sample chapter clinical neurophysiology 3e by misra and kalita to order call sms at 91 8527622422

251

NEUROMUSCULAR JUNCTION

Neuromuscular junction (NMJ) consists of presynap-tic axon terminal, synaptic cleft, and postsynaptic end-plate ( Fig. 6.1 ). Presynaptic axon terminal loses its myelin and is covered only by Schwann cell cytoplasm, which separates it from the adjacent tissue. One axon terminal innervates a single endplate. Each muscle fiber has in turn only one endplate, which is located in the middle of the muscle fiber. The axon terminal is rich in mitochon-dria and synaptic vesicles. A nerve terminal has an area of 4 μ m 2 containing about 50 synaptic vesicles/mm 2 . These are concentrated along the active zone of the transverse depression opposite to the postsynaptic cleft ( Engel and Santa, 1971 ). At this site, acetylcholine (Ach) exocytosis occurs and the entry of calcium into the axon terminal takes place. A synaptic vesicle has 5000 – 10,000 molecules of Ach, which is known as a “quantum”. Some quanta (about 1000) are located adjacent to the cell mem-brane and are available for immediate release. These constitute the “immediately available pool”. About 10,000 quanta move toward the membrane to replen-ish the liberated Ach, and constitute the “mobilization pool”. The bulk of Ach, i.e. about 300,000 quanta are stored in the main “storage pool” ( Fig. 6.2 ). The primary synaptic cleft is a space of 200 – 500 Å between presynap-tic axon terminal and postsynaptic endplate. From the primary synaptic cleft, there are numerous radial exten-sions of postsynaptic cleft, which increase the length of postsynaptic membrane by 10 times. The density of Ach receptors is highest at the crest of the secondary cleft. Ach receptor is a pentameric protein composed of two α , single β , δ , and ε subunit in adult isoform, and γ subunit substituted for the ε in the fetal isoform. In myasthenia gravis (MG), the postsynaptic membranes are flattened reducing the number of Ach receptors. In Lambert – Eaton myasthenic syndrome (LEMS), on the other hand, the postsynaptic folds are increased and elon-gated ( Fig. 6.3 ). In the axon terminal, Ach is synthesized

from acetyl CoA and choline in the presence of the enzyme choline acetylase. Ach is stored in the synaptic vesicles. At rest, the presynaptic terminals spontaneously release single Ach quantum at irregular interval, about a quantum every 5 s producing miniature endplate poten-tial (MEPP). By intracellular microelectrode recording, the amplitude of MEPP has been found to be 1 mV which is about 1% of normal excitatory postsynaptic potential ( Elmqvist, 1973 ). The amplitude of MEPP depends not only on the number of Ach molecules in a vesicle but also on the sensitivity and number of Ach receptors. The frequency of Ach quanta released depends upon extra-cellular concentration of calcium, potassium, and tem-perature ( Fukunaga et al., 1983 ). In MG, the amplitude of MEPP is reduced, although the frequency of quantal release is normal. In LEMS, the amplitude of MEPP is normal, but increasing extracellular potassium ion con-centration does not increase the frequency of quantal release suggesting a defect in Ach release. The action of Ach on postsynaptic membrane is normally terminated within a few milliseconds of its release. An enzyme Ach

C H A P T E R

6 Repetitive Ne rve Stimula tion

Myelin

Schwann cell

Ach receptor

Axonalterminal

Ach vesicle

Synapticcleft

Eaton Lambert syndrome Myasthenia gravis FIGURE 6.1 Neuromuscular jun ction. Ach, ac etylcholine.

REPETITIVE NERVE STIMULATION252

CLINICAL NEUROPHYSIOLOGY

esterase breaks down Ach into acetic acid and choline. A nerve impulse propagating down the nerve terminal results in its depolarization and influx of Ca 2+ ions into the presynaptic nerve terminal. Calcium influx triggers the release of a large number of Ach quanta (about 60). The released Ach diffuses across the synaptic cleft and binds to about 100,000 Ach receptors, which results in nonpropagating depolarization of postsynaptic mem-brane and generation of endplate potential (EPP). The amplitude of EPP is the summation of numerous MEPPs and is taken as an important evidence for quantal the-ory of neuromuscular transmission. The EPP if exceeds the threshold, generates muscle action potential (MAP), which follows an all-or-none phenomenon. The MAP propagates along the muscle fibers by local circuit cur-rent flow. The neuromuscular transmission has great reserve. There are numerous Ach receptors and far more Ach quanta are released than necessary for generating MAP. This reserve is known as “safety factor”. Safety factor prevents NMJ failure despite repetitive action potentials. The safety factor depends on quantal release, AchR conduction properties, AchR density, and acetyl-cholinesterase (AchE) activity. Postsynaptic folds form a high-resistance pathway that focuses the endplate cur-rent flow on voltage-gated sodium current in the depth of the fold. These factors reduce the action potential threshold at the endplate and increase the safety factor. Human NMJs are smaller and have more folding than other mammals suggesting an evolutionary contribu-tion to improve safety factor in humans. All the diseases

of NMJ result in the reduction of safety factor and that is what is tested in repetitive nerve stimulation (RNS) study.

PHYSIOLOGY OF RNS TEST

In RNS, usually the changes in the amplitude of com-pound muscle action potential (CMAP) following nerve stimulation are analyzed to study the neuromuscular transmission. CMAP is the sum of MAPs generated by a number of muscle fibers, which are activated by nerve stimulation. The amplitude of the negative deflection of CMAP represents the number of active muscle fibers.

Choline � Acetyl CoA

Cholinesterase

MEPP EPP MAP

Muscle contraction

Postsynaptic

Presynaptic

Ach quantum

Ach (60 quanta)

Acetic acid � Choline Ca2�

Immediately available pool

Mobilization pool

Main storage

Choline acetylase

Ach synthesis

FIGURE 6.2 Acetylcholine synthesis and its action at neuromuscular junction. Ach, acetylcholine; EPP, endplate potential; MAP, muscle action potential; MEP P , mi niature e ndplate po tential.

AchR

VGCC

LEMS

Neuromuscular junction

AbAch

MG Normal FIGURE 6.3 Neuromuscular junction in normal, myasthenia gra-vis (MG), and LEMS. In MG, there is flattening of synaptic fold and reduced number of AchR. In LEMS, there is elongation of secondary synaptic fold and increased number of AchR. Ab, antibody; AchR, ace-tylcholine receptor; Ach, acetylcholine; VGCC, voltage-gated calcium channel; LEMS, Lambe rt – Eaton myast henic sy ndrome.

VARIABLES INFLUENCING NEUROMUSCULAR TRANSMISSION 253


However, area measurement that requires computer analysis is considered more accurate.

Two events at the presynaptic membrane are impor-tant with reference to RNS: (i) depletion of immediately available Ach quanta and (ii) increase of Ach release by Ca 2+ influx. During RNS, these two events have oppos-ing influence. At low-rate RNS (below 5 Hz, interstimu-lus interval is more than 200 ms), there is progressive decline of Ach quanta from immediately available pool because of release of Ach. The other important event at the nerve terminal during RNS is calcium-mediated Ach release, which occurs immediately after nerve impulse. The increased Ca 2+ facilitates Ach release for about 100 – 200 ms, following each impulse ( Rahamimoff et al., 1978 ), after which the Ca 2+ ion is sequestrated by mito-chondria. At high-rate RNS (more than 5 Hz, interstimu-lus interval is less than 200 ms), there is production of a cumulative facilitation of transmitter release due to increasing Ca 2+ entry into the nerve terminal ( Figs. 6.4 and 6.5 ). In normal individuals, both at low- and high-rate RNS, the CMAP does not change significantly because of safety factor. Moreover, the contraction of muscle fibers follows the all-or-none phenomenon. In normal persons, occasionally, there is marginal incre-mental response following RNS, which is known as pseudofacilitation ( Fig. 6.6 ). Synchronous activation of muscle fibers due to increase in muscle fiber conduction velocity is responsible for pseudofacilitation.

VARIABLES INFLUENCING NEUROMUSCULAR TRANSMISSION

Neuromuscular transmission can be influenced by a number of variables such as age, exercise, temperature, location of muscle (proximal or distal), and ischemia. In newborns, because of immaturity and low neuromus-cular reserve, the CMAP is 30 – 50% of the adult value. The response to RNS after 6 months of age is not much

different compared to adults. The importance of tem-perature in neuromuscular transmission is illustrated by worsening of myasthenic symptoms during hot weather, after hot bath or during fever. Local warming increases the decrement and postactivation exhaustion. Similarly, cooling reduces the decremental response. It is, there-fore, recommended that the RNS studies should be car-ried out at 26°C ambient room temperature. Decremental response in normal subject varies in different muscles. Normal decrement in abductor digiti minimi (ADM) is 7%, orbicularis oculi is 8%, and deltoid is 13%. This vari-ation in decrement is attributed to temperature gradient along the extremities and constant tonic contraction of

3 Hz RNS

Axonterminal

Ca2�

Ach

N

MG

LEMS FIGURE 6.4 Low-rate RNS in normal (N), myasthenia gravis (MG), and Lambe rt – Eaton myast henic syn drome (LEM S).

Axon terminal

Ach

Normal

MG

LEMS

Ca2�

FIGURE 6.5 Schematic diagram of 30 Hz RNS in normal, myasthenia gravis (MG), and Lambert – Eaton myasthenic syndrome (LEMS).

4 mV

6 ms FIGURE 6.6 Slight incremental response at 30 Hz RNS at abduc-tor digiti minimi stimulating ulnar nerve at wrist in a normal subject (pseudofacilitation).



proximal muscle. Exercise can result in facilitation and postexercise exhaustion in patients with abnormal neu-romuscular transmission. However, in normal individu-als, 5% decrement before exercise and 7.7% after exercise are considered normal ( Oh, 1987 ).

RNS is a simple and one of the most frequently employed tests for the study of neuromuscular transmis-sion. A number of distal and proximal muscles can be examined. The test is simple and quick but is associated with some discomfort to the patient. For reliable results, the following precautions are necessary:

1. Cholinesterase inhibitors should be discontinued at least 12 – 24 h before the study without compromising the patient's ability to breathe or swallow.

2. The muscles should be warmed before testing. 3. The immobility and stability of the recording and

stimulating sites are essential throughout the test. 4. Supramaximal stimulation (10 – 20% greater than

maximal) is recommended. Very high current may be counterproductive by inducing pain and artifacts.

5. The CMAP of each response should be displayed at the maximum amplitude.

6. Trains of at least five supramaximal stimuli at 2 – 3 Hz should be given for low-rate and 100 stimuli at 30 Hz for high-rate RNS.

7. The course of muscle response during the train of stimuli should show a smooth progression and should be reproducible.

8. High-rate RNS should be carried out after completing the low-rate RNS study if presynaptic NMJ disorder is suspected.

9. The duration of exercise or tetanic stimulation should be adjusted according to the aim of the study (pre- or postsynaptic), nature of the study (facilitation or exhaustion), and size or strength of the musc le.

10. Low-rate RNS should be repeated every minute for 5 min after exercise or tetanic stimulation as maximum decrement occurs between 2 and 5 min after e xercise.

TECHNIQUE OF RNS

Most of the modern machines have preset program for RNS. The machine setup for RNS study in author's laboratory i s gi ven i n Table 6.1 .

The stimulation and recording parameters are similar to motor nerve conduction study. For RNS study, three modes of recording are possible: superimposed shots, raster, and continuous. The continuous recording is pre-ferred because the incremental decremental responses are easily recognized at a glance and any change in CMAP amplitude can be easily measured. The shape of

CMAP, however, cannot be recognized. The RNS test can be carried out in any muscle where nerve is accessible for stimulation and recording.

The patient should be explained the procedure of the test and again warned before delivering the stimulus train. This is essential to ensure patient's cooperation for reliable results. The recording electrodes should be placed in a belly tendon montage with the active elec-trode at the motor point. It is important that the electrode should be stabilized by adhesive plaster. Commercially available disposable electrodes are suitable. Excessive sweating may interfere with electrode stabilization and produce artifacts in RNS study. In such situation, needle electrodes may be used. The limb should be warmed and relaxed in a comfortable position. It is important to immobilize the limb during the test. Various types of splints and straps are used for this purpose. Authors are able to immobilize the limb manually themselves or with the help of a technician ( Fig. 6.7 ). The stimulat-ing electrode should also be secured on the nerve and should not move during the study. The stimulus should be supramaximal. Suboptimal stimulation will invali-date the results. Some of the important technical factors resulting in a false decremental response are shown in Figure 6.8 . For low-rate stimulation (<5 Hz), 5 – 6 stimuli are needed and for high rate (30 – 50 Hz), 50 – 100 stimuli are given. After each train, there should be sufficient rest (1 – 2 min). After the recording, one should check the results, i.e. whether the recording is of optimal quality, reproducible, and free from artifacts. A typical incremen-tal or decremental response is characterized by a gradual change in CMAP amplitude between successive CMAP potentials. After completing RNS study at rest, the effect of exercise or tetanic stimulation should be studied.

TABLE 6.1 Machine s etup f or R NS s tudy

Sensitivity (mV /division) 2 – 5

Sweep time (ms/division) 2

Filters

Low (H z) 2 – 5

High (kH z) 2 – 3

Audio On

Stimulus duration (ms) 0.1

Stimulus r ate/s

Low <5

High 30 – 50

Number of stimuli

Low r ate 5 – 6

High r ate 50 – 100

MEASUREMENT 255


For exercise, maximal voluntary contraction of target muscle for 10 – 60 s is carried out depending upon the strength of muscle and purpose of study. A decrement of more than 10% at rest should be followed by 10 s exercise to demonstrate postexercise facilitation. However, if the decrement is <10%, it should be followed by 1 min exercise (30 s exercise followed by 5 s rest and again 30 s exercise) to demonstrate exhaustion. For studying posttetanic or postexercise exhaustion, the test should be repeated every minute for 5 min because the amount of Ach released with each stimulus is at its minimum 2 – 5 min after exercise.

MEASUREMENT

The change in the amplitude or area of CMAP is used for the interpretation of RNS study. Although the area measurement has been found to be more accurate, it

requires computer analysis. The amplitude of CMAP can be measured either base-to-peak or peak-to-peak. At low-rate stimulation, the change between the first and fourth CMAP is generally measured ( Stålberg and Sanders, 1981 ); however, comparison of first CMAP with the fifth ( Desmedt, 1973 ), or the lowest of the first five ( Oh et al., 1982 ) has also been recommended. In MG, the decremental response is followed by an increment (dual response; Fig. 6.9 ; Grob et al., 1956 ), which can be seen in the first six CMAPs. A longer stimulus train lasting for 5 – 10 s may result in a triphasic response in MG, in which decrement is followed by increment and again a decre-ment. This method, however, is not popular because of pain due to prolonged stimulation. The decrement is calculated by the following formula:

[ ]

(b)(a) (c)

FIGURE 6.7 Method of stabilization during RNS studies in (a) abductor digiti minimi, (b) deltoid, and (c) trapezius recordings.

(b) (d)

4 mV

6 ms

(a) (c)

FIGURE 6.8 False decremental response in a normal subject due to technical factors: (a) electrode movement, (b) unstable electrode, (c) submaximal stimulation, and (d) stimulator misplacement.



Incremental response is calculated by comparing the amplitude of highest CMAP with the first CMAP fol-lowing high-rate stimulation, i.e. 30 Hz, 100 pulses. It is calculated as follows:

[ ]

To study the postexercise or posttetanic facilitation, there are two methods: (i) comparison of the decremen-tal response at low rate at rest with that on exercise or tetanic stimulation and (ii) comparison of first resting CMAP with the first CMAP following exercise or tetanic stimulation. The amplitude changes can be expressed as amplitude ratio or amplitude difference ratio with the resting first CMAP.

A number of muscles can be stimulated for the study of neuromuscular transmission. The above-mentioned principles are common. The details of stimulation, recording, and special technical precautions are summa-rized in Table 6.2 , which should be correlated with the illustration ( Fig. 6.10 ).

Selecting a Muscle for Low-Rate RNS Study

The choice of muscle for low-rate RNS in MG will depend on the diagnostic yield, patients' comfort and technical ease. In a study on 33 patients with MG, RNS was performed in eight muscles to address these ques-tions. The diagnostic yield was highest in deltoid and nasalis (78.8% each) followed by trapezius (65.5%). The technical difficulty was maximum in deltoid and

4 mV

6 ms

FIGURE 6.9 Dual type of decremental response in myasthenia gravis (3 Hz RNS, 10 impulses), initial decrement is followed by an incremental response. Recording from abductor digiti minimi and stimulating ulnar nerve.

TABLE 6.2 Technical aspects of stimulating and recording procedures of RNS test in different muscles

Muscle

Location of electrode

Recording Stimulating Technical c omments

Orbicularis o culi R 1 Midpoint of lower orbicularis oculi Below and anterior to tragus Lowest supramaximal stimuli

R 2 Above eyebrow

Nasalis R 1 Midpoint of nasalis Below and anterior to tragus Lowest supramaximal stimulation

R 2 Glabellar point

Trapezius R 1 Midway between acromion and C 7 spine

Behind sternocleidomastoid, midpoint between clavicle and mastoid

Lying lateral with a pillow or sitting and fixing the shoulder by assistant

R 2 Above clavicle

Deltoid R 1 Prominent part of deltoid Erb's point Shoulder immobilization by strap or assistant

R 2 Mid arm

Serratus an terior R 1 Midaxillary seventh rib Erb's point Shoulder immobilization

R 2 Anterior axillary line sixth rib

Flexor carpi ulnaris R 1 Upper one-third of muscle Ulnar groove at elbow Immobilize wrist and elbow

R 2 Ulnar styloid

Abductor digiti minimi R 1 Middle of hypothenar At wrist Immobilize the hand

R 2 Base of fifth digit

Quadriceps R 1 Rectus femoris Femoral nerve in groin Supine with leg immobilization

R 2 Patella Lateral to femoral artery

Tibialis an terior R 1 Belly of tibialis anterior Neck of fibula Patient sitting with thigh and leg restrained with strap

R 2 3 cm distal

INTERPRETATION OF RNS TEST 257


serratus anterior. The patients' discomfort was maximus with deltoid and nasalis. Combining diagnostic yield, patients' comfort and technical ease together ADM, tra-pezius and nasalis should be the initial choice for RNS in the evaluation of MG (Misra et al., 2006) .

INTERPRETATION OF RNS TEST

RNS studies are employed to diagnose and differen-tiate between presynaptic and postsynaptic disorders of neuromuscular transmission. The important neuro-muscular transmission disorders are summarized in Table 6.3 .

Interpretation of RNS

The interpretation of RNS test should include the changes in the following:

1. CMAP 2. Low-rate RNS 3. Effect of exercise and tetanic stimulation 4. High-rate RNS.

Compound Muscle Action Potential CMAP is influenced by the physiological integrity

of the nerve, neuromuscular transmission, and muscle.

The CMAP amplitude has a wide variation in normal subjects, hence it is not a sensitive indicator of neuro-muscular transmission disorders; but small amplitude is consistent with presynaptic and normal amplitude with a postsynaptic defect. Low amplitude of CMAP can also be found in neuropathies and atrophic muscles. These disorders should therefore be excluded before attributing low CMAP to presynaptic neuromuscular transmission abnormalities. In response to single nerve

R

S

(h)

R

S

(g)

R

S

(f)(e)

R

S

(b)(a) (c)

R

S

(d)

R

S

R

S

R

S

FIGURE 6.10 Electrode placement for RNS test in different muscles: (a) nasalis, (b) orbicularis oculi, (c) trapezius, (d) deltoid, (e) flexor carpi ulnaris, (f) abductor digiti minimi, (g) quadriceps, and (h) tibialis anterior. R, recording; S, stimulating electrodes.

TABLE 6.3 Neuromuscular t ransmission d isorders

Postsynaptic de fects

Myasthenia gr avis

Organophosphate po isoning

Curare-induced par alysis

Congenital myast henia

Presynaptic de fects

Eaton – Lambert syn drome

Botulism

Magnesium-induced par alysis

Combined de fects

Procainamide an d an tibiotic-induced par alysis

Overlap myast henic syn drome



stimulation, when the muscle fibers are activated repeat-edly, the repetitive discharges may be seen at the end of M wave. These are associated with multiple phase and prolonged duration. The repetitive discharges indicate excessive cholinergic activity, e.g. overtreatment with anticholinesterases in MG, organophosphate toxicity, and congenital myasthenic syndromes (CMSs). Irregu-larities at the tail of M response may occur in healthy subjects also but can be differentiated from the repetitive discharge. The repetitive activity does not occur after a second shock, within a short period of the first and after maximal voluntary effort ( Quesne Le and Maxwell, 1981 ). The CMAP changes in neuromuscular transmis-sion di sorders ar e summar ized i n Table 6.4 .

Low-Rate RNS Low-rate RNS is the most important step in RNS tests.

Normal decrement in hand muscles ranges between 5 and 8% ( Slomic et al., 1968 ). The diagnostic value of low-rate RNS is as follows:

1. Abnormal decremental response is usually indicative of neuromuscular transmission block.

2. The best diagnostic values of low-rate RNS are in MG and other postsynaptic neuromuscular transmission di sorders.

3. Dramatic improvement of abnormal decremental response with edrophonium is typical of MG.

Abnormal decremental response, however, is not pathognomonic of MG. It may also be found in amyo-trophic lateral sclerosis, poliomyelitis, multiple sclero-sis, hypothyroidism, and polymyositis suggesting that any neuromuscular disorder can result in an abnormal decremental response ( Fig. 6.11 ). Other clinical features, however, can diagnose these disorders and RNS test is not indicated in them. It is important, therefore, to apply the RNS test in appropriate clinical indication. The result of RNS study should be interpreted in the light of the clinical pi cture.

Effect of Exercise or Tetanic Stimulation The effect of exercise and tetanic stimulation help in

evaluating the presence of facilitation or exhaustion and constitute an important part of RNS study. Maximum voluntary contraction of the target muscle for a defined period is more popular than tetanic stimulation because of being painless. However, if the patient is uncoopera-tive or has severe weakness, tetanic stimulation may be necessary. The effect of exercise or tetanic stimulation can be measured in two ways: (i) change in the ampli-tude and (ii) change in the degree of decrement. These changes are measured with reference to the values at rest. After maximum voluntary contraction of ADM for 30 s, the upper limit of facilitation in normal individual may be up to 37% ( Oh et al., 1982 ). Significant postex-ercise facilitation suggests a presynaptic defect such as LEMS ( Fig. 6.12 ), botulism, and magnesium-induced weakness. In postsynaptic disorders such as MG, the postexercise facilitation may be in the normal range or the decrement present at the resting state may reduce after exercise. Posttetanic or postexercise exhaustion refers to the decrease in amplitude compared to that at resting state and is found 2 – 4 min after exercise or tetanic stimulation. Normally, the amplitude of CMAP declines up to 5% following 10 s exercise ( Lambert et al., 1961 ) and 20% after 30 s exercise ( Oh et al., 1982 ). Postexercise or posttetanic exhaustion is found in (i) MG, (ii) organophosphate toxicity where it may be associated with repetitive discharges, and (iii) myotonic

TABLE 6.4 Characteristic C MAP c hanges in t he di sorders of neuromuscular transmission

Reduced am plitude Normal amplitude Repetitive dis charge

LEMS Myasthenia gr avis Anticholinesterase toxicity

Severe botulism Mild botulism Organophosphate toxicity

Magnesium, procainamide, and antibiotic induced paralysis

Congenital myasthenia

Congenital myasthenia

(a) (b) (c)

1 mV

6 ms

FIGURE 6.11 Decremental response in a patient with amyotrophic lateral sclerosis: (a) resting decrement of 9%; (b) 10 s exercise decrement of 6%; and (c) 3 min postexercise decrement of 11%. Recording from abductor digiti minimi and stimulating ulnar nerve at wrist.

INTERPRETATION OF RNS TEST 259


dystrophy. The best diagnostic value of postexercise or posttetanic exhaustion is in MG, in which it increases the diagnostic sensitivity of low-rate RNS in 15 – 25% patients, in whom the results of low-rate RNS are nor-mal ( Oh et al., 1982 ). Presence of posttetanic facilitation

suggests milder degree of myasthenia, whereas its absence suggests a more severe disease ( Fig. 6.13 ).

High-Rate RNS High-rate RNS is the most important test for differen-

tiating between presynaptic and postsynaptic neuromus-cular transmission disorders. Since there are no clinical features, which are diagnostic of LEMS, on a number of occasions, LEMS is not suspected till high-rate RNS study is carried out. Increment in ADM above 42% and in flexor carpi ulnaris above 98.6% is considered abnor-mal ( Oh, 1988 ). Abnormal decrement at high-rate RNS occurs in postsynaptic disorders like MG ( Fig. 6.14 ) and abnormal increment (100%) in presynaptic disorder such as in LEMS ( Fig. 6.15 ). The diagnostic value of high-rate RNS is as follows:

1. It is the test of choice for diagnosing presynaptic neuromuscular transmission defects.

2. Abnormal decremental response is suggestive of postsynaptic disorder: severe MG, CMS, antibiotic or procainamide induced myasthenic syndrome, and organophosphate paralysis.

0.5 mV

3 ms

FIGURE 6.12 Postexercise 128% augmentation of CMAP ampli-tude in a patient with LEMS. Resting CMAP amplitude of abductor digiti minimi on supramaximal ulnar stimulation at wrist was 0.7 mV, which increased to 1.6 mV after 30 s maximum voluntary contraction.

10 s exercise

20%

2 mV

6 ms

(a)

Rest

30%

44%(b) 30% FIGURE 6.13 Relationship of postexercise facilitation at 3 Hz RNS with severity of myasthenia gravis: (a) mild myasthenia gravis and (b) severe myasthenia gravis. The postexercise facilitation is marked in mild, whereas there is increased decrement in severe myasthenia. Recording from abductor digiti minimi and stimulating ulnar nerve at wrist.



The results of RNS study in pre- and postsynaptic disorders are summarized in Table 6.5 . The electrodiag-nostic protocol for evaluation of NMJ disorders are sum-marized i n Table 6.6 .

CLINICAL APPLICATION OF RNS STUDY

RNS study is one of the most useful electrodiagnostic tests for diagnosing pre- and postsynaptic neuromuscu-lar transmission abnormalities. The role of RNS study in some important NMJ disorders is reviewed in the fol-lowing section.

Myasthenia Gravis

MG is an autoimmune disease of postsynaptic membrane attributed to Ach receptor antibodies and c omplement-mediated damage of Ach receptors ( Fig. 6.3 ). This results in fatigability and asymmetric voluntary muscle weakness with normal reflexes and sensations. Of the tests available

4 mV

4 ms FIGURE 6.14 Thirty hertz RNS study in a patient with myasthe-nia gravis. The initial incremental response is followed by decremental response.

200 μV

5 ms

Baseline�34%

30 s exercise�29%

3 min postexercise�34.7%(a)

2 mV

5 ms

(b)

(c)

(d)

FIGURE 6.15 RNS study in a patient with Lambert – Eaton myasthenia gravis. (a) Three hertz RNS study revealed baseline decremental response (34%), facilitation after 30 s exercise (29%), and postexercise exhaustion (34.7%). (b) Thirty hertz RNS revealed 545% incremental re-sponse. Stimulation ulnar nerve at wrist, recording ADM. (c) Photograph of the same patient showing ptosis and jaw hanging. He also had cer-ebellar sign, proximal muscle weakness, and areflexia. (d) Axial CT thorax showing mediastinal mass and biopsy was consistent with small cell lung c arcinoma.

CLINICAL APPLICATION OF RNS STUDY 261


for confirming the diagnosis of MG neurophysiological (low-rate RNS and single-fiber EMG (SFEMG)), prostig-mine test, and AchR antibody assay, RNS study is the first choice for evaluation of MG because it provides immedi-ate, reliable, and objective results. The relative usefulness of different tests is compared in Table 6.7 .

The diagnostic sensitivity of RNS test in MG is influ-enced by a number of variables such as medication, type and severity of disease (ocular or generalized, mild or severe), muscles tested (distal or proximal), and param-eters (resting, postexercise or posttetanic facilitation or exhaustion). The diagnostic yield of RNS test in proximal muscles is greater than the distal. Among the proximal muscles, deltoid is more frequently abnormal ( Schady and Mac Dermott, 1992 ) .

Anconeus also yielded better result compared to ADM and its yield was reported to be similar to deltoid ( Kennet and Fawcett, 1993 ). In ocular myasthenia, RNS study performed on nasalis was reported to be more sen-sitive compared to ADM ( Niks et al., 2003 ). Phrenic nerve RNS has also been reported to be useful for detecting impending respiratory failure but it is difficult to perform, needs patient's cooperation and is associated with respira-tory and ECG artifacts. RNS on serratus anterior has been reported as an alternative to phrenic RNS for detecting respiratory failure. In a study, serratus anterior RNS was abnormal (decrement >9.4%) in all eight patients who had respiratory symptoms and in six of them, vital capac-ity was <1 L ( Lo et al., 2003 ). The diagnostic yield of RNS

test can be improved by studying additional muscles and inducing ischemia. In a study on infant and childhood myasthenia, ulnar nerve RNS study was positive in 41%, but by producing ischemia, the yield went up to 66% and by facial and spinal accessory nerve stimulation tests, the positivity rate reached up to 88% ( Vial et al., 1991 ).

The abnormalities in MG on RNS study include nor-mal CMAP amplitude, decremental response at low-rate stimulation, normal or minimal postexercise facilitation, normal or decremental response at high-rate RNS, and postexercise or posttetanic exhaustion ( Table 6.8 ). Amer-ican Association of Electrodiagnostic Medicine (AAEM) Quality Assurance Committee reviewing the utility of RNS and SFEMG recommended that 10% decrement of amplitude from the first to fourth or fifth at 2 – 5 Hz stimulation is valid for the diagnosis of MG. SFEMG is more sensitive than RNS but may be less specific and may not be widely available. Therefore, RNS remains the preferred initial test for the diagnosis of MG and LEMS ( AAEM Quality Assurance Committee, 2001 ).

Two distinct types of RNS responses are found in MG, depending upon the severity of illness. (i) In mild MG, there is decremental response at low-rate RNS, normal response at high-rate RNS and prominent posttetanic facil-itation and exhaustion ( Fig. 6.16 ). (ii) In severe MG, there is a decremental response at both low- and high-rate RNS with less pronounced posttetanic facilitation and exhaus-tion ( Fig. 6.17 ). The RNS test has also been used for moni-toring the effect of treatment. In myasthenic patients with absent or few germinal centers in thymus and a short dura-tion of disease, there is early improvement in RNS result compared to those with thymoma, more germinal centers and longer duration of disease ( Papatestas et al., 1976 ; Genkins et al., 1975 ). The beneficial effect of corticosteroid and plasmapheresis has also been documented with the help of RNS study ( Walmolts and Engel, 1972 ; Campbell et al., 1980 ). Recently, MG due to anti-muscle-specific kinase antibody has been described. These patients mani-fest with predominant ocular and bulbar weakness with high frequency of respiratory crisis and relative preserva-tion of limb power. SFEMG although was abnormal in all the patients, RNS was abnormal in only 56.8% only ( Evoli et al., 2003 ). Variability in MUP amplitude on concentric needle EMG suggests NMJ disorders ( Fig. 6.18 ).

TABLE 6.5 Repetitive ne rve stimula tion ( RNS) i n pr e- a nd postsynaptic disorders

Parameters Presynaptic Postsynaptic

CMAP ampl itude Small Normal

Low-rate RNS

Rest Decrement Decrement

PEF + ±

PEE − +

High-rate RNS Increment Decrement or normal

CMAP, compound muscle action potential; PEE, postexercise exhaustion; PEF, postexercise facilitation.

TABLE 6.6 Electrodiagnostic protocol for the evaluation of pre- and postsynaptic neuromuscular junction transmission disorders

Disorders RNS rate Train of stimuli Findings Exercise duration Findings

Postsynaptic 2–5 H z 5 – 10 CMAP ampl itude n ormal >10% decrement

10 s 30 – 60 s

Facilitation (repair of decrement) Increased decrement after 3–4 min

Presynaptic 2–5 H z 5–10 CMAP ↓ >10% decrement

10 s exercise >100% increment immediately after exercise

20–50 H z 100 – 200 >100% i ncrement

Source: M odifi ed from Howard (2013) .



Lambert – Eaton Myasthenic Syndrome

LEMS is characterized by weakness and fatigability of proximal limb muscles with relative sparing of extraocu-lar and bulbar muscles, hyporeflexia, and dry mouth. There is a high association of small cell lung carcinoma with LEMS, which is attributed to voltage-gated calcium channel (VGCC) antibodies.

RNS test is diagnostic of LEMS and evaluation of dis-tal muscles is preferred. Three patterns of abnormalities have been described in LEMS:

1. Low-normal CMAP amplitude (<5 mV in ADM), decremental response at low-rate RNS, and relatively normal response at high-rate RNS.

2. The classical triad of RNS study in LEMS includes low CMAP amplitude, decremental response at low-rate RNS, and incremental response at high-rate RNS (more t han 100%) ( Fig. 6.19 ).

3. Low CMAP amplitude, decremental response at low-rate RNS, and initial decremental response at high-rate RNS.

TABLE 6.8 Characteristic R NS fi nding s in my asthenia g ravis

1. Normal CMAP 2. Decremental r esponse at l ow-rate RNS 3. Normal o r mi nimal po stexercise fac ilitation 4. Normal o r de cremental r esponse at h igh-rate RNS 5. Postexercise o r po sttetanic e xhaustion

TABLE 6.7 Relative use fulness of diffe rent te sts i n m yasthenia gravis

Diagnostic yield (%)

Procedure Defi nite Mild Ocular

RNS

Hand 68 31 4

Shoulder 89 68 19

Single-fiber EMG

Forearm 100 88 – 92 86 – 95

Face 2 59–77 2

Ach r eceptor an tibody 88 76–80 70 – 76

Source: Fr om Keesey (1989) .

4 mV

6 ms

(c)(b)(a) FIGURE 6.16 Three hertz RNS study in a patient with mild myasthenia gravis (stage II): (a) 30% decrement at rest; (b) 20% decrement after 10 s exercise; and (c) 34% decrement after 3 min. The postexercise facilitation is a feature of mild myasthenia.

(c)(b)(a) FIGURE 6.17 Three hertz RNS study in a patient with severe myasthenia gravis (stage III): (a) resting decrement of 32%; (b) 10 s exercise decrement of 44%; and (c) 3 min postexercise decrement of 50%. In severe myasthenia gravis, postexercise facilitation is lacking.



Since type III and I can be misdiagnosed as MG, pro-longed high-rate RNS is recommended (50 Hz, 10 s) ( Oh, 1989 ).

The incremental response following high-rate stimu-lation in LEMS may be of two types ( Fig. 6.20 ):

1. A gradual incremental response from the first CMAP. 2. Initial de crement fo llowed by i ncremental r esponse.

Although the first is more frequent, the second sug-gests more severe disease ( Oh, 1988 ). The RNS study should be carried out at least in two muscles including

both upper and lower limbs. A facilitation of 50% or more in any muscle may suggest LEMS but may also occur in MG. Facilitation if exceeds 100% in most of the muscles tested or 400% in any muscle is diagnostic of LEMS. If the facilitation is below 50%, the patient may still have LEMS especially if the duration of weakness is short. The classical findings of RNS study on LEMS are summarized in Table 6.9 ( Oh, 1989 ).

High-rate RNS is an unpleasant test. In a patient with suspected LEMS who had low CMAP amplitude, postexercise facilitation may be studied in ADM. The

1s 100μ1

FIGURE 6.18 On concentric needle EMG, there is variability of MUP amplitude in a patient with myasthenia gravis.

(a)

(c)(d)

(b)0.2 mV

6 ms

0.4 mV

6 ms

FIGURE 6.19 RNS study in a patient with Lambert – Eaton myasthenic syndrome. RNS at 3 Hz: (a) resting decrement 30%; (b) 10 s exercise 20% decrement; (c) 3 min postexercise decrement 34%; and (d) 30 Hz RNS results in 400% increment. Stimulation ulnar nerve, recording from abductor di giti mi nimi.



baseline CMAP should be obtained after several minutes of rest. Patient is asked to contract the target muscle with a maximum force for 10 s. CMAP is obtained within 5 s of exercise. Delay in obtaining CMAP may miss postex-ercise facilitation and longer exercise period may deplete the Ach store and miss the facilitation ( Juel, 2012 ).

In a study on 29 patients with LEMS, the CMAP amplitude was reduced in 75% of hand or foot muscles,

decremental response exceeding 10% on low-rate RNS in all the muscles and facilitation was >100% in 62% of 74 hands or foot muscles studied ( Sanders, 1995 ). The classical triad was present in 9, type (I) in 1, and type (III) in 3 patients in a study on 13 patients with LEMS ( Oh, 1989 ). In another study on 50 consecutive patients with LEMS, 25 patients had underlying carcinoma; of whom, 21 had small cell lung carcinoma, which mani-fested within 2 years in 20, and 38 years in 1 patient. In the noncarcinomatous group, 14 had history of LEMS exceeding 5 years. The amplitude of CMAP was low and the increment following maximum voluntary contrac-tion was present in 48 patients each ( O'Neill et al., 1988 ). Tim et al. (1998) prospectively evaluated 59 patients with LEMS; 98% patients had decrement at 3 Hz, 88% had normal CMAP at least in one muscle of the three muscles studied (abductor pollicis brevis, abductor digiti quinti, and extensor digitorum brevis) and 39% had potentia-tion >100% in all the three muscles. In abductor pollicis brevis, the CMAP was low in 86%, abnormal decrement in 98% and facilitation following postmaximal voluntary contraction >100% in 63% patients only. For abductor digiti quinti, these were 94, 98, and 78%; and for abduc-tor digitorum brevis, 80, 82, and 59%, respectively. In 12% patients with LEMS, no muscle showed increment >100%. This study therefore emphasized that the diag-nosis of LEMS should be based on clinical, VGCC anti-body, and CMAP amplitude ( Tim et al., 1998 ). AAEM Quality Assurance Committee reviewing the literature suggested that the degree of increment needed to diag-nose LEMS is at least 25% but most accurate when 100% ( AAEM Quality Assurance Committee, 2001 ). The effect of plasmapheresis has been monitored with the help of RNS study. The partial clinical improvement correlated with reduction in the extent of incremental response ( Fig. 6.21 ; Kalita e t al ., 1995 ).

Overlap Myasthenic Syndrome

Overlap myasthenic syndrome refers to the coex-istence of MG and LEMS in the same patient. The

(a)

(b) FIGURE 6.20 Pattern of increment following high-rate RNS in LEMS. (a) Classical LEMS, 30 Hz, 100 impulse, and gradual incremen-tal response. (b) More severe LEMS may need 50 Hz, 100 impulse, and initial decrement followed by incremental response.

TABLE 6.9 Characteristic fi nding s of R NS st udy i n LEM S

1. Low-normal CMAP 2. Decremental r esponse at l ow-rate RNS 3. Postexercise fac ilitation 4. High-rate RNS 100% i ncrement i n t wo musc les 400% i ncrement i n

any musc le

CMAP, compound muscle action potential; LEMS, Lambert – Eaton myasthenic syndrome; RNS, repetitive nerve stimulation.

2 mV

6 ms

(a) (b) FIGURE 6.21 Monitoring therapeutic response by high-rate RNS. (a) Incremental response on high-rate RNS in a patient with LEMS with rheumatoid arthritis is reduced following plasmapheresis, (b) which correlated with clinical improvement.



clinical picture includes oculobulbar symptoms, a positive edrophonium test suggesting MG and are-flexia suggesting LEMS. The RNS test shows classi-cal triad typical of LEMS (CMAP below 5 mV, more than 100% increment at high-rate stimulation and decremental response at low-rate stimulation). The effects of exercise and tetanic stimulation are less pronounced.

Congenital Myasthenic Syndrome

CMS constitutes a group of inherited disorders due to presynaptic, synaptic, or postsynaptic defect that compromises the safety margin of NMJ transmission. The slow-channel CMS is due to autosomal domi-nant and the remaining are due to autosomal reces-sive inheritance. CMS is a commonly undiagnosed or misdiagnosed entity. The diagnosis of CMS clinically is made by a history of fatigable weakness involving ocular, bulbar, and limb muscles since infancy or early childhood, a history of similar affected family member, decremental response on RNS and negative AchR anti-body ( Fig. 6.22 ). Some CMSs, however, manifest late with restricted distribution of weakness and intermit-tent RNS test abnormality making the diagnosis dif-ficult. Several genetic mutations have been described in CMS. The broad groups of CMS are summarized in Table 6.10 .

Analysis of 155 kinships of CMS from Mayo Clinic revealed presynaptic defect in 8%, synaptic in 16%, and postsynaptic in 75%. The following clinical and

neurophysiological tests have been suggested to be help-ful for the diagnosis of CMS ( Engel, 2003 ):

1. Slow-channel and endplate AchE deficiency CMS manifest with delayed pupillary light reflex, nonresponsive to cholinesterase inhibitors and repetitive CMAP discharges to single stimulus.

2. Slow-channel CMS due to endplate AchE deficiency manifests in older patients with selective severe muscle weakness of cervical and extensors of wrist and fi ngers.

3. Severe slow-channel CMS due to AchE deficiency manifests with hypoactive or absent tendon reflex.

4. Resynthesis and vesicular packaging defect of Ach manifest with recurrent apnoeic episodes provoked by stress. RNS test is negative on rested muscle but positive after 5 min stimulation at 10 Hz.

Botulism

Botulism is a disease of neuromuscular transmission caused by the toxin released by Clostridium botulinum . Adults show descending paralysis affecting the eyes, head, neck, trunk, and limbs sequentially. In infants, the clinical picture includes inability to suck, constipation, weakness, and hypotonia. In severe form of botulism, RNS study reveals the features of presynaptic defect, i.e. low CMAP amplitude, normal or decremental response at low-rate RNS, and significant incremental response at high-rate RNS. In mild cases, however, CMAP may be of normal amplitude and there may be no decrement at low-rate RNS. At high-rate RNS study, although incre-ment is present in botulism, it is less pronounced than in LEMS.

Magnesium-Induced Myasthenia

Magnesium intoxication can lead to rapidly develop-ing generalized muscle weakness including facial and respiratory muscles. The RNS tests reveal the findings consistent with presynaptic neuromuscular transmission defect; however, postexercise exhaustion on low-rate RNS is absent. On recovery from magnesium toxicity, RNS results return to normal. Edrophonium, prostig-mine, and intravenous calcium gluconate improve the weakness.

Antibiotic-Induced Myasthenia

Following aminoglycoside therapy especially in renal failure patients, there is acute flaccid paralysis with dilated fixed pupils, ophthalmoplegia, and bulbar weakness. The RNS test reveals low-amplitude CMAP, decremental response at low- and high-rate RNS but no posttetanic facilitation or exhaustion. Nerve conduction

FIGURE 6.22 A family suffering from congenital myasthenia; ar-rows show the affected members who had ptosis and proximal muscle weakness.



velocity is slow. The pathogenesis of this syndrome is attributed to both pre- and postsynaptic defects. It is suggested that lack of posttetanic facilitation is due to slow mobilization of Ach to immediately available pool.

Organophosphate Toxicity

Generalized weakness in organophosphate poison-ing is due to excessive Ach as a result of inactivation of AchE, which results in depolarization block at nico-tinic receptors. The RNS study reveals repetitive CMAP

discharges to a single stimulus, abnormal decremental response at low rate which is more pronounced at high rate, and worsening of decremental response on edro-phonium injection. There are only a few studies on the neurophysiological changes in organophosphate poi-soning. In a study on two patients with suicidal organo-phosphate poisoning, there was neither any change in the CMAP amplitude nor any repetitive muscle activity ( Jusic and Millic, 1977 ). In a study of neurophysiological changes in 350 organophosphate poisoning patients, 49% patients had proximal muscle weakness, cranial nerve

TABLE 6.10 Types of c ongenital m yasthenic s yndrome ( CMS) a nd t heir c haracteristics

Types of C MS Gene Clinical and neurophysiological characteristics

A.Presynaptic CMS

1. Episodic apnea—deficiency of Ach transferase CHAT Sudden bulbar weakness and apnea. 3 Hz RNS—decremental response

2. Paucity of synaptic vesicles and reduced quantal release Clinically mimic MG, RNS—presynaptic defect

3. Abnormal resynthesis and vesicular packaging of Ach 10 Hz RNS for 5 min, then 3 Hz RNS shows decremental response

4. Defect in P/Q type of VGCC or synaptic vesicle release complex

Resembles LEMS

B. Synaptic CMS

1. AchE de ficiency COLQ Slow pupi llary l ight r eflex, r epetitive di scharges decremental response, no response to AchE inhibitors

2. Lami nin β 2 chain-abnormal formation of NMJ LAMB2 CMS with ocular and renal malformation

C. Postsynaptic CMS

1. Sl ow-channel syn drome: ↑ AchR response to Ach CHRN-A,B,D.E Early onset disabled by the end of first decade or late onset slow progression with little disability. Repetitive discharges on NCS, RNS low rate—decrement, fast rate—increment, quinidine responsive

2. Fast -channel syn drome ↓ AchR response to Ach CHRN-A,D.E Mild to severe, resembles to MG clinically and RNS test, responds to 3,4-diaminopyridine and pyridostigmine

3. Primary AchR deficiency without kinetic abnormality CHRN-A,B,D.E Manifests during childhood to adulthood. Mild to severe. 3 Hz RNS-decrement, responds to pyridostigmine

4. D efect i n AchR c omplex

i. Rapsyn de ficiency RAPSN Neonatal o nset, ar throgryposis, 3 H z RNS-de crement

ii. D ok-7 de ficiency Dok-7 Severe l imb gi rdle we akness, 3 H z R NS-decrement.

iii. MuSk de ficiency MUSK Similar t o MG

5. V oltage-gated Na c hannel de fect SCN4A Similar t o MG

6. Agrin AGRN Similar t o MG

7. CMS wi th t ubular aggr egates GFPT1 Similar t o D ok-7 de ficiency

8. Ot hers- Escobar syn drome Plectin de ficiency CMS wi th c entronuclear myo pathy

CHRNG PLEC1

Arthrogryposis, pterygium, dyspnea CMS with muscular dystrophy with epidermolysis bulous simplex

AChR, acetylcholine receptor; Dok, downstream of tyrosine kinase; LEMS, Lambert – Eaton myasthenic syndrome; MG, myasthenia gravis; MuSK, muscle specific tyrosine kinase; NCS, nerve conduction study; RNS, repetitive nerve stimulation; VGCC, voltage-gated calcium channel. Source: M odifi ed from Lorenzoni et al. (2012) .



palsy, and areflexia. Motor conduction velocity and ter-minal motor latencies were affected in the severe group. On RNS study at 3 Hz, there was decrement in two, at 10 Hz in four, and at 30 Hz in several patients even in the absence of paralysis. Repetitive muscle activity was present in 60% patients ( Wadia et al., 1987 ). Following organophosphate poisoning, the RNS study revealed decremental response on tetanic stimulation, absence of decrement on low-rate stimulation and absence of posttetanic facilitation suggesting postsynaptic defect. In these patients, paralytic symptoms followed the cho-linergic crisis, which lasted up to 18 days. These patients were described as a distinct intermediate syndrome of organophosphate poisoning ( Senanayake and Karal-liedde, 1987 ). The RNS studies have been carried out in organophosphate-exposed agricultural workers with the aim of detecting subclinical abnormality in neuromuscu-lar transmission. In a study, 40% workers had abnormal RNS test and it was regarded more accurate than blood AchE estimation ( Jager et al., 1970 ). The author in his study found repetitive activity in 29% patients and there were no other significant abnormalities in RNS study ( Misra e t al ., 1988 ).

Arthropod and Snake-Bite

Clinical symptoms and outcome of snake-bite depend on venom composition of local snakes and availability of emergency care. Snake venoms are composed of a complex mixture of peptides; low- molecular-weight peptides are neurotoxic and produce both pre- and postsynaptic neuromuscular transmission abnormali-ties. It results in weakness with a predilection to neck flexors, ocular, bulbar, and proximal limb muscles; and at times, respiratory muscle paralysis and death ( Fig. 6.23 ). RNS reveals both pre- and postsynaptic defects; usually there is low CMAP amplitude, decre-mental response at 3 Hz stimulation and postexercise or posttetanic facilitation. NMJ transmission abnormal-ities following various arthropod and snake-bite are summarized in Table 6.11 .

(a)

Rest�28.5%

30 s exercise�31.6%

4 min postexercise�36.6%

500 �V

5 ms

(b)

FIGURE 6.23 Three hertz RNS study in a patient with snake-bite. (a) Significant decremental response at rest and following exercise. (b) Photograph of the same patient showing bilateral ptosis and inability to close the mouth.

TABLE 6.11 Types of neuromuscular junction (NMJ) transmission abnormalities following various snake and arthropod bites

Source Toxins Site of NMJ involvement RNS s tudy

Snake α -Bungarotoxin; cabrotoxin Postsynaptic AchR competitive blockade Decrement on 3 Hz RNS

Snake β -Bungarotoxin; c rotoxin, notexin, taiposin

Presynaptic inhibition of AchR Decrement on 3 Hz; increment on 30 Hz taiposin

Black widow spider α -Latrotoxin Presynaptic facilitation of Ach release → Ach depletion

Early stage—repetitive discharge. Late stage—decremental response

Scorpion Tityustoxin Presynaptic facilitation of Ach release and postsynaptic inhibition of Na + channel inactivation

Repetitive di scharge

Ach, acetylcholine; AchR, acetylcholine receptor; NMJ, neuromuscular junction; RNS, repetitive nerve stimulation.



Suggested Electrodiagnostic Approach to a Patient with Neuromuscular Junction Disorder

NMJ disorder since can mimic a number of muscles, anterior horn cell and peripheral nerve diseases, there-fore, a systematic approach is needed. History and clini-cal examination and electrodiagnostic tests are needed for the diagnosis of NMJ disorders. Sensory and motor nerve conduction of at least two limbs (one upper and one lower) should be done.

If a presynaptic disorder is suspected, baseline and postexercise CMAP of two distal motor nerves is car-ried out. If postexercise facilitation is more than 50%, high-rate RNS should be carried out. If the diagnosis

of a postsynaptic disorder is suspected, a low-rate RNS should be performed. The choice of muscle for RNS tests depends on the clinical picture. Generally, a weak mus-cle is preferred. Low-rate RNS if normal and a postsyn-aptic disorder is strongly suspected, SFEMG of extensor digitorum communis or frontalis muscle should be per-formed. The electrodiagnostic approach to NMJ disor-ders i s sh own i n Figure 6.24 .

The RNS studies are one of the most useful clini-cal electrodiagnostic tests and are essential for the diagnosis of pre- and postsynaptic neuromuscu-lar transmission disorders. Attention to technical details is extremely important for reliable results and interpretation.

Low CMAPNormal SNAP

NCS two nerves

NormalCMAP and SNAP

50% increment No increment

PresynapticNMJ defect Concentric needle EMG

Normal Abnormal

Low-rate RNSADM, nasalis, trapezius, deltoid

Normal Decrementalresponse

SFEMG

Normal

Normal

Concentric EMG

MG excluded MG confirmed

Normal

Concentric needle EMGLEMS orbotulism

MND, myopathy,neuropathy

Suspected NMJ disorder

↑Jitter and blocking

• ↑Postexercise CMAP in 2 motor nerves• High-rate RNS

FIGURE 6.24 Approach to a patient with suspected neuromuscular disorder. ADM, abductor digiti minimi; CMAP, compound muscle action potential; LEMS, Lambert – Eaton myasthenic syndrome; MG, myasthenia gravis; MND, motor neuron disease; NCS, nerve conduc-tion study; NMJ, neuromuscular junction; RNS, repetitive nerve stimulation; SNAP, sensory nerve action potential; SFEMG, single-fiber electromyography.



References AAEM Quality Assurance Committee , American Association of

Electrodiagnostic Medicine . Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the elec-trodiagnostic evaluation of patients with suspected myasthenia gravis and Lambert – Eaton myasthenic syndrome . Muscle Nerve 2001 ; 24 : 1239 .

Campbell Jr W W , Leshner R T , Swift T R . Plasma exchange in myasthenia gravis: electrophysiological studies . Ann Neurol 1980 ; 8 : 584 .

Desmedt J E . The neuromuscular disorder in myasthenia gravis (i) elec-trical and mechanical response to nerve stimulation in hand muscles . In: Desmedt J E , editor. New developments in electromyography and clinical neurophysiology , vol. 1 . Basel : Karger ; 1973 . p. 241 .

Elmqvist D . Neuromuscular transmission defects . In: Desmedt J E , editor. New developments in electromyography and clinical neurophysiol-ogy . Basel : Karger ; 1973 . p. 229 .

Engel A G . Myasthenic syndromes, congenital . In: Aminoff M J , Daroff R B , editors. Encyclopedia of neurological sciences , vol. 3 . Boston : Academic P ress ; 2003 . p. 315 .

Engel A , Santa T . Histometric analysis of the ultrastructure of the neu-romuscular function in myasthenia gravis and in the myasthenic syndrome . Ann NY Acad Sc i 1971 ; 183 : 46 .

Evoli A , Tonali P A , Padua L , et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis . Brain 2003 ; 126 : 2304 .

Fukunaga H , Engel A G , Lang B , Newsom-Davis J , Vincent A . Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones . Proc Nat l Acad Sc i U S A 1983 ; 80 : 7636 .

Genkins G , Papatestas A E , Horowitz S H , et al. Studies in myasthenia gravis: early thymectomy—electrophysiologic and pathologic cor-relations . Am J Me d 1975 ; 58 : 517 .

Grob O , Johns R J , Harvey A M . Studies in neuromuscular function. Introduction an d me thods . Bull Jo hns H opkins 1956 ; 99 : 115 .

Howard Jr J F . Electrodiagnosis of disorders of neuromuscular transmission . Phys Me d Re habil Cl in N Am 2013 ; 24 : 169 .

Jager K W , Roberts D V , Wilson A . Neuromuscular functions in pesticide wo rkers . Br J I nd Me d 1970 ; 27 : 273 .

Juel V C . Evaluation of neuromuscular junction disorders in the electro-myography l aboratory . Neurol Cl in 2012 ; 30 : 621 .

Jusic A , Millic S . Neuromuscular synaptic testing in 2 cases of suicidal organophosphorous po isoning . Arch En viron H ealth 1977 ; 33 : 240 .

Kalita J , Chaudhary N , Singh M K , et al. Coexistence of myasthenic Eaton Lambert syndrome and subacute cerebellar degeneration in a pat ient wi th r heumatoid ar thritis . Eur J Ne urol 1995 ; 2 : 1 .

Keesey J C . AAEM 33: electrodiagnostic approach to defect of neuro-muscular t ransmission . Muscle Ne rve 1989 ; 12 : 613 .

Kennet R P , Fawcett P R W . Repetitive nerve stimulation on anconeus in the assessment of neuromuscular transmission disorders . Electro-encephalogr Cl in Ne urophysiol 1993 ; 89 : 170 .

Lambert E H , Rooke E D , Eaton L M , et al. Myasthenic syndrome occa-sionally associated with bronchial neoplasm: neurophysiological studies . In: Viets H R , editor. Myasthenia gravis . Springfield, IL : Charles C T homas ; 1961 . p. 362 .

Lo Y L , Leoh T H , Dan Y F , et al. Repetitive stimulation of the long thoracic nerve in myasthenia gravis: clinical and electrophysi-ological correlations . J Neurol Neurosurg Psychiatry 2003 ; 74 : 379 .

Lorenzoni P J , Scola R H , Kay C S K , Werneck L C . Congenital myasthenic syndrome: a br ief review . Pediatr Ne urol 2012 ; 46 : 141 .

Misra U K , Nag D , Khan W A , et al. A study of nerve conduction velocity, late responses and neuromuscular synapse functions in organophos-phate workers in India . Arch Toxicol 1988 ; 61 : 496 .

Misra U K , Kalita J , Srivastava A . A study of diagnostic yield, technical ease and patient discomfort of low rate repetitive nerve stimulation test in patients with myasthenia gravis . Electromyogra Clin Neuro-physiol 2006 ; 46 : 337 .

Niks E H , Badrising U A , Verschuuren J J , et al. Decremental response of the nasalis and hypothenar muscles in myasthenia gravis . Muscle Nerve 2003 ; 28 : 236 .

Oh S J . 8 – 10% decremental response is not the normal limit for all the muscles. Myasthenia gravis: biology and treatment . Ann NY Acad Sci 1987 ; 505 : 851 .

Oh S J . Electromyography, neuromuscular transmission studies . Balti-more : Williams an d W ilkins ; 1988 .

Oh S J . Diverse electrophysiological spectrum of Lambert Eaton myas-thenic syn drome . Muscle Ne rve 1989 ; 12 : 464 .

Oh S J , Eslami N , Nishihara T , et al. Electrophysiological and clinical correlation in myasthenia gravis . Ann Neurol 1982 ; 12 : 348 .

O'Neill J H , Murray M M F , Newson Davis J . The Lambert Eaton myas-thenic syn drome . Brain 1988 ; 111 : 577 .

Papatestas A E , Genkins G , Horowitz S H , et al. Thymectomy in myas-thenia gravis: pathologic, clinical and electrophysiologic correla-tions . Ann NY Acad Sc i 1976 ; 274 : 555 .

Quesne Le P M , Maxwell I C . Effect of edrophonium bromide on neu-romuscular transmission in healthy human subjects . Neurotoxicol-ogy 1981 ; 2 : 675 .

Rahamimoff R , Erulkar S D , Lev-Tov A , et al. Intracellular and extracel-lular calcium ions in transmitter release at neuromuscular synapse . Ann NY Acad Sc i 1978 ; 307 : 583 .

Senanayake N , Karalliedde L . Neurotoxic effects of organo-phosphate insecticides . N En gl J Me d 1987 ; 316 : 761 .

Sanders D B . Lambert Eaton myasthenic syndrome: clinical diagnosis, immune mediated mechanism and update on therapies . Ann Neu-rol 1995 ; 375 : 563 .

Schady W , MacDermott N . On the choice of muscle in the electrophysi-ological assessment of myasthenia gravis . Electromyogr Clin Neu-rophysiol 1992 ; 32 : 99 .

Slomic A , Rosenfalck P , Buchthal F . Electrical and mechanical responses of normal and myasthenic muscles with particular reference to stair case ph enomenon . Brain Re s 1968 ; 10 : 1 .

Stålberg E , Sanders D B . Electrophysiological test of neuromuscular transmission . In: Stålberg E , Young R R , editors. Clinical neurophys-iology . London : Butterworth ; 1981 . p. 88 .

LEARNING POINTS

1. NMJ disorders may be presynaptic such as LEMS or postsynaptic such as MG.

2. In postsynaptic NMJ disorders, there is >10% decrement in RNS which may show postexercise facilitation in mild cases or absence of facilitation in severe cases.

3. For low-rate RNS, nasalis, trapezius, and ADM are the most appropriate muscles.

4. Attention to technical details, such as supramaximal stimulation, proper immobilization, free of artifacts and cooperation of the patient, is essential.

5. In presynaptic disorders, low CMAP, decrement on low-rate RNS and significant increment at high-rate RNS >100% in two muscles or 400% in any muscle are diagnostic.



Tim R W , Massey J M , Sanders D M . Lambert Eaton myasthenic syndrome (LEMS): clinical and neurophysiological features and response to therapy in 59 patients . Ann NY Acad Sci 1998 ; 841 : 832 .

Vial C , Charles N , Chauplannaz G , et al. Myasthenia gravis in child-hood and infancy. Usefulness of electrophysiologic studies . Arch Neurol 1991 ; 48 : 847 .

Wadia R S , Chitra S , Amin P B , et al. Electrophysiological studies in acute organophosphate poisoning . J Neurol Neurosurg Psychiatry 1987 ; 50 : 1442 .

Walmolts J R , Engel W K . Benefit from alternate day prednisone in myasthenia gr avis . N En gl J Me d 1972 ; 286 : 17 .

sample chapter clinical neurophysiology 3e by misra and kalita to order call sms at 91 8527622422

Health & Medicine

postsynaptic endplate

presynaptic axon terminal

postsynaptic cleft engel

postsynaptic membranes

postsynaptic folds

primary synaptic cleft

nerve terminal

amplitude of mepp