Electrodiagnosis of Neuromuscular Junction. · Neuromuscular Junction. Advancing the Vision of the...

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Bashar Katirji, M.D.Professor and Director, Neuromuscular Center and EMG Laboratory

Electrodiagnosis of Neuromuscular Junction.

Advancing the Vision of the Neurological InstituteAdvancing the Vision of the Neurological Institute

November 2019November 2019

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Neuromuscular Junction

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Muscle fiber

Nerveterminal

Axon

(4) AChR opening (EPP)

AChR

EPP (synaptic potential)Ca2+ channel

(2) Ca2+ entry into terminal

Na+

K+

(1) Presynaptic NAPNAP

Na+ K+

channels

(5) Postsynaptic MAP

MAP

(3) ACh release

ACh

Neuromuscular transmission



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Physiology of Neuromuscular Transmission

Ca+2 Entry

100 to 200 msec

7 to 20 mV required for generation of MAPEPP

NAP

60 Ach Vesicles

Ca+2 exit

Each Vesicle released results in a 1 mV change in the postsynaptic membrane potential.

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Neuromuscular Transmission.The Safety factor

• The EPP is well above the depolarization needed to trigger an action potential in that muscle fiber (“safety factor”)

• The safety factor is the effective excess acetylcholine released beyond the need to generate an EPP.



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Normal NMJ transmission• Under normal physiologic

conditions,

– each action potential in the pre‐synaptic nerve releases about 10‐20% of the immediate store vesicles of acetylcholine

– Therefore, every muscle fiber is activated with each stimulus and the sum of the muscle fiber action potentials is constant

• Successive CMAPs are identical.

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• Under pathologic conditions that reduce the safety factor of transmission, the endplate potential generated by the release of 10‐20% of the immediate store vesicles does not always generate a voltage change enough to trigger a muscle fiber action potential

• Therefore some muscle fibers increasing do not generate an action potential with each successive pre‐synaptic action potential ‐ thus the CMAP voltage that reflects the sum of all of the muscle fiber action potentials under the electrode (measured by amplitude) varies

Impaired NMJ transmission.What produces a decrement?



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Action potentialnumber

Normal MG Quanta to generate

threshold EPP(200 effective quanta at the post-synaptic membrane)

(150 effective quanta at the post-synaptic membrane)

Threshold end-plate potenetial(EPP) generates

an action potential

1 200 150 125

2 180 135 125

3 162 122 125

4 146 110 125

5 146 110 125

6 150 114 125

Slow RNS in MG

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Muscle FiberAction Potential

Endplate Current

Postsynaptic NMJ failure



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If subsequent NAPs arrive after less than 100 ‐ 200 msec, Calcium accumulates in the terminal. This leads to enhanced Ach release.

EPP

NAP< every 100 to 200 msec

Ca+2

Presynaptic NMJ failure

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Repetitive Nerve Stimulation

Slow Rapid

Interstimulus >100‐200msec <100‐200msec

Interval

Stimulation <5 to 10 Hz >5 to 10 Hz

Frequency (<5 HZ) (>10 HZ)

Common 2 or 3 Hz 20 to 50 Hz

Frequency

Avoid 5-10 Hz, results may be misleading



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Slow RNS (2‐3 HZ)

EPP

MAP

CMAP

Control MG LEMS

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CMAP decrement on slow RNS‐median nerve

Normal

MGLEMS



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Advantages of slow RNS in Myasthenia Gravis

1. It is an objective proof of disease and neuromuscular defect.

2. It is relatively easy and rapid.

3. It can be performed without patient cooperation:

children

ICU setting

confused or sedated patients.

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Limitations of slow RNS in Myasthenia Gravis

1. The decremental response is usually present only when recording from weak muscles.

2. In pure ocular myasthenia, a decrement from limb muscles is rare.

3. Movement artifacts can interfere with accurate readings of RNS.

4. Proximal RNS is painful, technically difficult, particularly in overweight patients where it is subject to significant movement artifacts.



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Factors which increase the sensitivity of slow RNS

• Avoid cool extremities

• Record from weak muscles.

• Record from proximal muscles.

• Record before & after exercise.

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Post‐exercise slow RNS

• Post‐exercise (tetanic) potentiation– Exercising muscle 60 seconds before RNS testing “repairs” the decremental response

– the size of decrement falls, e.g., from 15% to 8%

– Effect lasts for up to 30‐60 seconds

• Post‐exercise (tetanic) exhaustion – Increase in the size of the decrement after this exercise

– For example, from 15% to 20%

– Seen best 2‐4 minutes after exercise



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At rest

Immediately after exercise

2 to 4 minutesafter exercise

Slow RNS in MG before and after

exercise

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Action potentialnumber

Normal LEMS Quanta to generate

threshold EPP(200 effective quanta at the post-synaptic membrane)

(100 effective quanta at the post-synaptic membrane)

Threshold end-plate potenetial(EPP) generates

an action potential

1 200 100 125

2 180 120 125

3 162 135 125

4 146 150 125

5 146 160 125

6 150 175 125

Fast RNS in LEMS



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EPP

MAP

CMAP

Control LEMS

Fast RNS in LEMS

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CMAP increment after rapid RNS (50 Hz) in a patient with

LEMS

350 % increment



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CMAP and RNS in Neuromuscular Junction

disorders

Postsynaptic Presynaptic

Initial CMAP Normal Low

Slow RNS Decrement Decrement

Rapid RNS Decrement Increment

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Electrophysiological findings in Botulism vs. LEMS

• Although the defect and findings are similar to Lambert‐Eaton syndrome, there are some difference:

Botulism L E M SLow CMAPs proximal diffuse

Increment mild prominent (50‐200%) (150‐400%)



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CMAP increment after rapid RNS (50 Hz) in a patient with botulism

Normal control

150 % increment

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Post exercise CMAP in presynaptic disorders

• Rapid RNS is extremely painful– Cannot be justified to patients with low probability of having a presynaptic disorder (“screening”).

• Rapid RNS (50 Hz) is equivalent to voluntary tetanic stimulation

• Hence, voluntary exercise for 10 seconds is equivalent to rapid RNS

• Baseline CMAP is followed by forceful (tetanic) voluntary contraction and a post exercise CMAP is evoked.

• A very good screening for LEMS when illness is suspected or when CMAPs are low



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Postexercise CMAP is equal to rapid RNS in presynaptic disorders

LEMS Botulism

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#AANEM



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Single Fiber EMG• Simultaneously records potentials of two muscle fibers innervated by an individual axon – Measures this variability = "Jitter"

– SFEMG is the most sensitive test for MG

– Abnormal jitter is not specific for MG • May occur in other neuromuscular disorders, including ALS, neuropathy, myopathy and LEMS

• Is specific for NMJ defect (MG, LEMS or botulism) if abnormal with no other changes on EMG

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Single Fiber Electromyography

• Voluntary SFEMG

The most widely used technique.

Requires extreme patient cooperation.

Is highly sensitive in detecting NMJ defects.

Is not specific for disorders of NMJ.

• Stimulation SFEMG

Does not require patient cooperation.

Can be performed on children and patients with coma, involuntary movements or ataxia.

Stimulation rate can be adjusted to help differentiate between the various NMJ disorders.



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Recruitment single fiber EMG

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Normal Jitter (MCD)



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Measurement of jitter (mean consecutive discharge)

MCD = IPI2-IPI1 + IPI3-IPI2 + …..n - 1



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Jitter in a patient with myasthenia gravis (Frontalis)

Normal jitter Abnormal jitter

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Abnormal Jitter with blocking



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Abnormal jitter in MG

Superimposed RasterRaster

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Normal and Abnormal Jitter with blocking (triplet)



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Single fiber EMG jitter.C20 muscle pairs

• Normal mean• <1 pair above the ULN(<2 pairs in pts >60)• No blocking

• Abnormal mean• >1 pair above the ULN(>2 pairs in pts >60)• Blocking



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Single fiber volitional EMG jitter.Normal values – Single fiber Needle

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Stimulationsingle fiber EMG

Jitter evaluate one NMJ only Is about 77% of Jitter value of voluntary single fiber



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Stimulation single fiber EMG

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Changing rate in stimulationsingle fiber EMG

e.g. LEMS



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Needle electrodes andsingle fiber EMG Jitter

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- Despite methodologicalconcerns, however, the sensitivity and specificity of CN SF studies appear to be comparable to studies using the SF electrode.- CN is not recommended for stimulation SFEMG studies since multiple axons may be recorded simultaneously at the rate of stimulation

SFEMG using concentric facial needle electrode



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Reference Values for Jitter Measurements During Volitional Muscle Activation When Recorded with a Disposable, Concentric EMG Needle (from Stalberg E, et al. Muscle and Nerve 2016; 53:351‐362)

Volitional Orbicularis Oculi Frontalis Extensor Digitorum

Mean MCD (µs) [mean (SD)] 22.9 (3.9) 20.6 (3.6) 23.4 (3.0)

Upper limit 31 28 30

18th MCD (µs) [mean (SD)] * 29.0 (7.6) 25.8 (5.6) 30.0 (6.1)

Upper limit 45 38 43

*18th MCD (volitional) were determined to be the cutoff jitter values for any particular muscle fiber pair in a given muscle, a reading above which is considered an "outlier."

• Mean•1 pair above the 18th MCD outlier• 2 pairs above the 18th MCD outlier (borderline study)• 3 or more pairs above the 18th MCD outlier• No blocking

Single fiber volitional EMG jitterNormal values – Concentric facial Needle

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#AANEM

May 2006 CASE Medical Center 47



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Strategies in the Electrodiagnosis of Myasthenia Gravis and related disorders

• Clinical evaluation is extremely important

• Working diagnosis dictate the work up

– MG – slow RNS, single fiber

– LEMS – post exercise CMAP, rapid RNS

– Botulism – post exercise CMAP, raid RNS

• Occasionally, MG and LEMS or botulism are both considered in the differential Dx.

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MG: Sensitivity of Diagnostic Studies

Generalized(% positive)

Ocular(% positive)

AChR Abs 80 <50

AChR Abs + MuSK 90 <50

RNS 80 <50

SFEMG 95-97 85-95



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Diagnostic sensitivity of laboratory tests in Myasthenia Gravis

0%

20%

40%

60%

80%

100%

1 2 3 4

Ocular Generalized ALL

1 = Acetylcholine receptor Antibody

2 = Slow RNS recording distal muscle

3 = Slow RNS recording proximal muscle

4 = Single Fiber EMG of forearm muscle (EDC) Oh et al Muscle Nerve 1992;15:720-724)

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Sensory & motor

Nerve Conduction Studies

Low CMAP Normal CMAP

Suggested Electrodiagnostic Strategy in suspected NMJ disorder



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Normal CMAPs (suspect MG)

Slow RNS of spinal accessory +/- facial nerve at rest & after exercise

Single Fiber EMG of EDC +/- frontalis

Slow RNS of median or ulnar nerve at rest & after exercise

Diagnosis of Myasthenia Gravis Confirmed

>10% CMAP decrement

Increased Jitter +/- blocking

If Normal

If Normal


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Low CMAPs (suspect LEMS or Botulism)

Diagnosis of presynaptic NMJ defect (Lambert-Eaton syndrome or Botulism) confirmed

Postexercise CMAPs of multiple nerves

Rapid RNS

and / or >50-100% CMAP increment




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Conventional Needle EMG should be performed always to rule out other disorder in which a neuromuscular junction defect may occur.

• Motor Neuron Disorder including Amyotrophic lateral Sclerosis and poliomyelitis.

• Polyradiculopathy and peripheral neuropathy.

• Myotonic disorders.

• Myopathy including Muscular Dystrophies and polymyositis.


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