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Are you stupid and confused about the decreasing low-frequency repetitive stimulation of myasthenia gravis (MG) and the increasing high-frequency repetitive stimulation of Lambert-Eaton myasthenia syndrome (LEMS)? To the key point? Don't worry, this article will take you to sort out the repetitive stimulation
.
Author: Yilu Ping An This article is authorized by the author to publish Yimaitong, please do not reprint without authorization
.
First, let's understand the anatomy and physiological mechanism of the neuromuscular junction (NMJ) and the principle of repetitive stimulation
.
NMJ is composed of presynaptic membrane, synaptic cleft, and postsynaptic membrane
.
Presynaptic membrane: The presynaptic membrane contains vesicles that store acetylcholine (ACh) and is released in quantum form.
It is mainly divided into three parts: near the presynaptic membrane, described as zone 1, which stores about 1000 quanta; The middle zone of the pre-synaptic membrane, described as zone 2, stores about 10,000 quanta; the axons and cells of the pre-synaptic membrane, described as zone 3, store about 100,000 quanta
.
Acetylcholine in zone 1 can be released at any time, called immediate acetylcholine, and then acetylcholine in zone 2 is supplemented to zone 1, ready to be released at any time.
When voltage-dependent calcium channels are activated, a large amount of acetylcholine in zone 3 can be released and supplemented to zone 1.
.
Synaptic cleft: The protruding gap contains acetylcholinesterase (AChE), which hydrolyzes the ACh released into the synaptic cleft.
Only a small part of it diffuses to the postsynaptic membrane and binds to acetylcholine receptors (AChR) to generate endplate potentials.
However, Transmitters need to be continuously replenished, otherwise conduction block will occur
.
Postsynaptic membrane: The postsynaptic membrane is a tortuous fold with a large amount of (AChR) on the surface
.
After acetylcholine is released, it binds to the AChR of the postsynaptic membrane, the post-synaptic membrane ion channels are opened, the muscle membrane is depolarized, and the muscle fiber endplate potential is generated.
When the endplate potential exceeds the muscle cell excitability threshold (ie, the safety threshold), it will be excited In muscle fibers, many muscle potentials are superimposed to generate an action potential, and the cholinesterase in the protruding gap will hydrolyze the remaining acetylcholine
.
Figure 1 Low-frequency repetitive stimulation of synaptic structure When normal people are electrically stimulated at low-frequency (2-3 Hz), acetylcholine in area 1 of the presynaptic membrane is released
.
When repeated stimulation, acetylcholine in area 1 is gradually consumed, and then the acetylcholine in area 2 begins to be released and supplemented to area 1.
However, with repeated stimulation, the acetylcholine released in area 1 is gradually reduced as a whole, and it is produced by the post-synaptic model AChR.
The amplitude of the endplate potential is also getting smaller and smaller, but it is still above the safety threshold, enough muscle fibers can still be excited, and there is no obvious decrease in the amplitude of the compound muscle action potential
.
In MG patients, there is no problem with the presynaptic membrane.
Like normal people, under low-frequency 2-3HZ stimulation, acetylcholine in area 1 of the presynaptic membrane is released, and acetylcholine in area 2 is supplemented to area 1
.
However, the release of acetylcholine in area 1 generally decreases gradually, and the AChR in the postsynaptic membrane of MG patients is less than normal.
When repeated stimulation, the ACh gradually decreases.
At the same time, in the pathological state of AChR, some muscle fibers end up When the plate potential is below the safe threshold, the excitable muscle fibers are reduced, and the amplitude of the compound muscle action potential is significantly decreased, and in the end, the action potential cannot even be generated
.
Generally, we think that the fifth response amplitude is less than 10% lower than the first one is considered positive
.
However, the essence of LEMS patients is presynaptic membrane disease, and there are problems with the release of ACh
.
The pathological changes of Ach released in zone 1 and ACh in zone 2 cannot be quickly supplemented to zone 1.
During low-frequency stimulation, after the ACh in zone 1 is released, the ACh in zone 2 cannot be supplemented quickly to zone 1 as normal.
Repeat After stimulation, the release of ACh is reduced, some of the muscle fiber endplate potential is below the safe threshold, and the excited muscle fiber is reduced, and the amplitude of the compound muscle action potential generated will also be significantly decreased
.
In summary, both MG and LEMS will decrease in low-frequency RNS, but the principle is different.
MG is the pathological change of postsynaptic membrane AchR, and LEMS is the decrease of ACh release
.
High-frequency repetitive stimulation Normal people will activate the voltage-dependent Ca2+ channel during high-frequency (20-50Hz) electrical stimulation, so that the acetylcholine in zone 3 will diffuse out of the axon to reach zone 1 about 100-200ms after stimulation
.
Since zone 3 contains a large amount of acetylcholine, when high-frequency stimulation with a stimulation interval of less than 100-200ms is used, a large amount of acetylcholine will be continuously released
.
Under normal circumstances, super-strong (>20Hz) repetitive stimulation can activate all muscle fibers innervated by nerves
.
Even if more ACh is released, the muscle movement remains relatively stable and will not cause an increase in the amplitude of the subsequent stimulation
.
However, because the synapse structure of normal people is normal, enough muscle fibers are excited from the first stimulation, so the compound muscle action potential amplitude will not increase significantly after repeated stimulation
.
In MG patients, due to the AChR pathology of the postsynaptic membrane, even if a large amount of ACh is released during high-frequency electrical stimulation, since the combination of ACh and AChR has been saturated, the compound muscle action potential amplitude will not increase significantly
.
Of course, clinically, MG patients seldom do high-frequency repetitive electrical stimulation
.
In LEMS patients, because of the presynaptic membrane disease, there is a problem with the release of ACh, and the release of ACh into the protrusion gap is insufficient
.
When high-frequency stimulation, a large amount of ACh in zone 3 is supplemented to zone 1, and a large amount of ACh is released
.
When the stimulation is repeated, because the muscle fibers that are not excited by the first stimulus are recruited by the subsequent stimuli, the action potentials formed gradually increase
.
Generally, we think that after 10 seconds of stimulation, the action potential amplitude is increased by more than 100% compared with the first stimulation to be positive
.
High-frequency repetitive stimulation also involves an interesting phenomenon in LEMS-facilitation of tendon reflexes: that is, when the LEMS is examined, tendon reflexes are initially reduced, and when the patient is allowed to move his limbs quickly for a short time (allow the patient to actively move or examiner Auxiliary passive activities), and physical examination again, the patient's tendon reflexes returned to normal, the mechanism is similar to high-frequency stimulation
.
Patients move their limbs quickly in a short period of time.
The frequency of their muscle motor units is about 30-50HZ, which is basically the same as the frequency of high-frequency repetitive stimulation.
It will release a large amount of ACh in a short period of time in zone 3.
Therefore, the patient’s tendon reflexes will occur within a certain period of time after the activity.
Normal
.
There is also an interesting phenomenon about the neuromuscular junction.
In some diseases, a repetitive compound muscle action potential (R-CMAP) can occur in one electrical stimulation, which is very specific, and some people describe it as flying with two wings
.
Figure 2 R-CMAP: independent M2 wave after the main wave M1, that is, two CMAP waves appear in one stimulation.
Such diseases are mainly CoLQ and slow channel syndrome in congenital myasthenia syndrome (CMS)
.
CoLQ syndrome is the denaturation of the CoLQ protein in the cholinesterase complex in the synaptic cleft, resulting in AChE anchoring errors
.
Relatively lack of AChE, the synaptic cleft Ach will continue to diffuse to the postsynaptic membrane, and when combined with AChR, the post-synaptic membrane excitement can be prolonged, and a repetitive compound muscle action potential (R-CMAP) can appear after a current stimulation
.
Slow channel syndrome is due to genetic defects that lead to prolonged activation of postsynaptic membrane AChR
.
Due to the prolonged excitability of the postsynaptic membrane, repeated compound muscle action potentials (R-CMAP) can appear after a single current stimulation
.
Through the above description, everyone has clarified the electrical stimulation related to the neuromuscular junction, right? References: 1.
Kelly JJ.
Daube, Lennon.
VA.
The laboratory diagnosis of mild myasthenia gravis.
Ann Neurol, 1982,12:238-242.
2.
Litchy WJ, Albers JW.
Reapetive stimulation.
An AAEM Workshop, 1984,5: 1-18.
3.
Engel AG, Shen XM, Selcen D, Sine SM.
Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment.
Lancet Neurol.
2015 Apr;14(4):420-34.
.
Author: Yilu Ping An This article is authorized by the author to publish Yimaitong, please do not reprint without authorization
.
First, let's understand the anatomy and physiological mechanism of the neuromuscular junction (NMJ) and the principle of repetitive stimulation
.
NMJ is composed of presynaptic membrane, synaptic cleft, and postsynaptic membrane
.
Presynaptic membrane: The presynaptic membrane contains vesicles that store acetylcholine (ACh) and is released in quantum form.
It is mainly divided into three parts: near the presynaptic membrane, described as zone 1, which stores about 1000 quanta; The middle zone of the pre-synaptic membrane, described as zone 2, stores about 10,000 quanta; the axons and cells of the pre-synaptic membrane, described as zone 3, store about 100,000 quanta
.
Acetylcholine in zone 1 can be released at any time, called immediate acetylcholine, and then acetylcholine in zone 2 is supplemented to zone 1, ready to be released at any time.
When voltage-dependent calcium channels are activated, a large amount of acetylcholine in zone 3 can be released and supplemented to zone 1.
.
Synaptic cleft: The protruding gap contains acetylcholinesterase (AChE), which hydrolyzes the ACh released into the synaptic cleft.
Only a small part of it diffuses to the postsynaptic membrane and binds to acetylcholine receptors (AChR) to generate endplate potentials.
However, Transmitters need to be continuously replenished, otherwise conduction block will occur
.
Postsynaptic membrane: The postsynaptic membrane is a tortuous fold with a large amount of (AChR) on the surface
.
After acetylcholine is released, it binds to the AChR of the postsynaptic membrane, the post-synaptic membrane ion channels are opened, the muscle membrane is depolarized, and the muscle fiber endplate potential is generated.
When the endplate potential exceeds the muscle cell excitability threshold (ie, the safety threshold), it will be excited In muscle fibers, many muscle potentials are superimposed to generate an action potential, and the cholinesterase in the protruding gap will hydrolyze the remaining acetylcholine
.
Figure 1 Low-frequency repetitive stimulation of synaptic structure When normal people are electrically stimulated at low-frequency (2-3 Hz), acetylcholine in area 1 of the presynaptic membrane is released
.
When repeated stimulation, acetylcholine in area 1 is gradually consumed, and then the acetylcholine in area 2 begins to be released and supplemented to area 1.
However, with repeated stimulation, the acetylcholine released in area 1 is gradually reduced as a whole, and it is produced by the post-synaptic model AChR.
The amplitude of the endplate potential is also getting smaller and smaller, but it is still above the safety threshold, enough muscle fibers can still be excited, and there is no obvious decrease in the amplitude of the compound muscle action potential
.
In MG patients, there is no problem with the presynaptic membrane.
Like normal people, under low-frequency 2-3HZ stimulation, acetylcholine in area 1 of the presynaptic membrane is released, and acetylcholine in area 2 is supplemented to area 1
.
However, the release of acetylcholine in area 1 generally decreases gradually, and the AChR in the postsynaptic membrane of MG patients is less than normal.
When repeated stimulation, the ACh gradually decreases.
At the same time, in the pathological state of AChR, some muscle fibers end up When the plate potential is below the safe threshold, the excitable muscle fibers are reduced, and the amplitude of the compound muscle action potential is significantly decreased, and in the end, the action potential cannot even be generated
.
Generally, we think that the fifth response amplitude is less than 10% lower than the first one is considered positive
.
However, the essence of LEMS patients is presynaptic membrane disease, and there are problems with the release of ACh
.
The pathological changes of Ach released in zone 1 and ACh in zone 2 cannot be quickly supplemented to zone 1.
During low-frequency stimulation, after the ACh in zone 1 is released, the ACh in zone 2 cannot be supplemented quickly to zone 1 as normal.
Repeat After stimulation, the release of ACh is reduced, some of the muscle fiber endplate potential is below the safe threshold, and the excited muscle fiber is reduced, and the amplitude of the compound muscle action potential generated will also be significantly decreased
.
In summary, both MG and LEMS will decrease in low-frequency RNS, but the principle is different.
MG is the pathological change of postsynaptic membrane AchR, and LEMS is the decrease of ACh release
.
High-frequency repetitive stimulation Normal people will activate the voltage-dependent Ca2+ channel during high-frequency (20-50Hz) electrical stimulation, so that the acetylcholine in zone 3 will diffuse out of the axon to reach zone 1 about 100-200ms after stimulation
.
Since zone 3 contains a large amount of acetylcholine, when high-frequency stimulation with a stimulation interval of less than 100-200ms is used, a large amount of acetylcholine will be continuously released
.
Under normal circumstances, super-strong (>20Hz) repetitive stimulation can activate all muscle fibers innervated by nerves
.
Even if more ACh is released, the muscle movement remains relatively stable and will not cause an increase in the amplitude of the subsequent stimulation
.
However, because the synapse structure of normal people is normal, enough muscle fibers are excited from the first stimulation, so the compound muscle action potential amplitude will not increase significantly after repeated stimulation
.
In MG patients, due to the AChR pathology of the postsynaptic membrane, even if a large amount of ACh is released during high-frequency electrical stimulation, since the combination of ACh and AChR has been saturated, the compound muscle action potential amplitude will not increase significantly
.
Of course, clinically, MG patients seldom do high-frequency repetitive electrical stimulation
.
In LEMS patients, because of the presynaptic membrane disease, there is a problem with the release of ACh, and the release of ACh into the protrusion gap is insufficient
.
When high-frequency stimulation, a large amount of ACh in zone 3 is supplemented to zone 1, and a large amount of ACh is released
.
When the stimulation is repeated, because the muscle fibers that are not excited by the first stimulus are recruited by the subsequent stimuli, the action potentials formed gradually increase
.
Generally, we think that after 10 seconds of stimulation, the action potential amplitude is increased by more than 100% compared with the first stimulation to be positive
.
High-frequency repetitive stimulation also involves an interesting phenomenon in LEMS-facilitation of tendon reflexes: that is, when the LEMS is examined, tendon reflexes are initially reduced, and when the patient is allowed to move his limbs quickly for a short time (allow the patient to actively move or examiner Auxiliary passive activities), and physical examination again, the patient's tendon reflexes returned to normal, the mechanism is similar to high-frequency stimulation
.
Patients move their limbs quickly in a short period of time.
The frequency of their muscle motor units is about 30-50HZ, which is basically the same as the frequency of high-frequency repetitive stimulation.
It will release a large amount of ACh in a short period of time in zone 3.
Therefore, the patient’s tendon reflexes will occur within a certain period of time after the activity.
Normal
.
There is also an interesting phenomenon about the neuromuscular junction.
In some diseases, a repetitive compound muscle action potential (R-CMAP) can occur in one electrical stimulation, which is very specific, and some people describe it as flying with two wings
.
Figure 2 R-CMAP: independent M2 wave after the main wave M1, that is, two CMAP waves appear in one stimulation.
Such diseases are mainly CoLQ and slow channel syndrome in congenital myasthenia syndrome (CMS)
.
CoLQ syndrome is the denaturation of the CoLQ protein in the cholinesterase complex in the synaptic cleft, resulting in AChE anchoring errors
.
Relatively lack of AChE, the synaptic cleft Ach will continue to diffuse to the postsynaptic membrane, and when combined with AChR, the post-synaptic membrane excitement can be prolonged, and a repetitive compound muscle action potential (R-CMAP) can appear after a current stimulation
.
Slow channel syndrome is due to genetic defects that lead to prolonged activation of postsynaptic membrane AChR
.
Due to the prolonged excitability of the postsynaptic membrane, repeated compound muscle action potentials (R-CMAP) can appear after a single current stimulation
.
Through the above description, everyone has clarified the electrical stimulation related to the neuromuscular junction, right? References: 1.
Kelly JJ.
Daube, Lennon.
VA.
The laboratory diagnosis of mild myasthenia gravis.
Ann Neurol, 1982,12:238-242.
2.
Litchy WJ, Albers JW.
Reapetive stimulation.
An AAEM Workshop, 1984,5: 1-18.
3.
Engel AG, Shen XM, Selcen D, Sine SM.
Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment.
Lancet Neurol.
2015 Apr;14(4):420-34.
