REPETITVE NERVE STIMULATION

(RNS)By: Syed Irshad MurtazaNeurophysiology Dept AKUHKarachi

Date:12-06-2013

Content

Introduction to RNS Normal neuromuscular junction physiology. Myasthenia gravis. Lambert Eaton Myasthenic Syndrome (LEMS) Repetitive nerve stimulation (Types) Technical Factors that affect the RNS. Calculations of Decremental and incremental

responses. Protocol of RNS in EMG lab Protocol for evaluating NMJ disorder.

INTRODUCTION TO RNS

Also called Jolly test described first by Dr Friedrichson Jolly in 1895.

RNS has been validated as one of most useful electrophysiological tests in the evaluation of the:

Patients with suspected Neuromuscular Junction Disorder which includes: Myasthenia Gravis Syndrome. Lambert Eaton Myasthenic Syndrome. Botulism

Cont.

CLINICAL PRESENTATION INCLUDES: Fatigability Proximal muscle weakness. Dysphagia Dysarthrai Ocular abnormality.

All of these are suggestive of possible NMJ disorder.

ANATOMY AND PHYSIOLOGY OF NEUROMUSCULAR JUNCTIONThe NMJ essentially forms an

electrical-chemical- electrical link between the nerve and muscle.The chemical neurotransmitter at the NMJ is Acetylcholine (ACH).ACH molecules are packaged as vesicles in the presynaptic terminal in discrete units known as Quanta (Bags of neurotransmitter (ACH).)The quanta are located in three separate stores:

Primary or immediately available store1000 quanta- beneath presynaptic nerve terminal membrane.Secondary or mobilization store10,000 quanta- supplies the primary stores after few seconds.Tertiary or reserve store.More than 10,000 quanta –in the axon and cell body

PHYSIOLOGY When an nerve action potential invades and depolarizes the

presynaptic junction, voltage dependent calcium channels are activated, allowing an influx of calcium.

Results in release of ACH from the presynaptic terminals The greater the calcium inside the greater the more quanta (ACH) are

released. ACH then diffuses across the synaptic cleft and binds to ACH

receptors (ACHRs) on the post synaptic membrane In the post synaptic membrane – numerous junction are found with

ACH dependent gated channels and receptors. Thus the binding of ACH to ACHRs clustered opens ion channels…

resulting in a local depolarization, the End Plate Potential (EPP). The size of EPP depends on the amount of ACH that binds to the

ACHRs.

RNS EFFECT

During repetitive nerve stimulation in normal subjects, ACH quanta are progressively depleted from the primary store and fewer quanta are released with each stimulation.

The corresponding EPP falls in amplitude but b/c of normal safety factor it remains above the threshold to ensure generation of a muscle action potential with each stimulation.

After few seconds(1-2sec) the secondary store begins to replace the depleted quanta with a subsequent rise in the EPP.

PHYSIOLOGY OF RAPID RNS

In rapid RNS (10-50 Hz), depletion of quanta from the presynaptic terminals is counterbalanced not only by the mobilization or secondary stores but also by accumulation of calcium.

Normally it takes 100 msec for ca2+ to diffuse back out of thepresynaptic terminals. If RNS is rapid enough so that new ca2+influx occurs before previously infused ca2+ had diffused backout, ca2+ continues to accumulate in the presynaptic terminals,causing an increased release of quanta.

This combination of factors usually leads to an increased number of quanta released and a corresponding higher EPP. However, the result in normal subject is same ,i.e the generation of a muscle action potential.

SLOW AND RAPID RNS The effect of rapid and slow RNS is the same to generate the Muscle

action potential in normal subjects.In Pathological Conditions: Where the safety factors is reduced, i.e the baseline EPP is reduced

but still above the threshold) the slow RNS will cause depletion of quanta and may drop the EPP below threshold, resulting on the absence of muscle action potential.

In pathological conditions, where the baseline EPP is below the threshold and a muscle action potential is not generated, rapid RNS may increase the number of quanta released, resulting in a larger EPP so that threshold is reached.

This is the concept of increment with rapid RNS that are seen in neuromuscular Junction Disorders.

Physiology of Myasthenia GravisIn patients with MG, the number of ACHRs is reduced, lowering the safety factor. During RNS, some EPPs may not reach threshold and no action potential is generated. This results in the decrement in the amplitude of the CMAP and basis for the Decremental response in Repetitive Nerve Stimulation in Myasthenia Gravis Syndrome.

Repetitive Nerve Stimulation (RNS)

CALCULATIONS

Decremental response: The decrement is usually calculated by comparing the

lowest CMAP amplitude or area to the baseline CMAP. (lowest CMAP divided by baseline CMAP). With 3 Hz stimulation the lowest CMAP is usually the

4th.

Normal MGsafety factor =15, n=quantas available, m= quantas released.

Stimulus

n m EPP MFAP

CMAP

1 1000 200 20 + Normal

2 800 160 16 + Normal

3 640 128 13 - Dec

4 512 102 10 - Dec

5 640 128 13 - dec

Stimulus

n m EPP

MFAP

CMAP

1 1000 200 20 + Normal

2 800 160 16 + Normal

3 640 128 13 - Dec

4 512 102 10 - Dec

5 640 128 13 - dec

LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)

LEMS is a disorder of NMJ transmission characterized by

reduced release of ACH from the presynaptic terminal. There is now clear evidence that this disorder, like MG, is

an immune-mediated disorder. The pathogenesis of

LEMS is fairly well understood and involves the production of IgG antibodies directed at the presynaptic voltage gated calcium channel (VGCC). These antibodies interfere with the calcium-dependent release of ACH

quanta from the presyn

aptic membrane and subsequently

cause a reduced endplate potential on the postsynaptic

membrane, resulting in NMJ transmission failure.

Clinical Presentation

LEMS is quite rare. It affects adults, generally those older than 20 years and usually older than 40 years, of whom 70% are male and 30% are female.

Clinically, these patients present with proximal muscle weakness (especially the lower extremities) and fatigability.

The distinctive clinical finding is that of muscle facilitation.

After a brief period (10 seconds) of intense exercise of a muscle, the power and the deep tendon reflex to that muscle are transiently increased.

Incremental Response

The increment is usually calculated by comparing the highest CMAP amplitude or area with the baseline CMAP

(highest CMAP divided by baseline CMAP). Why we take 4th response In patients with MG, this decremental response

usually has a maximum decrement at the fourth or fifth response and then a tendency toward repair, by reaching of the next stimulus.

PROTCOL FOR RNS IN EMG LABI. Record one upper motor NCSII. Record one upper sensory NCSIII. Record RNS from motor nerves at 3 Hz. If

trapezius response is not satisfactory, record from the deltoid.

IV. EMG of proximal Muscle is performed, if RNS study is negative.

RNS can be performed by using any of the motor nerve. The most commonly used are:

Ulnar (ADQ) Accessory (Trapezius) Facial (Orbicularis Oculi) Axillary (Deltoid) Musculocutaneous (Biceps)

RNS PROTOCOL

Slow Repetitive Nerve Stimulation (RNS) is performed in following sequence  One Distal and one proximal motor nerves(preferable most involved muscles) One Sensory nerve RNS protocol

Resting or base line trace 6 trains at-least (10 trains are preferred) Post 10 second exercise 6 trains Post 1 minute exercise 6 trains 1 minute post 1 minute exercise 6 trains 2 minute post 1 minute exercise 6 trains 3 minute post 1 minute exercise 6 trains 4 minute post 1 minute exercise (optional) 6 trains If decrement is noted, perform Post 10 second exercise stimulation 6 trains,

for facilitation In Myasthenia gravis persistent Decremental Response > 10% is abnormal. The

maximum Decremental response is noted 2 or 3 minute post 1 minute exercise. If patient is unable to perform exercise, fast RNS at 30Hz or 50Hz may be used.

Exercise

Exercise play an important role in the electromyography evaluation of patients with suspected NMJ disorders.

Brief maximal voluntary exercise can be used instead of rapid RNS in cooperative patients.

Exercise testing has distinct advantage of being painless,where as rapid RNS is quite painful and often difficult to tolerate.

POST EXERCISE EFFECT

In normal subjects with a normal safety factor slow RNS is performed immediately after exercise and then 1,2,3,4 minutes later, the EPP never falls below the threshold and the CMAP and area will remain the same.

In patients with impaired NMJ transmission, however, the decrement in CMAP amplitude and area in response to slow RNS becomes more marked in 2-4 minutes after the exercise.

ABNORMAL DECREMENTAL RESPONSE

Any decrement of more than 10% is defined as abnormal. Normal subjects should have no decrement. The 10% cut off allows for inherent technical factor that are often encountered. However any reproducible decremental response of more than 10% is considered abnormal.

TECHNICAL FACTORS THAT AFFECT RNS:

Lower temperature. Immobilization of Electrodes position. Supramaximal Stimulation. Administration of ACh inhibitors . (use of

medicine). Nerve Selection. Stimulation Frequency. Number of Stimulations.

Temperature

Lower temperature increases the amplitude of the CMAPs. Patients with MG may report clinically significant improvement in cold temperatures. Thus ice bag test can be very helpful in MG.Typically they report worsening of ptosis in bright sunlight or on a warm day. Therefore maintaining a constant and perhaps higher-than-ambient temperature during RNS testing is important to bring out abnormalities of NMJ function. Temperature of skin overlying the tested muscle should be at least 34°C.

INHIBITORS SHOULD BE WITHHELD PRIOR TO STUDY It is best to advise patients to refrain from

taking acetylcolineasterase inhibitors

(e.g., Pyridostigmine Mestinon) for 6-8 hours before the study, unless medically contraindicated. These agents make more ACH available to bind at the ACHRs and may potentially diminished CMAP decrement, resulting in a normal study.

IMMOBILIZATION OF ELECTRODES

If the electrode is immobilized ---- result is the change in the CMAP amplitude which lead to misinterpretation.

So the recording electrodes should be secured well with tape. Stimulator secured with Velcro Strap Entire Hand with pad or board. The Goal is to minimize the movement of the limb.

SUPRAMAXIMAL STIMULATION:

Sub maximal stimulation can give art factual decrement or Increment in the CMAP amplitude.

So always Check to ensure that the stimulus is supra maximal before beginning of RNS

STIMULATION FREQUENCY

The optimal frequency for RNS is 2 or 3Hz Reason: RNS must be kept low to avoid accumulation of calcium

at presynaptic terminals.

NUMBER OF STIMULATIONS A train of 5-10 impulses is preferable for slow RNS. The

number should be kept minimum for the patients comfort.

As when the mobilization or secondary stores begins to re supply the immediately available store , the decrement begins to improve. The result is so called U Shaped Decrement. Which is a characteristic of NMJ disorders.

Protocol For Evaluating Disorder Of NMJ

Warm the extremity (33 degree centigrade) Immobilize the muscle as best as possible Perform Routine NCS first to ensure that the

nerve is normal Perform RNS at rest. After making sure that the

stimulus is supramaximal, perform at 3 Hz RNS, normally there is a less than 10% decrement b/w the first and the fourth response.

Cont. Protocol

If more than 10% decrement occurs and is consistently reproducible:

Has patient perform maximal voluntary exercise. Immediately repeat 3 Hz RNS post exercise If a less than 10% decrement or no decrement: Has patient perform maximal voluntary exercise for 1 min

and perform 3 Hz RNS immediately and at 1,2,3 and 4 mins.

If a significant decrement occurs after 1 min exercise (post exercise Exhaustion), have patient perform maximal voluntary exercise again for 10 sec and immediately repeat RNS at 3 Hz to demonstrate repair of the decrement.

Cont. Protocol

Perform RNS on one distal and one proximal muscles especially the weak muscles.

If no decrement is found with a proximal limb muscle, a facial muscle can be tested.

If the compound muscle action potential is low at baseline, have patient perform 10 sec exercise, then stimulate the nerve supramaximally immediately post exercise, looking for an abnormal increment response ( greater than 140% of the baseline). If the patient cannot exercises, rapid RNS should be used.

Thank you for the patience..