Neuromuscular junction disorders are a group of conditions that cause muscle weakness. Their etiology can be autoimmune, congenital, metabolic, or toxic mediated. The three most common neuromuscular junction disorders are Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and botulism. The primary pathology is impaired neurotransmission at the interface (synapse) between the nerve ending and the skeletal muscle fiber. In Myasthenia gravis, pathology occurs at the postsynaptic membrane. In Lambert-Eaton myasthenic syndrome and botulism, the presynaptic membrane is affected.
Neuromuscular Junction disorders patients present with complaints of muscle fatigue and weakness that fluctuate with episodes of worsening after activity. The sensory system is not affected, as sensory nerves do not have a neuromuscular junction. Patients present with proximal greater than distal muscle weakness. It is common to receive complaints related to bulbar or extraocular muscle weakness as well. Myasthenia gravis patients frequently present with bulbar weakness and limb weakness. It is important to investigate if the patient has a history of thymoma.
LEMS patients less commonly present with bulbar weakness but have diffuse proximal limb weakness. LEMS has a strong correlation with small cell carcinoma. Botulism is a rare condition caused by a toxin produced by clostridium botulinum. In the United States majority of the cases are seen in infants.
The diagnosis of the neuromuscular junction disorder derives from a thorough history and physical examination, in addition to electrodiagnostic studies with repetitive nerve stimulation RNS) with exercise testing and single-fiber EMG (SFEMG). SFEMG testing is the gold standard for neuromuscular junction study with a sensitivity of up to 99%. Anticholinesterase medication should be stopped 8 to 24 hours before performing the study.
There are few absolute contraindications in performing electrodiagnostic studies in neuromuscular junction disorder. Needle EMG is contraindicated in those with severe bleeding disorders. Needles should also never be inserted into areas of active soft tissue infection. NCS is contraindicated in patients with implanted cardiac defibrillators or if connected to external defibrillators. Patients should have screening for pacemakers, and electrical stimulation should not be performed directly on or near the device itself.
Before performing any diagnostic study, a comprehensive review of the patient’s history and clinical course, as well as a complete physical examination, are necessary. The diagnostician will inform the patient of the indications and overview of the studies which they will be performing. The diagnostician must thoroughly explain the risks and benefits of the exam to the patient and also obtain informed consent.
Routine motor and sensory nerve conduction study should first take place to make sure no other nerve pathology exists, and the clinician can interpret the repetitive nerve stimulation (RNS) results.
Repetitive nerve stimulation (RNS) involves supramaximal stimulation of a motor nerve 5-10 times at a frequency of 3 Hz to determine compound muscle action potential (CMAP) amplitude decrement. The 4th CMAP amplitude is compared with the first. A decrement of >10% is significant. RNS study should ideally be performed on the proximal and most affected muscle to increase sensitivity. However, this may not be possible or easily accomplished because of limitations in the immobilizing of the recording electrodes and the tested muscle. Limb and muscle movement during the test can alter the recording electrode leading to inaccurate results. Limb temperature should be kept warm at 32 degrees celsius. Colder temperature leads to increased amplitudes, prolonged latencies, slowed conduction velocities on NCS, and decrease CMAP decrement on RNS, leading to inaccuracy.
Exercise testing is part of the RNS study routine to determine post-exercise facilitation and exhaustion. If no significant decrement is observed (>10%) with baseline test, a 1-minute exercise follows, and RNS is repeated at 1-minute intervals for 3 to 4 minutes to look for decrement due to post-exercise exhaustion. The patient is finally instructed to perform maximal isometric contraction of the tested muscle for 10 seconds, and RNS is then performed at a 1-minute interval for five minutes to look for amplitude increment due to post-exercise facilitation and exhaustion.
Single-fiber EMG is the most sensitive test for a patient suspected with neuromuscular junction disorder. The exam is proven to be safe, however, technically challenging for both the patient and the physician performing it. It requires experience and technical knowledge.
To perform a single fiber EMG (SFEMG), you need a contracted single fiber electromyography needle or a facial concentric needle with a small recording surface. SFEMG study looks for variations in the action potential time interval amongst the muscle fibers from the same motor unit called a jitter. Jitter is the measurement of mean consecutive difference (MCD), calculated between the triggered potential and the second single muscle fiber action potential. Most contemporary EMG machines have software that automatically creates the MCD calculation for you. The study is abnormal if the mean jitter value exceeds the upper limit of the normal value.
Complications in performing electrodiagnostic studies are uncommon when observing proper precautions. There is a small risk of bleeding and infection with needle studies.
Motor Nerve Conduction Studies
Since the myelin is not affected in an NMJ disorder, motor nerve conduction velocities are normal. However, amplitudes may be affected, and they can assist differentiating myasthenia gravis from Lambert-Eaton myasthenic syndrome. In the patient with Lambert-Eaton, compound muscle action potential (CMAP) decreases. Meanwhile, in myasthenia gravis, compound muscle action potential (CMAP) is within normal limits.
Sensory Nerve Conduction Studies
The neuromuscular junction is not present in sensory nerves, and therefore the sensory nerve conduction study is normal.
Repetitive Nerve Stimulation/Exercise Testing
There is no amplitude decrement between the first and the succeeding CMAP in normal subjects. However, in patients with neuromuscular junction disorder, a decrement of more than 10% between the first and the fourth stimulation can be appreciated.
In Myasthenia Gravis (MG), the baseline CMAP amplitude decrement is observed more than 70% of the time with RNS in generalized MG. Not uncommonly, no decrement is appreciated on RNS of distal muscles. However, a significant decrement is observable after a 1-minute exercise. Post-exercise repair or facilitation is also observable following a brief 10-second maximum isometric contraction, followed by a decrement in two to five minutes post-exercise due to post-exercise exhaustion.
On the other hand, with Lambert-Eaton myasthenia syndrome, baseline CMAP amplitude decrement is usually noted. After a brief 10-second maximum isometric muscle contraction, post-exercise facilitation of up to 200% increase in CMAP amplitude is typical. In two to five minutes, the clinician should note post-exercise exhaustion.
Other neurologic disorders that can also show CMAP decrement on RNS include motor neuron disease, conditions where on-going denervation and reinnervation result in immature nerve endings/neuromuscular junction, and myopathies.
Single Fiber EMG
Single-fiber EMG reveals increased jitter and blocking in neuromuscular junction disorder. There is marked prolongation in jitter value, with MCD of more than 100 microseconds. It is highly sensitive in the diagnosis of NMJ disorder but is not specific to myasthenia gravis. Pathologic conditions that involve reinnervation and hence immature nerve endings will also show increased jitter. Due to the high sensitivity of the test, neuromuscular junction disorder can be ruled out with a normal SFEMG study of a weak muscle.
H-reflexes and F-reflex are not routinely part of the process in a neuromuscular junction study as it does not provide additional useful information.
For a neuromuscular junction study, all muscles that are weak in the patient should be examined in the needle EMG portion of the test. During the exam, the diagnostician may notice unstable MUAPs with normal recruitment. Most Neuromuscular junction disorders will not show abnormal spontaneous activity except for in botulism. CMAP decrement on RNS in patients with findings of muscle denervation or myotonic discharge on needle EMG study does not signify NMJ disorder.
Neuromuscular junction disorders is a condition often seen in the outpatient setting. Patients frequently come with complaints of muscular proximal weakness in the extremities with/without bulbar and extraocular findings. Electrodiagnostic studies should follow a comprehensive history and a physical exam. It is essential to take an interprofessional team, including a team of physicians, physical therapists, occupational therapists, social workers, and case managers who can work together to provide aggressive multifaceted rehabilitation care to improve a patient's functional status.
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