You are in: eMedicine Specialties > Neurology > Electromyography and Nerve Conduction Studies Assessment of Neuromuscular TransmissionArticle Last Updated: May 17, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 15
 
Author: Stephen A Berman, MD, PhD, Professor, Department of Internal Medicine, Section of Neurology, Dartmouth Medical School; Chief, Neurology Service, White River Junction Veterans Medical Center Stephen A Berman is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Phi Beta Kappa Coauthor(s): Donald B Sanders, MD, EMG Laboratory Director, Professor of Medicine (Neurology), Division of Neurology, Duke University Medical Center Editors: Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants Author and Editor Disclosure Synonyms and related keywords: assessment of neuromuscular transmission, motor signals, neuromuscular transmission, NMJ, neuromuscular junction testing, repetitive nerve stimulation, Harvey-Masland test, Tensilon test, single-fiber EMG, myasthenia gravis, MG, acetylcholine, Lambert-Eaton myasthenic syndrome, LEMS, conventional needle electromyography, congenital myasthenic syndromes, slow channel syndrome, congenital acetylcholinesterase deficiency, low-affinity fast channel syndrome, botulism, botulinum toxin INTRODUCTIONSection 2 of 15
 
Our current understanding of how the motor signal travels from nerve to muscle came to us through the efforts of clinical and basic scientists whose work represents an amazing triumph of human understanding. Equally amazing is the fact that we can analyze many aspects of these minute molecular and cellular processes in the clinic or at the bedside by using the relatively simple methods discussed in this article. This is truly one of the best examples of what is now called translational research (ie, application of basic science knowledge to the clinical situation). The modern physician usually thinks of myasthenia gravis (MG) when hearing the term neuromuscular junction (NMJ). This is entirely appropriate because research on MG has always been at the center of our understanding of the NMJ. A brief history is discussed. The first patient with MG ever to be described in medical writings may have been a Native American named Chief Opechankanough. Accounts of his weakness and ptosis, which improved with rest, were given by colonial physicians who examined him in the early 1600s and who sent accounts of his condition back to England. These accounts were not published in a formal medical journal. Chief Opechankanough was the uncle of a much more famous Native American named Matoaka (better known as Pocahontas). In 1672, Thomas Willis (known for the Circle of Willis) described and published the case of an English woman who also probably had MG. These physicians had no idea about the origin of the disease. Numerous cases were noted after that. In 1879, William Erb described several. In 1893, Samuel Goldflam gave excellent clinical descriptions. In 1895, Friedrich Jolly originated the term myasthenia gravis pseudoparalytica. He also pioneered one of the assessment methods discussed later; the method is now called repetitive stimulation, but some still call it the Jolly test. Still, there was little clue regarding the basic etiology of the condition. The next great advance came in the 1930s when the English doctor, Mary Broadfoot Walker (one of the first British female physicians), showed that injections of physostigmine could temporarily increase the strength of persons with MG and reverse such symptoms as ptosis. She reported her findings in the Lancet in 1934. The modern Tensilon test, another assessment method described later, is essentially the same as Dr Walker's technique. Her work, especially when combined with the basic pharmacologic studies of such contemporaries as Dale and Feldberg on cholinergic neuromuscular transmission, was a clear indication that some aspect of cholinergic transmission at the nerve-muscle synapse was impaired in MG. However, the nature of the impairment and how it could be further assessed were still unknown. About 30 years before Dr Walker's triumph, another clue along a different line was discovered—the immune system. In 1901, the famous pathologist Karl Weigert noted that lymphoid cells were present in muscle and other tissue of persons with MG and made the connection between MG and thymic hypertrophy and/or neoplasia. In 1905, neurologist E. Farquhar Buzzard noted collections of lymphocytes ("lymphorrhages") in muscle and other tissue of those with MG. In 1936, similar findings led clinician-scientist E. H. Norris to consider the thymus as a fundamental source of the pathology in MG. In fact, clinicians began to use thymectomy as a treatment of MG shortly after Weigert's and Buzzard's observations. At first, they operated for actual thymoma but later for thymic hyperplasia and ultimately for MG without any apparent thymic abnormality. In 1911, Ernst Ferdinand Sauerbruch, who then practiced in Throughout the first part of the 20th century, evidence connecting the thymus and immunity to MG continued to accumulate. In 1960, Dr John A. Simpson enunciated an interesting hypothesis: the cause of MG "is an ‘auto-immune' response of muscle in which an antibody to end-plate protein may be formed." Some later authors referred to this as "guessing it right," but it was far more than a guess. He had a deep understanding of disease processes and profound knowledge of other immunologic processes, which he brought to bear on the question. He thoroughly understood the neuromuscular assessment techniques of his day, and he had the overall insight and knowledge to make a brilliant extrapolation. Nonetheless, he really did not prove his case, and many other competing hypotheses remained active for almost 15 years. The two big points of contention were the following: (1) which side of the nerve-muscle junction contained the defect in MG—the presynaptic nerve endings or the postsynaptic motor endplate and (2) what was the fundamental etiology of the disease? Was it really autoimmune as Simpson speculated? In the 1970s, a tremendous amount of information came together about the neuromuscular junction. Use of a snake toxin, alpha-bungarotoxin, which bound specifically to certain portions of the acetylcholine receptor (AChR) was pioneered by pharmacologists C. C. Chang, C. Y. Lee, and L. F. Tseng. Pioneering work by clinician-scientists such as Andrew Engel, Douglas Fambrough, Edward Lambert, Vanda Lennon, Daniel Drachman, Eric Stalberg, Joze Trontelj, Jan Ekstedt, John Newsom-Davis, David Richman, Marjorie Seybold, and Klaus Toyka helped tie together the emerging immunologic/neurophysiologic linkages that hinted strongly at the postsynaptic immunologic nature of the disease. The group at the Salk Institute, especially Jim Patrick, Jon Lindstrom, and their associates, raised antibodies to various subunits of the receptor and ultimately showed that the disease could be reproduced by antibodies to AChR. Largely as a result of the scientific focus on the neuromuscular junction related to MG and other neuromuscular junction diseases, today we have a highly detailed knowledge of the basic science behind neuromuscular transmission. Although there are still aspects that are not known, the essential framework is well known to most first- or second-year medical students. As a simple summary, the major steps are listed below.
Perhaps as amazing as our ability to understand what goes on at the myoneural synapse, is the fact that we can even assess many parts of this detailed molecular process right in our medical offices using techniques and devices that are not exotic or costly. The clinician now has at least 4 ways of assessing neuromuscular transmission:
In the following sections, how these 4 types of assessments apply to MG is described in detail. In so doing, the major features of the assessment methods are documented. Then, many of the other neuromuscular junction disorders and how the assessment methods apply to them are discussed. MYASTHENIA GRAVIS: CLINICAL EVALUATIONSection 3 of 15
History A hallmark of MG is fatigability, particularly greater fatigue and weakness toward the end of the day. Unfortunately, this is not very specific. Often, a more specific question is "If you rest for a few minutes, does that temporarily restore your ability to continue?" However, this is also not highly specific and should not be confused, in the case of walking, with the effect of rest on the pain experienced from claudication or pseudoclaudication. A history of diplopia, ptosis, difficulty swallowing, or other bulbar signs is common in MG, although, of course, they are present in other entities. Physical examination The physical examination typically flows out of the history, and one should be especially careful to follow up and specifically test for any problems that have been mentioned. Fatigability can be tested, at least to an extent, by asking the patient to perform repetitive motions or to hold fixed postures. Often, the examiner can use him or herself, or another observer, as a control. Following up on what has been mentioned in the history is often best. Eyelid function, especially the ability to keep the eyes open, is one of the easiest things to observe, and if MG is suspected, it is probably worth testing even if the history of ptosis is not definite. In fact, because ptosis is such a common sign in MG, many physicians have focused upon it and developed a number of diagnostic methods to use ptosis as an index of impaired neuromuscular transmission, especially in MG. Knowing some of the relatively easy physical diagnostic methods of detecting ptosis can be useful. None of these are specific for MG or for any type of neuromuscular transmission, but, in the proper setting, they can be very helpful. The Simpson test is the simplest. Simply ask the patient to look up at a fixed point for an extended period. This frequently brings out the ptosis in a patient with MG, ie, preexisting ptosis may become more exaggerated after this maneuver or one may see ptosis that was not initially present. A possibly quicker test is to look for a Cogan lid twitch sign. Ask the patient to look down and then rapidly look up. Often in MG, one or both eyelids will overshoot the final position. The lid will go up and then drop down a little into a ptotic position. One can ask the patient to try this several times. Another rapid test, the extended fatigue and recovery bedside test, has recently been published by Toyka.1 If the patient does not initially have ptosis, one can provoke it as in the Simpson sign. Then, instruct the patient to close both lids maximally for 10-30 seconds. Next, ask the patient to open both eyes. Initially upon opening, the ptosis may go away, only to return again in 10-30 seconds. Also, sometimes on opening, one will see the Cogan lid twitch sign. The above tests depend essentially on the fatigability of the neuromuscular junction. The test for enhanced ptosis brings the central nervous system into play. If a patient has ptosis in one eye but not the other eye, simply hold the ptotic eye open (ie, pull the lid up further than the patient can do on his or her own). Frequently, this will cause ptosis to appear in the other eye. The reason is supposedly that the CNS is directing more effort to keeping the ptotic eye open. However, according to the Herring law, the CNS distributes the impetus to both eyes. Thus, by helping the patient keep the ptotic eye open, the CNS is tricked into reducing the effort and this brings out the ptosis in the other eye. Ice pack test The ice pack test can be viewed as a transition between the clinical methods listed above and the more complicated studies discussed later. The above tests use no equipment. For the ice pack test, a simple ice pack made from a rubber glove with ice in it can be used (be sure to tie the glove so the ice does not fall out). The idea behind this test is also simple. Mild-to-moderate cooling tends to ameliorate the deficits seen in MG. Thus, cooling applied to the area of the deficit, such as the eye in the case of ptosis, should produce improvement. This test is often useful in those cases where one would like to do an edrophonium chloride (Tensilon) test for ptosis, but Tensilon is not available. Also, in the case of very old or medically unstable patients, use of Tensilon may be risky, but holding an ice pack over the eye for a minute or two is unlikely to cause harm. A positive result is one in which the ptosis significantly diminishes in the cooled eye. This test is generally believed to have good sensitivity and specificity, though it is probably more subject to false-positive and false-negative results than the Tensilon test. Tensilon test Weakness from abnormal neuromuscular transmission improves after intravenous administration of Tensilon. For a Tensilon test result to be considered positive, a dramatic, unequivocal improvement in muscle function should be observed directly by the examiner. This test is most reliable when the patient has ptosis, ocular muscle weakness, or nasal speech, and results are positive in about 90% of such patients. Strength after Tensilon also may improve in motor neuron disease and in lesions of the oculomotor nerves. When performing the Tensilon test, select only a few muscle functions to be tested, and observe the degree of weakness in these muscles for several minutes before administering Tensilon. The best dose of Tensilon varies among patients and cannot be determined in advance. Administration of 10 mg in fractional doses is commonly recommended. After an initial injection of 2 mg, the response in the selected muscles is monitored for 60 seconds. Subsequent injections of 3 and 5 mg then are given. If definite improvement is seen within 60 seconds after any dose, no further injections are necessary. Total dose in children is 0.15 mg/kg. An AMBU bag should be handy when administering Tensilon because some people are supersensitive to even small amounts. Worsening weakness after administration of these doses of Tensilon (a paradoxical response) is also an indication that neuromuscular transmission is impaired. Bradycardia is a possible adverse effect, particularly in elderly patients. Especially for elderly person, ECG monitoring is advisable, and some hospitals require it for inpatients receiving the Tensilon test. A syringe with atropine sulfate, which may be administered if necessary, also should be available when injecting Tensilon. In the past, many have advocated also giving a placebo in a single-blinded fashion (ie, the patient does not know which injection is the Tensilon and which is the placebo). Usually, this has little usefulness, and it should not be necessary with a well-defined endpoint, such as relief of ptosis. There may be an occasional case in which giving placebo versus Tensilon may help clarify whether an actual response versus a placebo reaction occurs. However, in many cases for which the placebo used to be most strongly advocated, such as a patient strongly suspected of malingering or who gives a strong impression of hysteria, it may be best not to do the Tensilon test at all. Patients receiving both Tensilon and placebo generally say, if asked, that they can tell which is which by the way the Tensilon makes them feel. Therefore, if a placebo is used, it should be given first. Also, some patients may later resent the placebo because they feel that it is an attempt to "trick" them (which, Patients who do not respond to Tensilon may respond to intramuscular neostigmine, which has a longer duration of action. This is particularly useful in infants and children, whose response to Tensilon may be too brief for adequate observation. In some, a therapeutic trial of oral pyridostigmine for several days may produce improvement that cannot be appreciated after a single dose of Tensilon or neostigmine. Unlike most patients with MG, many patients with MUSK-positive MG, a variant, do not improve with Tensilon or pyridostigmine. Immunologic testing Three available antibody tests pertain to MG: (1) anti-acetylcholine receptor (anti-AChR) antibody test, (2) anti-striated muscle (anti-SM) antibody test, and (3) anti-MUSK test. The anti-AChR antibody test is the mainstay of immunologic testing. It is a good test with a high sensitivity and an extremely high specificity. The sensitivity varies with the clinical presentation of the MG. For patients with generalized MG, the sensitivity is roughly 85-90%. For ocular MG, sensitivity is 50-60%. The specificity is very high, although, interestingly, false-positive results are not uncommon in Lambert-Eaton myasthenic syndrome (LEMS). False-positive results are also seen in thymoma without MG and lung cancer. Anti-SM antibodies are a reasonably sensitive and specific marker for the existence of thymoma, especially in the younger patient (<40 y). In older patients, they are less specific for thymoma. Thus, in a patient already believed to have MG, a positive anti-SM test result should prompt a very thorough check for thymoma (via chest MRI and/or CT scan with and without contrast). If the scan results are negative, a follow-up scan within a year of diagnosis may also be a good idea. However, the anti-SM antibody test is not primarily a test for MG itself. Recently, it has been learned that some of the previously antibody-negative patients with MG (ie, those who have a negative test result for anti-AChR antibodies) test positive for antibodies to MUSK. The percentages vary from series to series, but roughly 50% of the previously antibody-negative patients have a positive anti-MUSK test result. Patients with positive anti-MUSK MG are predominantly women.2, 3 The distribution of muscle involvement may be different than that seen in the more common AChR antibody-positive MG. One group has found that anti-MUSK-positive patients display significant oculobulbar involvement less frequently than typical anti-AChR-positive patients and more frequently show neck, shoulder, and respiratory muscle involvement. In addition, they found no purely ocular cases.2 In a follow-up study, they found the patients with anti-MUSK myasthenia were more likely to have respiratory symptoms and neck extensor weakness and less likely to show single-fiber EMG abnormalities in the limb muscles as compared to anti-AChR myasthenic patients. In addition to the previously known female preponderance, anti-MUSK patients tended to be younger and a larger proportion were African American.4 Another group has noted greater impairment of facial and bulbar muscle function in the anti-MUSK-positive group.5 A third group used quantitative measures of oculobulbar, facial, and respiratory muscle involvement and concluded that they did not see a significant difference in distribution of muscle weakness between their MG patients with anti-AChR antibodies and those with anti-MUSK antibodies.6 Each of these series had on the order of 20-30 patients; thus, we await larger studies. Also, the limited studies so far suggest that less thymic pathology may exist in anti-MUSK MG, but it seems that thymectomy may still confer a benefit. REPETITIVE NERVE STIMULATIONSection 4 of 15
Electrodiagnostic studies are used to demonstrate abnormal neuromuscular transmission and to exclude other diseases of the motor unit that mimic or contribute to the clinical findings. Such studies may also be useful in measuring the severity of involvement and demonstrating changes as the disease evolves or improves. The most commonly used electrodiagnostic test of neuromuscular transmission involves repetitive stimulation of a motor nerve (RNS) while recording compound muscle action potentials (CMAP) from a muscle innervated by that nerve. This is essentially the Jolly test originated by Dr Friedrich Jolly, as mentioned in the Introduction. In his recordings, he quantified the force produced by the muscle rather than the CMAP (however, the force generally correlates with the CMAP). The result is abnormal if progressively fewer muscle fibers respond to nerve stimulation during a train of stimuli, producing a "decrementing" pattern in the CMAP (see Media file 1). Although the technique is straightforward, it is not without technical pitfalls for the unwary. Most common errors result from movement of the recording electrode, variations in the stimulus intensity, and inadequate warming of the muscle. Recording technique Surface recording electrodes are placed so that an initial sharp negative (upward-going) deflection of the CMAP is produced by supramaximal nerve stimulation, indicating that the active electrode is over the motor point of the muscle. The reference-recording electrode should be over a distal point where electrical activity from the muscle is minimal. Intramuscular needle electrodes should not be used to record the responses, since they cannot be kept at a constant position within the muscle during nerve stimulation. Appropriate joints should be immobilized to minimize movement artifact. Muscle temperature Decremental response in MG is lessened when the muscle is cool. When the abnormality is mild, no decrement may be seen unless the muscle is warmed. Hand or foot muscles should be warmed to a surface temperature of at least 34°C to obtain maximum diagnostic sensitivity. Cooling is not as great a factor in proximal muscles, which need not be warmed before testing. Stimulation technique Stimulation of the motor nerve usually is performed with surface electrodes. Stimulation also can be performed with near-nerve needle electrodes, in which case, shorter-duration and lower-intensity stimulation pulses may be used, which are less painful when the needles are placed optimally. To ensure maximal responses throughout the testing session, the stimulus intensity should be 10-25% greater than required to activate all muscle fibers. A decremental response in MG is best demonstrated at stimulation rates of 3-5 Hz. Some laboratories also use 2 Hz. Decrement increases with the stimulation rate, up to 10 Hz. At rates greater than this, the CMAP size may increase during stimulation (ie, potentiation), and artifacts due to movement are common. Amplitude increments up to 50% have been reported in normal muscle with stimulation at rates of 10-50 Hz. Potentiation may result from an increase in the number of activated muscle fibers (ie, facilitation) or from an increase in the amplitude or summation of action potentials of the individual muscle fibers (ie, pseudofacilitation) (see Media file 2). Facilitation results when 2 or more nerve action potentials occur within a short time, producing a transient increase in the amount of ACh released from the motor nerve. Each nerve depolarization releases calcium into the periterminal space, which increases the local concentration of calcium for a short period of time. If the nerve depolarizes during this period, the increased calcium increases the number of ACh quanta released. In conditions of impaired neuromuscular transmission, this greater ACh release may improve synaptic transmission briefly, producing facilitation. Pseudofacilitation has been attributed to increased synchronization of muscle fiber action potential propagation velocities or to hyperpolarization of the muscle fiber membrane from increased sodium-potassium pumping. In normal muscle, pseudofacilitation may increase the CMAP amplitude 50% during stimulation at rates up to 50 Hz. This can mask a decrementing response or may be mistaken for true facilitation. Measurement technique The size of the CMAP may be assessed by measuring either the amplitude or the area of the negative peak of the CMAP. The CMAP should be observed at a fast display sweep speed (50-100 msec sweep duration) during repetitive stimulation to detect technical artifacts. Movement of the stimulating electrode or the muscle may produce irregular patterns of change in CMAP size during trains of stimuli (these do not correspond to patterns expected in disease). In MG, the typical pattern is a progressive decrement of the second through the fourth or fifth response, with some return toward the initial size during the subsequent responses, a so-called U-shaped pattern (see Media file 1). This pattern also is seen in Lambert-Eaton myasthenic syndrome (LEMS), motor neuron disease, and rarely in peripheral nerve disease. Changes in CMAP size are quantified by calculating the percentage change in amplitude (or area) between the first and a later response, usually the fourth or fifth response in a train. Stimulation at rates of 3-5 Hz may produce a decrement up to 8% in normal muscles. A decrement greater than 10% usually is abnormal. Even a decrement of 5% may be considered abnormal if artifacts demonstrably are not responsible for the change. The following observations help distinguish true decrements from artifactual changes in CMAP size:
If no decrement is seen before or after activation, mild abnormalities in MG may be revealed during the exhaustion period that follows prolonged nerve stimulation at slow rates (3 Hz for 4-5 min). Producing ischemia in the tested muscle during the period of prolonged stimulation and subsequent exhaustion may enhance the sensitivity of this technique further. To do this, a blood pressure cuff is placed around the upper arm and inflated to above systolic pressure, and a distal nerve is stimulated. In patients with MG who have normal RNS studies in the hand muscles, this enhancing technique has been shown to be slightly more sensitive than repetitive stimulation of the trapezius; however, it is only 60% as sensitive as single-fiber electromyography (EMG) of the hand muscle. ELECTROMYOGRAPHYSection 5 of 15
Conventional needle electromyography This is not always appreciated, but study of the motor unit action potentials (MUAPs) with the standard concentric or monopolar EMG needles can actually provide considerable information about transmission at the neuromuscular junction. The abnormality appears in EMG recordings as variability in the shape or amplitude of MUAPs (see Media file 5). This occurs, because with a neuromuscular junction problem, the muscle fibers that are part of the motor unit do not always fire in the same sequence. In addition, some of them fail to fire. The fact that the sequence varies is reflected in the idea of "jitter," which is discussed in the next section (single-fiber electromyography). The fact that sometimes some of them fail to fire at all is actually the same thing as the "blocking" discussed in single-fiber electromyography. Unstable MUAPs also are observed in denervating disease, especially motor neuron disease; thus; MUAPs are not specific for MG. When seen without other evidence of neuronal disease, unstable MUAPs should prompt an assessment for MG or other disease of neuromuscular transmission. Single-fiber electromyography Single-fiber EMG (SFEMG) is the most sensitive electrodiagnostic test of neuromuscular transmission. SFEMG demonstrates increased jitter in a limb or face muscle in almost all patients with MG. Because of its marked sensitivity, SFEMG also demonstrates abnormal jitter in other nerve and muscle diseases; thus, the results must be interpreted in conjunction with the results of more conventional electrodiagnostic studies. The details of this technique are well described in the eMedicine article Single-Fiber EMG by Stickler and Sanders. However, some basic principles of the single-fiber method are described below. The single-fiber technique was developed by Stalberg and Ekstedt in order to study muscle fatigue. It is the most sensitive test of dysfunction at the neuromuscular junction. Ordinarily, it requires a special needle electrode. The needle is thin, 25 μm in diameter, but no thinner than most monopolar needles or the smaller concentric needles. Its configuration is quite unusual. Although it has a pointed bevel at the very tip, the opening for the recording surface is located on the side, a bit proximal (3-5 mm) to the tip. The recording surface is very small, and the volume of tissue from which it effectively records is tiny, only about 300 μm3 compared to 1 cm3 for most standard concentric needles. Another factor that limits the range from which significant potentials can be recorded is the filter setting. Single-fiber EMG typically uses a 500-Hz high-pass filter. This filter attenuates the lower frequency distant Because of the small size of the area sampled, a single-fiber needle is able to pick up and discriminate potentials from single nearby muscle fibers, as opposed to the composite motor unit potential (MUP) (also called motor unit action potential [MUAP]), which is picked up by the standard monopolar or concentric EMG needle. The examiner asks the patient to contract a muscle slightly with the single-fiber needle in place. Under those circumstances, the needle usually records a single MUP at a time. However, occasionally, it picks up two MUPs that fire at slightly different times. Because the recording volume of the needle is so small, it is a good bet that the two MUPs are coming from two individual muscle fibers that are very close together and which are part of the same motor unit. As the muscle continues to contract, one might expect that if muscle fiber Ma contracted T microseconds before muscle fiber Mb, then each time Ma contracts Mb will contract exactly T microseconds later. Of course, biological processes always have some variation, but if one tries to keep all conditions the same, the differences should be small. Indeed, for normal neuromuscular junctions they are small, usually in the range of 10-50 microseconds (ms). However, when a problem occurs with the function of the neuromuscular junction, A second type of abnormality that may be observed is called blocking. Assuming that one has found a pair of fibers that tend to fire one after the other, blocking is the failure of one of the two to fire at all. One could look at it as the extreme case of exaggerated jitter (ie, the interval goes to infinity). If blocking occurs, then actual weakness of the muscle should be present because this means that some of the fibers that should be consistently firing and contracting are not always contracting. Muscles with a significant amount of blocking should also show a decrement when tested with repetitive stimulation. However, muscles with only an increased jitter will generally not show significant weakness, and they are the ones that are generally negative (ie, normal) on repetitive stimulation but abnormal on single-fiber studies. The excessive jitter and the blocking contribute to an unstable appearance of the MUAPs in MG and other diseases of neuromuscular transmission. Stimulated single-fiber EMG Some patients are unable to voluntarily contract the muscle in order to allow SFEMG to be performed. In those cases, often the examiner can produce the contraction by electrically stimulating a branch of the nerve innervating the muscle. See Single-Fiber EMG for more detail. RNS VERSUS SINGLE-FIBER EMGSection 6 of 15
RNS demonstrates an abnormal decrement in a hand or shoulder muscle in 75% of patients with generalized MG and in only 50% of patients with ocular MG. Testing a facial muscle increases the yield somewhat, especially in patients with weakness that predominates in these muscles. SFEMG demonstrates abnormal jitter in at least 1 muscle in 99% of patients with generalized MG and in 97% of those with ocular MG. Increased jitter and blocking frequently are found in muscles in which no decrement is seen on RNS, but the converse is not observed. SFEMG is most valuable clinically in the patient with suspected MG in whom other tests of neuromuscular transmission and AChR antibody measurements are normal. When abnormal neuromuscular transmission has been demonstrated by RNS, the finding of abnormal jitter does not add to the diagnosis, although baseline jitter values may be useful for comparison with subsequent studies. In patients with MUSK-positive MG, RNS and SFEMG studies are frequently normal in commonly tested muscles, and examining the most severely involved muscles to demonstrate a decremental response or abnormal jitter may be necessary. LAMBERT-EATON MYASTHENIC SYNDROMESection 7 of 15
LEMS is described in the eMedicine article Lambert-Eaton Myasthenic Syndrome. The emergency department aspect is reviewed in Lambert-Eaton Myasthenic Syndrome. Some key points that particularly highlight neuromuscular transmission are discussed here. LEMS is caused by autoantibodies to the voltage-gated calcium channels (VGCC) on the presynaptic side of the neuromuscular junction. Frequently, it is a paraneoplastic disease (remote effect of cancer), with the most common cancer being small-cell carcinoma of the lung (SCLC). Tests for these antibodies are now commonly available. Although thinking of LEMS as the opposite of MG should be avoided, some aspects of LEMS are, more or less, the opposite. LEMS is presynaptic, whereas MG is postsynaptic. Regarding points that can be discerned on history and physical examination, patients with MG typically have considerable bulbar weakness and those with LEMS usually do not. In LEMS, the most common weakness is in the legs, especially the proximal muscles. In addition, it is not uncommon for patients with LEMS to report an increase in strength with repeated exercise rather than a decrease as in MG. With continued exercise, however, weakness will eventually develop. In about one half of patients, an increase in strength with exercise does not occur. Responses to RNS are highly characteristic in LEMS. CMAP amplitudes are small, often less than 10% of normal, and a decrementing pattern is observed with low-frequency stimulation (see Media file 6). The most characteristic electrodiagnostic feature is facilitation, which is an increase in the size of the CMAP after activation by maximum voluntary contraction or during stimulation at rates of at least 20 Hz. The degree of facilitation varies considerably among patients with LEMS. Findings may be masked partially by low muscle temperature; thus, tested muscles should be warmed for best results. Facilitation greater than 100% (doubling of the CMAP from resting values) most frequently is observed in hand muscles. Not all muscles show this pattern; in some patients with LEMS, facilitation may be less than 100% in all muscles tested. Characteristic findings are demonstrated in most patients with LEMS by the following protocol:
Perform these measurements in at least 1 hand and 1 foot muscle. If facilitation less than 100% is seen in a hand muscle, another hand muscle should be tested. Nerve stimulation at 20 Hz may be used instead of voluntary contraction to activate the muscle, although the authors find the voluntary contraction technique to be more sensitive and less painful. The size of the maximum CMAP after stimulation for 5-7 seconds is compared with that of the initial response (see Media file 3). Measuring the area of these CMAPs is difficult, so the amplitudes usually are measured instead. In patients with LEMS, MUAPs are unstable and vary in shape during voluntary activation. The jitter measured by SFEMG is increased markedly, frequently out of proportion to the severity of weakness; impulse blocking is frequent. In many endplates, jitter and blocking decrease as firing rate increases. This pattern is not pathognomonic for LEMS and may be observed in some endplates in patients with MG. Thus, improvement of jitter and blocking at higher activation rates (unless dramatic) does not indicate a presynaptic abnormality. Overlap syndrome The seemingly opposite nature of some of the MG findings versus the LEMS findings are not invariably found. Either one of these diseases can somehow imitate the other in what is sometimes called an overlap syndrome. Thus, no single clinical or electromyographic feature distinguishes MG from LEMS in all patients. Some patients with clinically typical MG have facilitation greater than 50% or even up to 100% in some muscles at high stimulation rates. Conversely, patients with LEMS may have EMG features more characteristic of MG at some point during their illness. CONGENITAL (GENETIC) MYASTHENIC SYNDROMESSection 8 of 15
Several forms of myasthenia are due to genetic defects and have no immunologic abnormality. Some forms of genetic myasthenia have characteristic electrodiagnostic findings. Congenital myasthenia This clinical term is used to describe patients with one of several genetic neuromuscular defects who usually have ophthalmoparesis and ptosis at birth or shortly thereafter. Electrodiagnostic findings are similar to those of acquired MG. RNS studies demonstrate a decremental response, which is corrected by edrophonium, and SFEMG shows increased jitter. Intracellular recordings of muscle biopsy samples must be obtained to determine the physiologic abnormality and the specific diagnosis in these patients. In some of these diseases, the specific gene is now known, and the potential for diagnosis via genetic testing exists. This is an area of active ongoing research, and new mutations continue to be discovered. Listed below are some of the major variants together with their Online Mendelian Inheritance in Man (OMIM) number. OMIM is a comprehensive human gene catalog edited by Dr. Victor A. McKusick and his colleagues and placed on the Web by the Congenital myasthenic syndrome associated with episodic apnea Congenital myasthenic syndrome associated with episodic apnea is also called familial infantile myasthenia (OMIM #254210). This form of congenital myasthenia has unique clinical and electrophysiological features. Physiological studies in familial infantile myasthenia have demonstrated findings consistent with abnormalities of ACh synthesis, resynthesis, or mobilization. The Mayo Clinic group has identified many specific mutations in the choline acetyl transferase (ChAT) gene on chromosome arm 10q that give rise to this condition. However, another mutation on chromosome 17 (near or actually in the gene for Synaptobrevin-2) appears to produce the same phenotype. Weak muscles usually have a decremental response to RNS. Strong muscles may have a decremental response only after sustained voluntary muscle activity or prolonged nerve stimulation (see Media file 8), performed as follows: Stimulate the nerve at 3-5 Hz for 5 minutes, then deliver brief trains of 3- to 5-Hz stimuli. These trains demonstrate a decrement that clears over a 20- to 30-minute period and can be corrected by Tensilon. Slow channel syndrome In slow channel syndrome (OMIM #601462), the underlying physiological cause of the abnormalities is a prolonged open time of the AChR ion channel (ie, the channel closes too slowly, hence the name slow channel syndrome). This can be caused by a number of mutations. Typically, they are autosomal dominant mutations in the alpha, beta, delta, or epsilon subunits of the AChR. Rarely, the mutation is autosomal recessive (and in that case, it is usually an epsilon mutation). This syndrome may not produce weakness until the patient is an adult, which makes distinguishing it from acquired MG difficult. Because most of the cases are autosomal dominant, if a dominant family history is found in what otherwise looks like acquired MG, this extremely rare condition needs to be considered. RNS studies produce a decremental response. Characteristic repetitive discharges are seen after single-nerve stimulation in most, but not all, muscles. Electrodiagnostic findings are similar to those seen with cholinesterase (ChE) inhibitor toxicity and congenital acetylcholinesterase (AChE) deficiency (see Media file 9). Congenital acetylcholinesterase deficiency In congenital AChE deficiency (OMIM #603034), weakness of facial, oropharyngeal, neck, and limb muscles is noted in the neonatal period (or shortly thereafter). Patients show generalized weakness, which is exacerbated by exertion. Frequently, the pupillary light reflex is slowed (or even absent), and ophthalmoparesis may be present. Scoliosis also may be present. The severity of the different symptoms varies considerably from patient to patient. The disease is caused by an autosomal recessive gene (COLQ; 603033) that codes for the collagenlike tail of endplate AChE. Histochemical stains show that AChE is absent from the nerve terminals, which are reduced in size and exhibit a reduced postsynaptic membrane density and degeneration of the postsynaptic folds. Anti-AChE medications such as physostigmine have no beneficial effect, as one would expect; sometimes, they have a detrimental effect (possibly because a small amount of residual AChE activity exists, which is blocked). RNS produces a decrement on 2-Hz stimulation in all muscles. Single-nerve stimulation produces repetitive CMAPs 6-10 milliseconds after the initial response, which fade quickly during repetitive stimulation, even at rates as low as 0.2 Hz. This is similar to findings in slow channel syndrome (see Media file 9). Low-affinity fast channel disease The symptoms of low-affinity fast channel disease (OMIM #608930) are somewhat variable. Usually, patients have weakness of ocular muscles with mild-to-moderate weakness of musculature of the face, neck, trunk, limbs, or (more worrisome) respiratory muscles. Like most other types of myasthenia, there is easy fatigability. During infancy, children frequently manifest a poor cry and hypotonia. The genetics of fast channel disease are usually autosomal recessive, but some autosomal dominant cases have been found. The problem is caused by mutation in certain subunits of the acetylcholine receptor such as alpha 1, epsilon, and delta. On electron microscopy, the morphology appears intact: the synapses look normal with normal-appearing junctional folds and a normal distribution of AChRs. Some response to anti-AChE medications, such as pyridostigmine, occurs, but a better response occurs to 3,4-diaminopyridine (3,4-DAP). The basic neurophysiology is interesting. The kinetics of the openings and closings of the channel are roughly the opposite of what is seen in slow channel syndrome (ie, in fast channel syndrome, it opens too slowly and closes too fast). Fewer, shorter openings are available, thus a decreased number of openings and an even greater decrease in the open time. This leads to small miniature endplate potentials (MEPPs) and small miniature endplate currents (MEPCs). However, quantal content (amount of ACh in each vesicle) is normal. In clinical neurophysiologic studies, decremental responses are seen on repetitive stimulation (but not very many patients have been studied). The authors could not find published studies of single-fiber EMG in fast channel syndrome. From the physiology, it would be expected to be abnormal. In the hereditary congenital myasthenia, mutations are found in all the known important parts of the neuromuscular junction: AChR (acetylcholine receptor) mutations; mutations in one of the associated membrane proteins (rapsyn); AChE (acetylcholinesterase) mutations; Chat (choline acetyl-transferase) mutations; and mutations in (or near) synaptobrevin, one of the proteins involved in vesicle fusion. BOTULISMSection 9 of 15
Botulism is discussed in several other eMedicine articles: emergency and terrorist aspects in CBRNE - Botulism by Taillac and Kim, a pediatric perspective in Botulism by Tolan and Fratarelli, an infectious disease perspective in Botulism by Chan-Tack and Bartlett, and an ophthalmologic perspective in Botulism by Patel and Taylor. Other articles on botulinum toxin and its uses include Botulinum Toxin (BOTOX®): Dystonia Treatment, BOTOX® Injections, Botulinum Toxin, and Botulinum Toxin: Overview. First, the basic science facts about how botulinum toxin works are reviewed. Botulinum toxin is a presynaptic blocker. In order for the neuronal cell to release ACh into the synaptic cleft, the synaptic vesicles that contain the ACh must fuse with the membrane. This fusion requires a synaptic fusion complex that is composed of SNARE proteins. SNARE proteins are involved in the release of numerous neurotransmitters in many species from mammals through yeast, and they are part of a large superfamily of proteins. For ACh release at the neuromuscular junction, some of the key SNARE proteins are synaptobrevin, SNAP-25, and syntaxin I. Botulinum toxin, which can bind to the nerve cell membrane and be taken up by endocytosis, cleaves some of these proteins. In particular, botulinum toxins A, C, and E cleave SNAP-25 (the commercially available Botox® and Dysport® are both type A). Types B, D, F, and G cleave synaptobrevin (Myobloc® and Neurobloc® are type B). Type C also cleaves syntaxin. Any of the cleavages can block the formation of the complex, thus blocking ACh release and consequently blocking muscle contraction. The history and physical examination can provide many clues about whether botulism is a possibility. Remember the potential sources of the disease. As described by Taillac and Kim7 (see CBRNE – Botulism), the categories include the following:
With regard to physical (neurologic) findings, these are generally symmetric, and the "dozen D’s", as noted in the Taillac and Kim article (see CBRNE – Botulism), that summarize the neurologic involvement should be considered: "dry mouth, diplopia, dilated pupils, droopy eyes, droopy face, diminished gag reflex, dysphagia, dysarthria, dysphonia, difficulty lifting head, descending paralysis, and diaphragmatic paralysis."7 The dilated pupils in particular and a poor pupillary contraction to light in general are not part of MG, though they are common findings in botulism poisoning. Dry mouth also is a feature of botulism that is not seen in MG (but it is seen in Lambert-Eaton myasthenic syndrome). The Tensilon test may help direct the examiner toward botulism. Consider the physiology. Botulinum toxin blocks the release of ACh. Tensilon blocks the degradation of ACh. Thus, in theory, Tensilon should ameliorate the weakness of botulism, and it sometimes does. However, it cannot differentiate botulism from MG. The Tensilon test result is sometimes falsely positive in amyotrophic lateral sclerosis (ALS) and in some cases of myopathy. Generally, the history and other aspects of the context of the presentation will aide the examiner in determining the cause of a positive Tensilon test result. With respect to blood tests, the criterion standard is presently a mouse toxicity assay. It is often necessary for the mouse to be observed for days. Thus, the neurophysiologic tests described below, which can be performed rapidly, are particularly valuable for investigation of poisoning. An enzyme-linked immunosorbent assay (ELISA) test has become available for rapid screening, though it is not as sensitive or specific as the mouse bioassay. More recently, a procedure using a combination of endopeptidase cleavage followed by mass spectroscopy (Endopep-MS) has been developed; this test may ultimately become the new criterion standard. However, neurophysiologic testing will remain very important because it can be performed immediately in the office or at the bedside. Electrophysiologic findings in botulism tend to evolve with time and may not be present early in the disease. EMG findings typical of botulism include the following:
Not all patients with botulism will have the first finding. If none are found, the diagnosis of botulism is unlikely. If all 4 are present, only hypermagnesemia is in the differential diagnosis (and that can be quickly proven or dispelled by blood Mg levels). Generally, caveats exist with most checklists of diagnostic findings, and this is true of botulism. As has been pointed out by Maselli8 and others, the findings in botulism can vary from case to case. CMAP amplitudes usually are reduced, but the reduction is not so striking as is seen in LEMS for example. The reduction could easily be in the range seen in patients with axonal neuropathies. Facilitation with tetanic stimulation is not always seen. If it is not seen, then one can not look for persistence of facilitation or exhaustion after the facilitation. SFEMG demonstrates markedly increased jitter and blocking and has been abnormal in all reported cases of food-borne or wound botulism. Jitter and blocking may decrease as the firing rate increases, but this is not a consistent finding. ANTI-ACETYLCHOLINESTERASE TOXICITYSection 10 of 15
The most common cause of poisoning by anti-acetylcholinesterases is accidental poisoning via inadvertent pesticide ingestion. In addition to such pesticides as malathion and parathion, chemists have created nerve agents such as sarin and soman, which are much more potent and are designed to be used for military purposes. They also have fallen into the hands of terrorists. These agents work by stopping endogenous acetylcholinesterases from inactivating acetylcholine at the synapse. This causes excess acetylcholine to accumulate. So much acetylcholine accumulates that the muscles are in a constant state of depolarization causing depolarization block. Most such agents also cause central and GI effects with excess acetylcholine accumulation at muscarinic receptors. In fact, the muscarinic effects tend to be a key to the diagnosis. As detailed in the eMedicine article Toxicity, Organophosphate, one should keep in mind the mnemonics SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation). As acetylcholine levels accumulate in the peripheral, autonomic, and central nervous systems, the effects can be variable and fluctuating:
It is often useful to divide organophosphate poisoning into stages in which initially, in addition to the muscle paralysis, the immediate cholinergic effects of salivation, lacrimation, urination, diarrhea, GI upset, emesis, diaphoresis, miosis (sometimes alternating with myadriasis), bradycardia (sometimes alternating with tachycardia), bronchospasm, and bronchorrhea predominate. A variable degree of mental effects from anxiety to severe delirium may be present. Then, an "intermediate syndrome" dominated by muscle paralysis alone, especially the proximal and respiratory muscles, occurs. However, the initial symptoms may still persist in various degrees. Finally weeks or months later, peripheral neuropathies, muscle necrosis (presumably from overstimulation), CNS damage (perhaps resulting from impaired respiration and circulation but perhaps direct effects of cholinergic overdose), and other long-term sequelae may occur. Some of the sequelae may be partially reversible over time. As is the case for botulism, blood tests for anti-acetylcholinesterase poisoning present a problem, considering the need for rapid diagnosis. One approach is to do an enzyme activity assay for cholinesterases. Although this has been automated recently using robotic techniques, one still needs to send the blood to a high-level laboratory and wait for processing. Another approach is to detect the organophosphate compound. This also presents difficulties including the question of which organophosphate compounds are detected. Recently, various rapid methods have been developed including biosensors, which use genetically engineered bacteria whose membranes contain enzymes capable of breaking down certain organophosphates into more easily identified compounds. In most hospital situations, the blood would have to be sent to a highly specialized reference laboratory. Thus, the neurophysiologic techniques, though imperfect, can be especially useful for rapidly deciding whether or not individual or multiple cases of Far fewer cases of acetylcholinesterase toxicity have been studied neurophysiologically than is the case for myasthenia gravis. Many of the cases that were studied were examined under emergency conditions of mass intoxications and, thus, could not be studied as fully as is the situation for myasthenia gravis. Therefore, the significance of the findings are less certain. In this, as in most other situations, combining neurophysiologic findings with information from the history and physical examination is best. The following is a summary of the main neurophysiologic findings that have been seen in cases of anti-acetylcholinesterase intoxication:
NEUROMUSCULAR TRANSMISSION AND TERRORISMSection 11 of 15
Blocking neuromuscular transmission is a potential mode of terrorism. Neuromuscularly oriented clinicians should think about how they might use the neuromuscular assessment techniques to help combat this threat. Botulinum toxin and anti-acetylcholinesterases (organophosphates) are probably the two toxins that are the most likely to be used because they could be made available in sufficient amounts. In response to a possible terrorist attack with such agents, the principles and methods of neuromuscular transmission assessment described above could prove helpful in the initial as well as later stages of victim assessment. As in medical cases, the initial history and clinical evaluation of the patients takes precedence. For botulism, consider contaminated food, wounds, or marks indicating injections, and the possibility of toxin inhalation. On physical examination, the previously mentioned “dozen D’s” may be helpful: “dry mouth, diplopia, dilated pupils, droopy eyes, droopy face, diminished gag reflex, dysphagia, dysarthria, dysphonia, difficulty lifting head, descending paralysis, and diaphragmatic paralysis.”7 For organophosphate poisoning, some independent evidence that it might have been a gas attack would be suggestive. Organophosphates act in minutes, so the context would be people suddenly stricken in a relatively confined area such as a subway tube. In contrast, botulinum bacteria takes hours to days for onset; therefore, the context might be many people who were once at the same place where they might have eaten from the same food source but who had later dispersed and were in widely separated locations when the signs and symptoms first appeared. Alternatively, the purified toxin could be presented as an aerosol. This could act faster than food poisoning. Still, some time lag would exist, depending on how much toxin was delivered. For example, in toxin injected for treatment of blepharospasm, the patient usually does not notice much of an effect until the next day. However, extremely high doses could work faster. The previously mentioned mnemonics SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorr |