerve terminals, which remain encased by cytoplasmic processes of the Schwann cell Moderate simplification of postsynaptic folds and intact expression of the endplate acetylcholinesterase	Autosomal recessive inheritance	Ephedrine and albuterol (but not pyridostigimine) appear to improve neuromuscular transmission via an unknown mechanism
Postsynaptic	Myasthenia gravis: seropositive or seronegative	Autoimmune	Antibodies to nAChRs Antibodies to MuSK	End-plate regions have simplified architecture with smaller folds and marked reduction in nAChR (approximately 30% of that in normal NMJ)	Age at onset of myasthenic symptoms is earlier in MuSK antibody–positive patients Neck muscles are commonly involved in MuSK antibody–positive patients, and limb muscles in MuSK antibody–negative patients	Preoperative optimization by plasmapheresis and continued pyridostigmine therapy Patients are extremely sensitive to NDMRs Response to SCh and mivacurium depends on butyrylcholinesterase activity, which is expected to decrease after plasmapheresis or pyridostigmine
	Reduced expression of nAChR or rapsyn deficiency	Genetic	Mutations in nAChR or in rapsyn decrease expression of nAChRs	Changes in end-plate regions are similar to those seen with autoimmune MG	Autosomal recessive inheritance Patients exhibit myasthenic symptoms from birth or infancy Facial malformations are common in rapsyn deficiency	Response to anticholinesterase is incomplete Combined therapy with 3,4-diaminopyridine (which increases ACh release) is beneficial
	Slow-channel congenital myasthenic syndromes	Genetic	Kinetic defects and/or gain-of-function mutations in nAChR cause lengthy nAChR opening and excessive Ca ²⁺ influx with postsynaptic degeneration	Postsynaptic degeneration with loss of nAChRs; AChE is normal	Usually dominant inheritance Selective weakness in cervical, scapular, and finger extensor muscles; variable weakness in other muscles	Open channel blockers (quinidine, fluoxetine) normalize slow-channel mutant opening durations No response to AChE medications Avoid SCh because it can worsen excitotoxicity
	Fast-channel congenital myasthenic syndromes	Genetic	Mutations in nAChR markedly reduce binding affinities, resulting in rapid ACh dissociation from binding sites, reducing the rate of channel opening, and increasing its closure rate	NMJ structure normal; density of nAChRs normal or decreased	Autosomal recessive inheritance Moderate symptoms from birth to infancy Partial response to AChE inhibitors	Combination treatment with 3,4-diaminopyridine and AChE

ACh, Acetylcholine; AChE, acetylcholinesterase; MG, myasthenia gravis; MuSK, muscle-specific kinase; nAChR, nicotinic acetylcholine receptor; NDMR, nondepolarizing muscle relaxant; NMJ, neuromuscular junction; SCh, succinylcholine.

TABLE 14.2

Differential Diagnosis of Myasthenic Disorders

	Myasthenia Gravis	Lambert-Eaton Myasthenic Syndrome	Congenital Myasthenic Syndromes
Cause	Autoantibodies targeting nAChRs or MuSK	Autoantibodies targeting presynaptic voltage-gated (P/Q) calcium (Ca ²⁺ ) channels or synaptotagmin	Genetic mutations of presynaptic, synaptic, or postsynaptic proteins Dominant or recessive inheritance (no antibodies against nAChRs, MuSK, or P/Q type Ca ²⁺ channels)
Associated conditions	Thymic lymphoid follicular hyperplasia present in 70% of MG patients Thymoma present in 12% of MG patients (paraneoplastic autoimmune response) Associated autoimmune conditions include thyrotoxicosis, systemic lupus erythematosus, rheumatoid arthritis, and pernicious anemia	60% of LEMS patients have paraneoplastic autoimmune response Small cell lung carcinomas express voltage-sensitive Ca ²⁺ channels; antitumor antibodies to these channels cross-react with prejunctional voltage-gated Ca ²⁺ channels at the NMJ to impair ACh release
Target location	Postsynaptic	Presynaptic	Presynaptic, synaptic, or postsynaptic component of NMJ
Dysautonomias	Absent	Present in approximately 30% of patients (dry mouth, impotence)	Absent
Improvement in muscle strength	After rest	After exercise	After rest
Antibody transfer	From myasthenic mother to fetus, causing neonatal MG Injecting healthy animals with MG IgG causes signs of MG	IgG from LEMS patients can block Ca ²⁺ channels, inhibiting muscle contraction	Antibodies are not present
Electromyography (response to 30–50 Hz stimulation)	Fade	Facilitation	Fade
Effect of plasmapheresis	Transient	Transient	No effect
Anticholinesterases	Effective in managing symptoms	Minimal therapeutic value	Minimal therapeutic value
Response to 3,4-diaminopyridine	No effect	Significant improvement in symptoms	Effective in fast-channel congenital myasthenic syndromes
Response to succinylcholine	Resistant	Sensitive	Variable, not recommended due to potential hyperkalemic response in slow-channel mutations
Response to nondepolarizing neuromuscular blockers	Sensitive	Sensitive	Sensitive

ACh, Acetylcholine; IgG, immunoglobulin G; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; MuSK, muscle-specific kinase; nAChR, nicotinic acetylcholine receptor; NMJ, neuromuscular junction.

Recognition, Risk Assessment, and Implications

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