Repetitive Nerve Stimulation

Anatomy and Physiology

Neuromuscular Junction Structure

The NMJ facilitates signal transduction between peripheral nerves and skeletal muscles. Peripheral nerve axons, surrounded by Schwann cells, end at the presynaptic terminus, also called the terminal bouton. The region of the distal presynaptic terminus that is referred to as the active zone contains localized voltage-gated calcium channels, synaptosomal associated proteins (SNAPs), SNAP receptors (SNAREs), synaptic vesicles, and various essential cell structures.

The synaptic cleft is the space between the presynaptic axon terminus and the postsynaptic muscle membrane. This space is filled with a highly electroconductive material called ground substance. Acetylcholine (ACh) is released into this space and either travels to bind with ACh receptors on the skeletal membrane or is degraded by acetylcholinesterase within the ground substance.

The postsynaptic motor endplate has a highly folded cellular membrane that receives nerve terminals. After binding released ACh, nicotinic ACh receptors within this endplate membrane undergo conformational changes permitting sodium ion influx to the myocyte cytoplasm. This influx generates an endplate potential that transmits the action potential signal to the muscle when above a certain threshold and induces contraction.[4][5]

Action Potential Signal Transduction

Voltage-gated calcium channels at the presynaptic terminal active zone trigger the release of the neurotransmitter ACh into the synaptic cleft; this neurotransmitter relays the signal between nerve axons and muscle motor endplates. Acetylcholine is stored within discrete presynaptic vesicles, with each vesicle referred to as a quantum. Each quantum is released according to one of three tiers based on availability; primary, secondary, or tertiary. Primary quanta are for immediate release, secondary quanta are for storage and primary quanta replenishment, while tertiary quanta are held in reserve.The number of primary quanta released into the synaptic cleft is determined by the action potential received. Spontaneous release occurs in small quantities and might be only a single quantum. n this situation, depolarization at the postsynaptic membrane is localized, nonpropagating, and referred to as a miniature endplate potential (MEPP). Receipt of a larger action potential results in a larger number of quanta released and greater depolarization; this is the endplate potential (EPP). An EPP that exceeds the threshold for action potential generation at the postsynaptic muscle membrane causes muscle contraction, completing the signal relay.The primary quanta pool is approximately 1000 vesicles and is depleted quickly. Sustained muscle contraction requires replenishment from secondary quanta, which number approximately 10000 vesicles. There is a 1- to 2-second lag between the release of primary and secondary quanta. Therefore, neurotransmitters in excess of that required to generate an action potential in the muscle fiber are released, contributing to the safety factor and ensuring reliably sustained muscle contraction while quanta stores are replenished.[5][6][7]

Disorders of the Neuromuscular Junction

Immune-mediated disorders, genetic disorders, or toxins can disrupt presynaptic, synaptic, or postsynaptic transmission across the NMJ. Examples include acquired or congenital myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), organophosphate poisoning, and botulism.[8][9][10][11]Presynaptic NMJ disorders, such as LEMS, result in attenuated neurotransmitter vesicle release and therefore reduced EPPs. This is manifested in RNS as reduced CMAP amplitudes. By comparing slow-rate and fast-rate stimulation, characteristic waveform patterns emerge.[12]Synaptic NMJ disorders include acquired or congenital acetylcholinesterase deficiency. These disease processes require RNS only infrequently; the medical history and clinical manifestations make the diagnosis clear. However, it is important to understand that patients taking prescribed acetylcholinesterase inhibitors to treat other conditions may have falsely normal results on RNS and SFEMG.[13][14]Postsynaptic NMJ disorders, such as MG, result in a reduced number of functional acetylcholine receptors and thus lower the safety factor. Muscle fibers cannot deliver sustained muscle contraction since they cannot respond typically to supramaximal ACh release. This effect, known as blocking, can manifest as reduced CMAP amplitudes during slow-rate RNS, known as a decremental response. A 10% or more decrease between the first and fourth CMAP waveforms is abnormal.[15]

Indications

Patients with symptoms, signs, and physical examination findings suggestive of a neuromuscular disorder are candidates for RNS testing. Patients with standard electrodiagnostic study findings suggestive of a neuromuscular disorder are candidates for RNS testing. Patients for whom a comprehensive medical history, physical examination, and routine electrodiagnostic testing have been nondiagnostic for other peripheral nerve pathologies are also candidates for more specific RNS testing.

Contraindications

Modern pacemakers and implantable cardioverter-defibrillators (ICDs) with bipolar sensing are not an absolute contraindication to RNS testing; however, the function of older devices or models that use unipolar sensing may be negatively affected during RNS testing. Placing a stimulating electrode near these devices should be avoided whenever possible. In situations where this is impossible, a discussion with the managing cardiologist is warranted, as it may be possible to deactivate the device temporarily while performing RNS testing.  During RNS testing, implanted deep brain stimulators, vagal nerve stimulators, and similar devices may generate artifacts of unknown significance, complicating the interpretation of RNS test results. Therefore, temporarily deactivating these devices before the study should be considered in consultation with the relevant specialist.Patients with external pacing wires and intravenous or intraarterial catheters may be at an elevated risk for conducting increased electrical current to the heart, and RNS testing should be avoided.[16]RNS is performed via surface electrodes; antiplatelet or anticoagulant therapy is not a contraindication to RNS.

Equipment

The following equipment is commonly used when performing RNS.

• Temperature-controlled study room with warming blankets available
• Examination table that permits relaxed patient positioning and avoids involuntary movement
  • Padded bolsters or bumps may be used
• Medical tape to secure the electrodes or immobilize digits
• Hand or elbow brace to immobilize joints
• Alcohol preparation pads
• RNS surface electrodes and recording interface

Preparation

Acetylcholinesterase inhibitors should be discontinued at least 12 hours before the study. Patients should not have received injections of botulinum toxin or similar derivatives to the target muscles within the last 3 to 6 months.

The patient should arrive at the study center rested, hydrated, nourished, and allowed to acclimate in the test room for 20 minutes. The patient must be kept warm; cooler muscle temperatures can increase the safety factor and confound results. The patient should be informed of the procedural steps and potential discomfort to reduce anticipatory anxiety. RNS is generally well tolerated.[17]

Technique or Treatment

Muscle selection for RNS testing is dictated by clinical symptoms, the ease of access to and immobilization of the target muscle and electrodes, the diagnostic probability of abnormal results, and the potential for patient discomfort. The smaller, distal muscles of the extremities are often the best initial study site; they are frequently easier to test and can acclimate the patient to RNS. The study can proceed with more proximal muscles as needed, which often have a higher diagnostic yield. RNS is most sensitive for facial muscles, and the orbicularis oculi are frequently tested whenever feasible. Despite presenting technical challenges, other muscles innervated by cranial nerves, such as the masseter, nasalis, orbicularis oris, or trapezius, can be used.[18]

After the patient has rested and the target sites warmed to 35 °C, prepare the skin with alcohol pads. Apply the active electrode over the target muscle and the reference electrode over the corresponding distal tendon.[1][19]

Slow-Rate RNS

Slow-rate RNS is initiated with a stimulation train of 5 to 10 impulses at 2 to 5 Hz, repeated three times, with 1-minute intervals in between.[1] Record the decrement between the first and fourth CMAPs.

If the decrement is >10%, direct the patient to perform maximum isometric contraction of the target muscle for 10 seconds. Immediately follow the contraction with RNS at 3 Hz to assess postexercise facilitation (recovery) and exhaustion.

If the decrement is <10% or no decrement is observed, direct the patient to perform maximum isometric contraction of the target muscle for 1 minute. Immediately follow the contraction with 3Hz RNS performed at 1-minute intervals for five intervals to assess postexercise exhaustion. If a significant decrement is noted after this testing, direct the patient to perform maximum isometric contraction for another 10 seconds, followed by 3Hz RNS, to assess the facilitation of the decrement.

Fast-Rate RNS

After the supramaximal baseline and slow-rate RNS results for the test muscle have been recorded, perform tetanic stimulation with high-frequency RNS by delivering a stimulation train of 15 to 30 Hz over 2 to 3 seconds. If the patient cannot voluntarily produce maximal isometric contraction in the target muscle, higher frequency RNS, up to 50 Hz, can be performed; this is often reserved for unconscious patients as this level of stimulation is painful. CMAP amplitudes are recorded, and any incremental response is noted.[20]

Complications

Complications from RNS are uncommon, although severe adverse events such as cardiac arrhythmia and its sequelae have been reported. Precautions should be taken for patients with implanted electrical devices or intravascular lines.[21]

Clinical Significance

Postsynaptic NMJ disorders such as MG have reduced safety factors and manifest with decremental CMAP responses with characteristic waveforms during slow-rate RNS. MG often initially presents with ocular manifestations; these can be the only presenting symptoms in a subgroup of patients.[22][23]

Presynaptic NMJ disorders such as LEMS may also have reduced safety factors; however, the causative pathology is a radical reduction in ACh release resulting in decreased baseline CMAPs of resting muscle. In patients with LEMS, supramaximal stimulation with high-frequency pulses can significantly increase presynaptic quanta activation and release, raising the abnormally low CMAP amplitudes. Typically, the fifth waveform can demonstrate CMAPs with a ≥100% increase compared to the initial waveform. 

Patients with LEMS can demonstrate both a decremental response on slow-rate RNS and an incremental response on fast-rate RNS. LEMS can be a paraneoplastic syndrome or a nonparaneoplastic process resulting from an autoimmune disease. Paraneoplastic LEMS is most commonly associated with small carcinoma of the lung. Rarely, the underlying malignancy may be a non-small cell bronchogenic carcinoma, prostate cancer, or a lymphoproliferative disorder. Regardless of etiology, patients with LEMS often present with proximal lower extremity muscle weakness, dysreflexia, and autonomic dysfunction due to presynaptic inhibition of ACh release.[24][25][26][27][28]

Organophosphate poisoning and botulism typically demonstrate a decremental response on slow-rate RNS.[29]

Enhancing Healthcare Team Outcomes

Neuromuscular disorders can manifest with various symptoms across diverse populations, making the diagnosis challenging. Therefore, primary care providers, neurological specialists, nurses, pharmacists, technicians, and other healthcare professionals operating as interprofessional teams must communicate effectively and coordinate care to improve patient outcomes.

While neurologists and electrodiagnostic technicians are always involved in performing and interpreting RNS and related electrodiagnostic studies, other health professionals can help efficiently guide the patient through the process. RNS is most useful when confirming the suspicion of an NMJ disorder rather than as a screening tool. Primary care providers who recognize signs and symptoms, paired with a relevant clinical and social history, can recommend further evaluation by the electrodiagnostic team.

In the hospital setting, nurses interact with patients frequently and have real-time knowledge of the patient's physical status and the location of venous, arterial, or pacing lines. Understanding the safety precautions necessary when performing RNS in the inpatient setting reduces the risk of complications and improves patient safety. Pharmacists play an essential role in recognizing medications that may interfere with the interpretation of RNS results and assist with managing the treatment regimen. This interprofessional team approach, where all members are empowered to make decisions, will yield the best patient outcomes.[Level 5]