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Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422
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Sample Chapter Clinical Neurophysiology 3e by Misra and Kalita To Order Call Sms at 91 8527622422

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  • 1. C H A P T E R 6 RepetitiveNe rveStimula tion NEUROMUSCULAR JUNCTION Neuromuscular junction (NMJ) consists of presynaptic axon terminal, synaptic cleft, and postsynaptic endplate (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 mitochondria and synaptic vesicles. A nerve terminal has an area of 4 μm2 containing about 50 synaptic vesicles/mm2. 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 membrane and are available for immediate release. These constitute the “immediately available pool”. About 10,000 quanta move toward the membrane to replenish 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 presynaptic axon terminal and postsynaptic endplate. From the primary synaptic cleft, there are numerous radial extensions 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 elongated (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 potential (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 extracellular concentration of calcium, potassium, and temperature (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 concentration 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 251 Axonal terminal Myelin Schwann cell Ach vesicle Ach receptor Synaptic cleft Eaton Lambert syndrome Myasthenia gravis FIGURE 6.1 Neuromuscularjun ction. Ach,ac etylcholine.
  • 2. 252 REPETITIVE NERVE STIMULATION Choline ϩ Acetyl CoA Choline acetylase Ach synthesis Presynaptic Main storage Mobilization pool Immediately available pool Acetic acid ϩ Choline Cholinesterase Ca2ϩ Ach (60 quanta) Ach quantum MEPP EPP MAP Postsynaptic Muscle contraction FIGURE 6.2 Acetylcholine synthesis and its action at neuromuscular junction. Ach, acetylcholine; EPP, endplate potential; MAP, muscle action potential;MEP P,mi niaturee ndplatepo tential. esterase breaks down Ach into acetic acid and choline. A nerve impulse propagating down the nerve terminal results in its depolarization and influx of Ca2+ 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 membrane 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 theory 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 current 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 acetylcholinesterase (AchE) activity. Postsynaptic folds form a high-resistance pathway that focuses the endplate current 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 contribution to improve safety factor in humans. All the diseases Neuromuscular junction Ab VGCC Ach AchR MG Normal LEMS FIGURE 6.3 Neuromuscular junction in normal, myasthenia gravis (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, acetylcholine receptor; Ach, acetylcholine; VGCC, voltage-gated calcium channel;LEMS,Lambe rt–Eatonmyast henicsy ndrome. 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 compound 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. CLINICAL NEUROPHYSIOLOGY
  • 3. 253 VARIABLES INFLUENCING NEUROMUSCULAR TRANSMISSION Axon terminal Ca2ϩ Ach N 3 Hz RNS Axon terminal Ca2ϩ Ach Normal MG MG LEMS FIGURE 6.4 Low-rate RNS in normal (N), myasthenia gravis (MG), andLambe rt–Eatonmyast henicsyn drome(LEM S). However, area measurement that requires computer analysis is considered more accurate. Two events at the presynaptic membrane are important with reference to RNS: (i) depletion of immediately available Ach quanta and (ii) increase of Ach release by Ca2+ influx. During RNS, these two events have opposing influence. At low-rate RNS (below 5 Hz, interstimulus 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 Ca2+ facilitates Ach release for about 100–200 ms, following each impulse (Rahamimoff et al., 1978), after which the Ca2+ ion is sequestrated by mitochondria. At high-rate RNS (more than 5 Hz, interstimulus interval is less than 200 ms), there is production of a cumulative facilitation of transmitter release due to increasing Ca2+ entry into the nerve terminal (Figs. 6.4 and 6.5). In normal individuals, both at low- and highrate 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 incremental 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 neuromuscular reserve, the CMAP is 30–50% of the adult value. The response to RNS after 6 months of age is not much LEMS 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 abductor digiti minimi stimulating ulnar nerve at wrist in a normal subject (pseudofacilitation). different compared to adults. The importance of temperature 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, therefore, recommended that the RNS studies should be carried 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 variation in decrement is attributed to temperature gradient along the extremities and constant tonic contraction of CLINICAL NEUROPHYSIOLOGY
  • 4. 254 REPETITIVE NERVE STIMULATION proximal muscle. Exercise can result in facilitation and postexercise exhaustion in patients with abnormal neuromuscular transmission. However, in normal individuals, 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 transmission. 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 themusc 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 aftere xercise. TECHNIQUE OF RNS Most of the modern machines have preset program for RNS. The machine setup for RNS study in author's laboratoryi sgi veni n Table6.1 . 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 preferred because the incremental decremental responses are easily recognized at a glance and any change in CMAP amplitude can be easily measured. The shape of TABLE 6.1 Machines etupf orR NSs 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 Stimulusr ate/s Low <5 High 30–50 Number of stimuli Lowr ate 5–6 Highr ate 50–100 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 electrode 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 stimulating electrode should also be secured on the nerve and should not move during the study. The stimulus should be supramaximal. Suboptimal stimulation will invalidate 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 incremental 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. CLINICAL NEUROPHYSIOLOGY
  • 5. 255 MEASUREMENT (a) (b) (c) FIGURE 6.7 Method of stabilization during RNS studies in (a) abductor digiti minimi, (b) deltoid, and (c) trapezius recordings. 4 mV 6 ms (a) (c) (b) (d) 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. 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 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 decrement. This method, however, is not popular because of pain due to prolonged stimulation. The decrement is calculated by the following formula: 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 CLINICAL NEUROPHYSIOLOGY [ ]
  • 6. 256 REPETITIVE NERVE STIMULATION Incremental response is calculated by comparing the amplitude of highest CMAP with the first CMAP following high-rate stimulation, i.e. 30 Hz, 100 pulses. It is calculated as follows: [ ] 4 mV 6 ms To study the postexercise or posttetanic facilitation, there are two methods: (i) comparison of the decremental 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 summarized in Table 6.2, which should be correlated with the illustration( Fig.6.10 ). Selecting a Muscle for Low-Rate RNS Study 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 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 questions. 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 Technical aspects of stimulating and recording procedures of RNS test in different muscles Location of electrode Muscle Tibialisan terior R1 Midpoint of nasalis Below and anterior to tragus Glabellar point Lowest supramaximal stimulation R1 Midway between acromion and C7 spine Above clavicle Behind sternocleidomastoid, midpoint between clavicle and mastoid Lying lateral with a pillow or sitting and fixing the shoulder by assistant R1 Prominent part of deltoid Erb's point Mid arm Shoulder immobilization by strap or assistant R1 Midaxillary seventh rib Erb's point Shoulder immobilization Anterior axillary line sixth rib R1 Upper one-third of muscle Ulnar groove at elbow Immobilize wrist and elbow Ulnar styloid R1 Middle of hypothenar At wrist Immobilize the hand Base of fifth digit R1 Rectus femoris Femoral nerve in groin Supine with leg immobilization R2 Quadriceps Above eyebrow R2 Abductor digiti minimi Lowest supramaximal stimuli R2 Flexor carpi ulnaris Below and anterior to tragus R2 Serratusan terior Midpoint of lower orbicularis oculi R2 Deltoid R1 R2 Trapezius Technicalc omments R2 Nasalis Stimulating R2 Orbiculariso culi Recording Patella Lateral to femoral artery R1 Belly of tibialis anterior Neck of fibula R2 3 cm distal CLINICAL NEUROPHYSIOLOGY Patient sitting with thigh and leg restrained with strap
  • 7. 257 INTERPRETATION OF RNS TEST serratus anterior. The patients' discomfort was maximus with deltoid and nasalis. Combining diagnostic yield, patients' comfort and technical ease together ADM, trapezius 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 differentiate between presynaptic and postsynaptic disorders of neuromuscular transmission. The important neuromuscular transmission disorders are summarized in Table 6.3. The CMAP amplitude has a wide variation in normal subjects, hence it is not a sensitive indicator of neuromuscular 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 TABLE 6.3 Neuromusculart ransmissiond isorders Postsynapticde fects Myastheniagr avis Organophosphatepo isoning Interpretation of RNS Curare-inducedpar alysis The interpretation of RNS test should include the changes in the following: 1. 2. 3. 4. CMAP Low-rateRNS Effect of exercise and tetanic stimulation High-rateRNS. Congenitalmyast henia Presynapticde fects Eaton–Lambertsyn drome Botulism Magnesium-inducedpar alysis Combinedde fects Compound Muscle Action Potential CMAP is influenced by the physiological integrity of the nerve, neuromuscular transmission, and muscle. R Procainamidean dan tibiotic-inducedpar alysis Overlapmyast henicsyn drome R S S S R (a) (b) S (c) S S S R S R R R R (d) (e) (f) (g) (h) 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. CLINICAL NEUROPHYSIOLOGY
  • 8. 258 REPETITIVE NERVE STIMULATION stimulation, when the muscle fibers are activated repeatedly, 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). Irregularities 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 transmissiondi sordersar esummar izedi n Table6.4 . 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 transmissiondi sorders. 3. Dramatic improvement of abnormal decremental response with edrophonium is typical of MG. TABLE 6.4 CharacteristicC MAPc hangesint hedi sorders of neuromuscular transmission Reducedam plitude Normal amplitude Repetitivedis charge LEMS Myastheniagr avis Anticholinesterase toxicity Severe botulism Mild botulism Organophosphate toxicity Magnesium, procainamide, and antibiotic induced paralysis Congenital myasthenia Congenital myasthenia Abnormal decremental response, however, is not pathognomonic of MG. It may also be found in amyotrophic lateral sclerosis, poliomyelitis, multiple sclerosis, 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 clinicalpi 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 uncooperative 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 amplitude 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 postexercise 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 1 mV 6 ms (a) (b) (c) 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. CLINICAL NEUROPHYSIOLOGY
  • 9. 259 INTERPRETATION OF RNS TEST 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 normal (Oh et al., 1982). Presence of posttetanic facilitation 0.5 mV 3 ms FIGURE 6.12 Postexercise 128% augmentation of CMAP amplitude 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. 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 differentiating between presynaptic and postsynaptic neuromuscular 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 abnormal (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. Rest 10 s exercise 2 mV 6 ms (a) 30% 20% (b) 30% 44% 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. CLINICAL NEUROPHYSIOLOGY
  • 10. 260 REPETITIVE NERVE STIMULATION The results of RNS study in pre- and postsynaptic disorders are summarized in Table 6.5. The electrodiagnostic protocol for evaluation of NMJ disorders are summarizedi n Table6.6 . CLINICAL APPLICATION OF RNS STUDY RNS study is one of the most useful electrodiagnostic tests for diagnosing pre- and postsynaptic neuromuscular transmission abnormalities. The role of RNS study in some important NMJ disorders is reviewed in the following section. 4 mV Myasthenia Gravis 4 ms FIGURE 6.14 Thirty hertz RNS study in a patient with myasthenia gravis. The initial incremental response is followed by decremental response. MG is an autoimmune disease of postsynaptic membrane attributed to Ach receptor antibodies and complementmediated 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 200 μV 5 ms BaselineϪ34% (c) 30 s exerciseϪ29% (a) 3 min postexerciseϪ34.7% 2 mV 5 ms (b) (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 response. Stimulation ulnar nerve at wrist, recording ADM. (c) Photograph of the same patient showing ptosis and jaw hanging. He also had cerebellar sign, proximal muscle weakness, and areflexia. (d) Axial CT thorax showing mediastinal mass and biopsy was consistent with small cell lungc arcinoma. CLINICAL NEUROPHYSIOLOGY
  • 11. 261 CLINICAL APPLICATION OF RNS STUDY for confirming the diagnosis of MG neurophysiological (low-rate RNS and single-fiber EMG (SFEMG)), prostigmine test, and AchR antibody assay, RNS study is the first choice for evaluation of MG because it provides immediate, 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 influenced 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 parameters (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 andMac 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 sensitive 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 respiratory 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 capacity was <1 L (Lo et al., 2003). The diagnostic yield of RNS TABLE 6.5 Repetitivene rvestimula tion( RNS)i npr e-a nd postsynaptic disorders Parameters Presynaptic Postsynaptic CMAPampl itude Small Normal Rest Decrement Decrement PEF + ± PEE − + Increment Decrement or normal Low-rateRNS High-rate RNS CMAP, compound muscle action potential; PEE, postexercise exhaustion; PEF, postexercise facilitation. TABLE 6.6 Disorders 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 normal 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). American 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 facilitation 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 exhaustion (Fig. 6.17). The RNS test has also been used for monitoring the effect of treatment. In myasthenic patients with absent or few germinal centers in thymus and a short duration 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 manifest with predominant ocular and bulbar weakness with high frequency of respiratory crisis and relative preservation 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). Electrodiagnostic protocol for the evaluation of pre- and postsynaptic neuromuscular junction transmission disorders RNS rate Train of stimuli Findings Exercise duration Findings Postsynaptic 2–5H z 5–10 CMAPampl ituden ormal >10% decrement 10s 30–60s Facilitation (repair of decrement) Increased decrement after 3–4 min Presynaptic 2–5H z 5–10 CMAP↓ >10% decrement 10 s exercise >100% increment immediately after exercise 20–50H z 100–200 >100%i ncrement Source:M odified from Howard (2013). CLINICAL NEUROPHYSIOLOGY
  • 12. 262 REPETITIVE NERVE STIMULATION TABLE 6.7 gravis Relativeuse fulnessofdiffe rentte stsi nm yasthenia Diagnostic yield (%) Procedure Definite Mild Ocular RNS Hand 68 31 4 Shoulder 89 68 19 100 88–92 59–77 2 88 76–80 70–76 Single-fiberEMG Forearm Face Achr eceptoran tibody Source:Fr om Keesey(1989) . TABLE 6.8 1. 2. 3. 4. 5. LEMS is characterized by weakness and fatigability of proximal limb muscles with relative sparing of extraocular 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 distal muscles is preferred. Three patterns of abnormalities have been described in LEMS: 86–95 2 Lambert–Eaton Myasthenic Syndrome CharacteristicR NSfinding sinmy astheniag ravis NormalCMAP Decrementalr esponseat l ow-rateRNS Normalo rmi nimalpo stexercisefac ilitation Normalo rde crementalr esponseat h igh-rateRNS Postexerciseo rpo sttetanice xhaustion 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 lowrate RNS, and incremental response at high-rate RNS (moret han100%)( Fig.6.19 ). 3. Low CMAP amplitude, decremental response at lowrate RNS, and initial decremental response at highrate RNS. 4 mV 6 ms (a) (b) (c) 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. (a) (b) (c) 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. CLINICAL NEUROPHYSIOLOGY
  • 13. 263 CLINICAL APPLICATION OF RNS STUDY Since type III and I can be misdiagnosed as MG, prolonged high-rate RNS is recommended (50 Hz, 10 s) (Oh,1989 ). The incremental response following high-rate stimulation in LEMS may be of two types (Fig. 6.20): 1. A gradual incremental response from the first CMAP. 2. Initialde crementfo llowedbyi ncrementalr esponse. Although the first is more frequent, the second suggests 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 1 1s 100μ FIGURE 6.18 On concentric needle EMG, there is variability of MUP amplitude in a patient with myasthenia gravis. (a) (b) 0.2 mV 0.4 mV 6 ms 6 ms (c) (d) 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 abductordi gitimi nimi. CLINICAL NEUROPHYSIOLOGY
  • 14. 264 REPETITIVE NERVE STIMULATION 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 postexercise 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, (a) (b) FIGURE 6.20 Pattern of increment following high-rate RNS in LEMS. (a) Classical LEMS, 30 Hz, 100 impulse, and gradual incremental response. (b) More severe LEMS may need 50 Hz, 100 impulse, and initial decrement followed by incremental response. TABLE 6.9 1. 2. 3. 4. Characteristicfinding sofR NSst udyi nLEM S Low-normalCMAP Decrementalr esponseat l ow-rateRNS Postexercisefac ilitation High-rateRNS100%i ncrementi nt womusc les400%i ncrementi n anymusc le CMAP, compound muscle action potential; LEMS, Lambert–Eaton myasthenic syndrome; RNS, repetitive nerve stimulation. 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 manifested 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 contraction 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 potentiation >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 abductor digitorum brevis, 80, 82, and 59%, respectively. In 12% patients with LEMS, no muscle showed increment >100%. This study therefore emphasized that the diagnosis of LEMS should be based on clinical, VGCC antibody, and CMAP amplitude (Tim et al., 1998). AAEM Quality Assurance Committee reviewing the literature suggested that the degree of increment needed to diagnose 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 ; Kalitae tal .,1995 ). Overlap Myasthenic Syndrome Overlap myasthenic syndrome refers to the coexistence of MG and LEMS in the same patient. The 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 NEUROPHYSIOLOGY
  • 15. CLINICAL APPLICATION OF RNS STUDY clinical picture includes oculobulbar symptoms, a positive edrophonium test suggesting MG and areflexia suggesting LEMS. The RNS test shows classical 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 dominant and the remaining are due to autosomal recessive 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 antibody (Fig. 6.22). Some CMSs, however, manifest late with restricted distribution of weakness and intermittent RNS test abnormality making the diagnosis difficult. 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 265 neurophysiological tests have been suggested to be helpful 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 andfi 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 increment is present in botulism, it is less pronounced than inLEMS. Magnesium-Induced Myasthenia Magnesium intoxication can lead to rapidly developing 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, prostigmine, and intravenous calcium gluconate improve the weakness. Antibiotic-Induced Myasthenia FIGURE 6.22 A family suffering from congenital myasthenia; arrows show the affected members who had ptosis and proximal muscle weakness. 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 CLINICAL NEUROPHYSIOLOGY
  • 16. 266 REPETITIVE NERVE STIMULATION 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 poisoning is due to excessive Ach as a result of inactivation of AchE, which results in depolarization block at nicotinic receptors. The RNS study reveals repetitive CMAP TABLE 6.10 discharges to a single stimulus, abnormal decremental response at low rate which is more pronounced at high rate, and worsening of decremental response on edrophonium injection. There are only a few studies on the neurophysiological changes in organophosphate poisoning. In a study on two patients with suicidal organophosphate 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 Typesof c ongenitalm yasthenics yndrome( CMS)a ndt heirc haracteristics Typesof C MS Gene Clinical and neurophysiological characteristics CHAT Sudden bulbar weakness and apnea. 3 Hz RNS— decremental response A.PresynapticCMS 1. Episodic apnea—deficiency of Ach transferase 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. AchEde ficiency COLQ Slowpupi llaryl ightr eflex,r epetitivedi scharges decremental response, no response to AchE inhibitors 2.Lami nin β2 chain-abnormal formation of NMJ LAMB2 CMS with ocular and renal malformation 1.Sl ow-channelsyn 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 -channelsyn 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 i.Rapsyn de ficiency RAPSN Neonatalo nset,ar throgryposis,3H zRNS-de crement ii.D ok-7de ficiency Dok-7 Severel imbgi rdlewe akness,3H zR NS-decrement. iii.MuSkde ficiency MUSK Similart oMG 5.V oltage-gatedNac hannelde fect SCN4A Similart oMG 6. Agrin AGRN Similart oMG 7.CMSwi tht ubularaggr egates GFPT1 Similart oD ok-7de ficiency 8.Ot hersEscobarsyn drome Plectinde ficiency CMSwi thc entronuclearmyo pathy CHRNG PLEC1 Arthrogryposis, pterygium, dyspnea CMS with muscular dystrophy with epidermolysis bulous simplex C. Postsynaptic CMS 4.D efecti n AchRc omplex 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 odified from Lorenzoni et al. (2012). CLINICAL NEUROPHYSIOLOGY
  • 17. 267 CLINICAL APPLICATION OF RNS STUDY palsy, and areflexia. Motor conduction velocity and terminal 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 cholinergic crisis, which lasted up to 18 days. These patients were described as a distinct intermediate syndrome of organophosphate poisoning (Senanayake and Karalliedde, 1987). The RNS studies have been carried out in organophosphate-exposed agricultural workers with the aim of detecting subclinical abnormality in neuromuscular 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 (Misrae tal .,1988 ). 500 ␮V 5 ms RestϪ28.5% 30 s exerciseϪ31.6% 4 min postexerciseϪ36.6% (a) 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 abnormalities. 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, decremental response at 3 Hz stimulation and postexercise or posttetanic facilitation. NMJ transmission abnormalities following various arthropod and snake-bite are summarized in Table 6.11. TABLE 6.11 (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. Types of neuromuscular junction (NMJ) transmission abnormalities following various snake and arthropod bites Source Toxins Site of NMJ involvement RNSs 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 Repetitivedi scharge Ach, acetylcholine; AchR, acetylcholine receptor; NMJ, neuromuscular junction; RNS, repetitive nerve stimulation. CLINICAL NEUROPHYSIOLOGY
  • 18. 268 REPETITIVE NERVE STIMULATION Suspected NMJ disorder NCS two nerves Normal CMAP and SNAP Low CMAP Normal SNAP • ↑Postexercise CMAP in 2 motor nerves • High-rate RNS 50% increment Normal No increment Presynaptic NMJ defect Low-rate RNS ADM, nasalis, trapezius, deltoid Concentric needle EMG Decremental response SFEMG Normal Abnormal Normal ↑Jitter and blocking LEMS or botulism MND, myopathy, neuropathy Concentric EMG Concentric needle EMG Normal Normal MG excluded MG confirmed 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 conduction study; NMJ, neuromuscular junction; RNS, repetitive nerve stimulation; SNAP, sensory nerve action potential; SFEMG, single-fiber electromyography. 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, therefore, a systematic approach is needed. History and clinical 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 carried 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 muscle is preferred. Low-rate RNS if normal and a postsynaptic disorder is strongly suspected, SFEMG of extensor digitorum communis or frontalis muscle should be performed. The electrodiagnostic approach to NMJ disordersi ssh owni n Figure6.24 . The RNS studies are one of the most useful clinical electrodiagnostic tests and are essential for the diagnosis of pre- and postsynaptic neuromuscular transmission disorders. Attention to technical details is extremely important for reliable results and interpretation. CLINICAL NEUROPHYSIOLOGY
  • 19. CLINICAL APPLICATION OF RNS STUDY 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. 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 electrodiagnostic evaluation of patients with suspected myasthenia gravis and Lambert–Eaton myasthenic syndrome. Muscle Nerve 2001;24:1239. Campbell Jr WW, Leshner RT, Swift TR. Plasma exchange in myasthenia gravis: electrophysiological studies. Ann Neurol 1980;8:584. Desmedt JE. The neuromuscular disorder in myasthenia gravis (i) electrical and mechanical response to nerve stimulation in hand muscles. In: Desmedt JE, editor. New developments in electromyography and clinical neurophysiology, vol. 1. Basel: Karger; 1973. p. 241. Elmqvist D. Neuromuscular transmission defects. In: Desmedt JE, editor. New developments in electromyography and clinical neurophysiology. Basel: Karger; 1973. p. 229. Engel AG. Myasthenic syndromes, congenital. In: Aminoff MJ, Daroff RB, editors. Encyclopedia of neurological sciences, vol. 3. Boston: AcademicP ress; 2003.p. 315. Engel A, Santa T. 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