Case 17

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Case 17

HISTORY AND PHYSICAL EXAMINATION

A 21-year-old woman developed intermittent binocular diplopia, primarily with distant vision. Within a few weeks, the symptoms worsened and she noted droopy eyelids, first on the right, then on the left. She had increasing fatigue and weakness, primarily after activity, and had fallen a few times. On system review, she admitted to fatigue and weakness while chewing but denied swallowing and speech difficulties. All symptoms improved after rest. The patient was otherwise in excellent health.

On examination, the patient was alert, oriented, and in no distress. She had mild bilateral ptosis, which worsened with sustained upgaze. Extraocular muscles showed bilateral lateral rectus muscle weakness with nystagmoid movements on lateral gaze. Pupils and fundi were normal. There was mild bilateral peripheral facial weakness and weakness of eye closure. Speech, tongue, and palate were normal. The patient had moderate weakness in the limb muscles particularly in the legs and worse proximally. Her outstretched arms became fatigued in 1 to 2 minutes and could not be sustained. Deep tendon reflexes were +2/4 throughout. Sensation and coordination were normal. Gait was slow and waddling. Romberg test was negative. Tensilon (Edrophonium) test was equivocal, with possible improvement of ptosis only.

An electrodiagnostic (EDX) examination was performed.

Please now review the Nerve Conduction Studies and Needle EMG tables.

QUESTIONS

1. Decremental response on slow repetitive stimulation is commonly seen in all of the following except:

A. Botulism.

B. Amyotrophic lateral sclerosis.

C. Myasthenia gravis.

D. Corticosteroid myopathy.

E. Lambert-Eaton myasthenic syndrome (LEMS).

2. In patients with suspected ocular myasthenia, which test is most sensitive in establishing the diagnosis?

A. Serum acetylcholine receptor antibody.

B. Single-fiber jitter study of the frontalis muscle.

C. Slow repetitive stimulation of the facial nerve.

D. Slow repetitive stimulation of the spinal accessory nerve.

E. Single-fiber jitter study of the extensor digitorum communis.

3. Factors that increase the sensitivity of electrodiagnosis in myasthenia gravis include all of the following except:

A. Slow repetitive stimulation, recording weakened muscles.

B. Slow repetitive stimulation before and after exercise.

C. Rapid repetitive stimulation, recording a proximal muscle.

D. Single-fiber EMG jitter study.

E. Slow repetitive stimulation on warm limbs.

EDX FINDINGS AND INTERPRETATION OF DATA

Pertinent EDX findings include the following:

1. Normal sensory and motor nerve conduction studies (NCSs). In particular, the amplitudes of the compound muscle action potentials (CMAPs), of all motor nerves tested, are normal.

2. Slow repetitive stimulation (at a rate of 2 Hz) of the median and spinal accessory nerves reveals reproducible CMAP decrement at rest and after exercise (Figures C17-1 and C17-2). Also, the median nerve decrement corrects after exercise (postexercise facilitation. Compare Figure C17-1A, train 1 to train 2).

3. No increment of the CMAP amplitude after brief (10 seconds) exercise (not shown).

4. Normal needle EMG, except for motor unit action potential (MUAP) instability (moment-to-moment variation of MUAP amplitude) in the deltoid muscle.

Figure C17-1 Slow repetitive stimulation (2 Hz) of the median nerve, recording the abductor pollicis brevis, at rest and for 3 minutes after 1 minute of exercise in this patient with MG (A) and in an age-matched control (B). Train 1 was at rest, and Trains 2 through 5 were done every minute following 1 minute of exercise. The upper tracing of each panel shows all five stimulations, and the lower tracings represent Train 1, Train 3, and Train 5. Note the significant decrement of the compound muscle action potential (CMAP) at rest (35%) and after exercise in this patient, but not in the control. Note also the postexercise facilitation in the patient (Train 2, A). There was no significant postexercise exhaustion (compare Trains 1 and 3, 4, and 5 in A).

Figure C17-2 Slow repetitive stimulation (2 Hz) of the spinal accessory nerve, recording the trapezius, at rest and for 4 minutes after 1 minute of exercise in this patient. Train 1 is at rest, and Trains 2 through 6 are done every minute following 1 minute of exercise. The upper tracing of each panel shows all six stimulations, and the lower tracings represent Train 1, Train 3, and Train 5. Note the significant decrement of the compound muscle action potential at rest (33%) and after exercise, with no significant postexercise facilitation or exhaustion.

Case 17: Nerve Conduction Studies

Case 17: Needle EMG

These findings are diagnostic of a neuromuscular junction defect of the postsynaptic type and are consistent with myasthenia gravis. Normal CMAP amplitude at rest and the absence of CMAP increment after brief exercise exclude a presynaptic defect, as is seen with LEMS or botulism. The absence of denervation on needle EMG excludes a lower motor neuron disease (as seen with amyotrophic lateral sclerosis), which may be associated with a decremental response on slow repetitive stimulation.

DISCUSSION

Anatomy and Physiology

Neuromuscular Junction

The neuromuscular junction (NMJ) is the site where the motor neuron makes contact with the skeletal muscle fiber’s membrane (sarcolemma). It is near the center of the muscle fiber where there is a cup-shaped depression of the sarcolemma, called the endplate. The NMJ is a chemical synapse that is essential for transmitting action potentials from the terminal nerve branches to muscle fibers. This synapse utilizes acetylcholine (ACH) as a transmitter that binds to specific receptors in the junctional membrane, resulting local depolarizations that spread and trigger all-or-none muscle action potential. The NMJ is divided into a presynaptic terminal, a synaptic cleft, and a postsynaptic region (Figure C17-3).

Figure C17-3 Neuromuscular junction. (A) A longitudinal section through the endplate. (B) Overhead view of (A). (C) Enlarged view of the junction, showing the presynaptic region, the synaptic cleft, and the postsynaptic membrane and junctional clefts.

(From Fawcett DW. Bloom and Fawcett: a textbook of histology. Philadelphia, PA: WB Saunders, 1986, with permission.)

1. The presynaptic terminal is composed mainly of an unmyelinated nerve terminal covered by a Schwann cell and is loaded with synaptic vesicles. Each synaptic vesicle is 50 nm diameter in structure and contains approximately 5000 to 10 000 molecules of ACH, called the quanta. The synaptic vesicles cluster around the terminal’s active zones, the site for their eventual release facing the muscle fiber. Acetylcholine is packaged into vesicles to protect the molecules from hydrolysis (by the presynaptic acetylcholinesterase) and to maximize the required amount of transmitter release. The ACH supply is saved in immediately available stores, which are ready for release near the active zone region. Much larger ACH depots are stored more proximally in the axon and may be mobilized to replenish the immediately available stores whenever depleted. ACH is synthesized as follows:

2. The synaptic cleft is a small space (∼60 nm) between the synaptic terminal and the sarcolemma. It is lined by a basement membrane and is abundant in acetylcholinesterase, which breaks down ACH into choline and acetate. A large amount of acetylcholinesterase is present in neuromuscular junction, enough to quickly hydrolyze the ACH released into the synaptic cleft.

3. The postsynaptic membrane is the main constituent of the postsynaptic region and faces the active zone of the presynaptic terminal. The postsynaptic membrane forms highly convoluted invaginations, the junctional folds, where nicotinic ACH receptors are embedded at the top of the folds, with a density of 10 000–15 000 per μm², a thousand-fold more than in the rest of the sarcolemma. The nicotinic ACH receptor is a glycoprotein composed of five subunits (α2βδε), i.e., two α subunits, one β subunit, one ε subunit, and one δ subunit. The ε subunit replaces the γ subunit, which is present during development. They are arranged like barrel staves around a central iron pore (Figure C17-4). The binding site of the ACH molecule is located around amino acids 192 and 193 of both α subunits. The receptor channel opens transiently when the binding sites of both α subunits are locked by two ACH molecules. The opened channel of the ACH receptor behaves as a cation channel with little selectivity. The half-life of the nicotinic ACH receptor is approximately 8.5 days. A recently identified sarcolemmal protein, muscle specific tyrosine kinase (MuSK), is expressed exclusively at the NMJ and is closely associated to the ACH receptor. Its exact role in adult muscle is still unknown. In the developing muscle, MuSK is essential for aggregating the ACH receptors and is activated by nerve-derived agrin.

Figure C17-4 The acetylcholine receptor. Each subunit winds through the junctional membrane four times (M1 through M4).

(From Drachman DB. Myasthenia gravis. N Engl J Med 1994;330:1797–1810, with permission.)

Neuromuscular Transmission

Neuromuscular transmission involves the transmission of action potential from the motor neuron’s axon to the muscle fiber. The delay between the depolarization of the presynaptic terminal and the generation of endplate potential at the postsynaptic membrane is short (0.3–1 ms), and is mostly due to the exocytotic release of ACH from the presynaptic terminal. Neuromuscular transmission may be divided into three processes: (1) presynaptic terminal depolarization and ACH release; (2) ACH binding and ion channel opening; and (3) postsynaptic membrane depolarization and muscle action potential generation.

• Presynaptic terminal depolarization and ACH release. With the arrival of the action potential to the nerve terminal, voltage gated calcium channels (VGCCs) open allowing calcium to enter the presynaptic terminal. With the increase in cytosolic calcium concentration, several complex interactions, that involves several proteins and receptors, lead to the ensuing docking and fusion of synaptic vesicles with the presynaptic membrane in the active zone and release of ACH release into the synaptic cleft.

• Acetylcholine binding and ion channel opening. The released ACH molecules diffuses through the cleft and bind with the ACH receptors on the postsynaptic junctional folds. For a single receptor channel to open and allow the rapid passage of cations, two ACH molecules must bind to the α subunits of the receptor. The channels remain open for about 1 ms after ACH binding and then they close and ACH dissociates from the receptors.

• Postsynaptic membrane depolarization and muscle action potential generation. The passage of cations through the open cation channels following their electrochemical gradients (Na⁺ ions flow inward, and K⁺ ions flow outward) leads to a local depolarization in the endplate region. This endplate potential (EPP) is a slow potential with a large amplitude that ranges from 50 to 70 mV. It spreads electrotonically to the depths of the synaptic folds triggering the opening of Na⁺ voltage-gated channels and the development of a muscle action potential that propagates along the muscle fiber. After closure of the nicotinic receptor, ACH is released and subsequently is hydrolyzed by acetylcholinesterase into choline and acetate. Choline is taken back by the presynaptic terminal and ACH is resynthesized (Figure C17-5).

Figure C17-5 Neuromuscular transmission.

(From McComas AJ. Neuromuscular function and disorders. Boston, MA: Butterworth, 1977, with permission.)

Clinical Features

Myasthenia gravis (MG) is the best understood and most thoroughly studied of all human organ-specific autoimmune diseases. It is characterized by a reduction of skeletal muscle postsynaptic ACH receptors resulting in a decrease in the EPP necessary for action potential generation. In the majority of patients, MG is caused by an antibody-mediated attack on the postsynaptic nicotinic ACH receptors in the neuromuscular junction. In a small number of patients, other antigenic targets, such as the muscle specific tyrosine kinase (MuSK), may exist. Myoid cells and other stem cells within the thymus gland, which is hyperplastic in at least two-thirds of patients with MG, may serve as autoantigens by expressing on their surface the ACH receptor or one of its protein components.

The prevalence of MG is between 50 and 125 cases per million population. There is strong evidence that its prevalence is increasing, which may be in part attributed to better case recognition and aging of the population. As with many other autoimmune disorders, the disease afflicts mostly women, affected nearly twice as often as men. The annual incidence of MG ranges between 1.1 and 6 per million. MG incidence has two distinct peaks: the first occurs in the second and third decades and affects mostly women; and the second peak strikes mostly men during the sixth and seventh decades.

The hallmarks of MG are muscle weakness and fatigability. The symptoms are intermittent and are usually worse with activity and improve after rest. Generally, patients are much better in the morning than in the evening. Ocular symptoms (diplopia and/or ptosis) are extremely common and are the presenting signs in more than one half of patients. Most importantly, almost all patients at some point during the course of their illness develop ocular manifestations. Also, the disorder continues to be restricted to the extraocular muscles in 15% of patients, hence the designation ocular myasthenia. Additionally, only 3–10% of patients with ocular myasthenia generalize if no other symptoms appear after three years from initial presentation. Bulbar muscle weakness is the initial presenting manifestation in about 20% of patients and is seen in over 30% of patients during the course of their disease. Bulbar weakness is a major contributor to disability throughout the course of the disease. It manifests as dysarthria, nasal speech, dysphagia, chewing difficulties, or nasal regurgitation. Occasionally, the jaw muscle weakness may be severe leading to a “jaw drop” and patients often hold their jaw closed, a highly pathognomonic manifestation of MG. Limb weakness, mostly of proximal muscles, is seen as the initial symptom in 20% of patients. At times, the generalized weakness is severe and involves the respiratory muscles, resulting in respiratory failure that requires mechanical ventilation, a situation often referred to as myasthenic crisis. Because of variable clinical severity, MG is usually classified into five main categories (Table C17-1).

Table C17-1 Myasthenia Gravis Foundation of America Clinical Classification

Class I	Any ocular muscle weakness
	May have weakness of eye closure
	All other muscle strength is normal
Class II	Mild weakness affecting other than ocular muscles
Class II	May also have ocular muscle weakness of any severity
IIa	Predominantly affecting limb, axial muscles or both
IIa	May also have lesser involvement of oropharyngeal muscles
IIb	Predominantly affecting oropharyngeal, respiratory muscles, or both
IIb	May also have lesser involvement of limb, axial muscles, or both
Class III	Moderate weakness affecting other than ocular muscles
Class III	May also have ocular muscle weakness of any severity
IIIa	Predominantly affecting limb, axial muscles or both
IIIa	May also have lesser involvement of oropharyngeal muscles
IIIb	Predominantly affecting oropharyngeal, respiratory muscles, or both
IIIb	May also have lesser involvement of limb, axial muscles, or both
Class IV	Severe weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity
IVa	Predominantly affecting limb, axial muscles or both May also have lesser involvement of oropharyngeal muscles
IVb	Predominantly affecting oropharyngeal, respiratory muscles, or both
IVb	May also have lesser involvement of limb, axial muscles, or both
Class V	Defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb

The findings on neurologic examination parallel the symptoms, often revealing ptosis, weakness of extraocular muscles, flaccid dysarthria, or neck extensor or proximal muscle weakness. Although many muscles are fatigable, the most objective finding is fatigable eyelids, i.e., ptosis developing within 1–2 minutes of sustained upgaze. Deep tendon reflexes are preserved. Sensation is normal.

The diagnosis of MG may be made on clinical grounds, especially when reproducible fatigability of eyelids or extraocular muscles is confirmed. However, laboratory testing is frequently needed, and recommended, for confirmation (Table C17-2):

1. Tensilon test. Edrophonium (Tensilon) is a short-acting anticholinesterase inhibitor that transiently improves muscle strength in myasthenic patients. By inhibiting ACH degradation, it allows the ACH that is released into the junction to interact repeatedly with the decreased number of nicotinic ACH receptors. When given intravenously, its effect is quick (20–30 seconds) but transient, lasting around 5 minutes. Before the test, baseline muscle weakness should be established, preferably of muscles that can be tested objectively, such as eyelids or extraocular muscles. Difficulties in interpretation of the test are common when attempting to evaluate improvement in limb strength or bulbar function. A 1 to 2 mg test dose is given intravenously; if no improvement occurs within 45 seconds, the rest of the10 mg dose is administered. For results to be considered positive, the weakness should correct or improve unequivocally. False-positive and false-negative results are rare. Side effects usually are minor and include abdominal cramps, bradycardia, and hypotension. The patient’s pulse and blood pressure should be monitored during the test, and atropine should be readily available to counteract significant bradycardia.

2. Acetylcholine receptor antibodies. Approximately 85 to 90% of patients with generalized MG have elevated serum ACH receptor antibody, while the test is positive in only about 50 to 65% of patients with ocular myasthenia. A positive serum ACH receptor binding antibody is the most sensitive test and is highly specific for MG. ACH receptor modulating antibody test increases the diagnostic yield slightly. ACH receptor antibodies may be found in all subtypes of immunoglobulin G (IgG) and are heterogenous. They can be directed against many different epitopes of one or more of the five peptide chains of the ACH receptor. The majority of these antibodies bind at sequences of the α chains, particularly in the main immunogenic region (see Figure C17-4). There is no correlation between total ACH receptor binding, as measured in routine radioimmunoassay, and the severity of the disease. However, there is some correlation between antibody titer and clinical status in individual patients in response to various treatment modalities.

3. Muscle specific tyrosine kinase (MuSK) antibody. It has been long known that seronegative MG is also an autoimmune disease and likely mediated by antibodies directed at epitopes of other constituents of the motor endplate. Antibodies to MuSK antibody, a NMJ sarcolemmal protein, are present in about 40 to 70% of patients with generalized seronegative MG. These antibodies probably interfere with maintenance of normal ACH receptor density at the NMJ, since they were shown, in vivo, to interfere with ACH receptor clustering. Patients with MuSK positive antibodies are difficult to distinguish from other myathenics. However, they often may show a preponderance to bulbar, facial, and shoulder muscles and may not be responsive to cholinesterase inhibitors.

4. Striated muscle antibodies. These autoantibodies may be positive but only assist in suggesting the diagnosis of MG. Antistriated muscle antibodies are, however, useful markers for thymoma, particularly in patients between the ages of 20 and 50 years, since false positive and negative tests are common in children and older adults.

5. Repetitive nerve stimulation and single-fiber EMG. These are discussed separately in the electrodiagnosis section.

Table C17-2 Confirmatory Diagnostic Tests in Myasthenia Gravis

Edrophonium (Tensilon) test

Serum antibody assay

Acetylcholine receptor antibody

Muscle specific kinase (MuSK) antibody

Antistriatal muscle antibody

Repetitive nerve stimulation

Single-fiber electromyography

The differential diagnosis of generalized MG includes Lambert-Eaton myasthenic syndrome (LEMS), botulism, congenital myasthenic syndromes, and chronic fatigue syndrome. LEMS presents with generalized weakness, areflexia, and autonomic symptoms, but it is not uncommon to confuse its EDX findings with those of MG (Table C17-3). Botulism is subacute and has usually prominent autonomic manifestations, including dilated pupils and ileus. Congenital myasthenic syndromes are extremely rare disorders and usually begin in childhood. The fatigue associated with chronic fatigue syndrome may mimic generalized MG, except for normal ocular and bulbar strength and normal serologic and EDX studies. Ocular myasthenia should be distinguished from Graves disease (thyroid orbitopathy), progressive external ophthalmoplegia, Kearns-Sayre syndrome, oculopharyngeal muscular dystrophy, congenital myasthenic syndromes, and orbital apex or cavernous sinus mass compressing cranial nerves. In Graves disease, there is proptosis, conjunctival edema, and muscle enlargement (on imaging of the orbit); the forced duction test is positive. Progressive external ophthalmoplegia and Kearns-Sayre syndrome have usually symmetrical and slowly progressive ophthalmoplegia and ptosis. In Kearns-Sayre syndrome, there is associated multisystem involvement including pigmentary retinopathy, cerebellar ataxia, and cardiac conduction defects. Oculopharyngeal muscular dystrophy is a late onset autosomal dominant disease with slowly progressive dysphagia and ophthalmoplegia. In compressive mass lesions, the extraocular weakness usually follows one or more oculomotor nerve distribution and the pupils are frequently involved. Imaging studies, such as magnetic resonance imaging (MRI), might be required to rule out such a mass lesion within the orbit or cavernous sinus.

Table C17-3 Differential Diagnosis Between Generalized Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome

	Myasthenia Gravis	Lambert-Eaton Myasthenic Syndrome
Ocular involvement	Common and prominent	Uncommon and subtle
Bulbar involvement	Common and prominent	Uncommon and subtle
Myotatic reflexes	Normal	Absent or depressed
Sensory symptoms	None	Paresthesias are common
Autonomic involvement	None	Dry mouth, impotence and gastroparesis
Tensilon test	Frequently positive	May be positive
Serum antibodies directed against	Postsynaptic Ach receptors or MuSK	Presynaptic voltage-gated calcium channels
Baseline CMAPs	Normal	Low in amplitude
Postexercise CMAPs	No change	Significant facilitation
Slow repetitive stimulation	Decrement	Decrement
Rapid repetitive stimulation	No change or decrement	Increment
Single-fiber EMG	Increased jitter with blocking	Increased jitter with blocking
Rapid-rate stimulation jitter	Does not change or worsens jitter	Improves jitter

CMAPs = compound muscle action potentials; EMG = electromyography, Ach = acetylcholine, MuSK = muscle-specific kinase.

Once the diagnosis of MG is confirmed, certain commonly associated disorders must be considered and excluded. Thymoma occurs in approximately 10% of all patients with MG. This is age specific and is most common in adult patients between the ages of 20 and 60 years. Elevated antistriated muscle antibodies, which occur in certain myasthenics, are useful markers for thymoma, particularly in patients between the ages of 20 and 50 years, while false positive and negative tests are common in the young (<20 years) and older (>60 years) MG patients. Thus, a computed tomography (CT) scan or an MRI of the chest should be performed on all patients with MG. Because hyperthyroidism occurs in 3 to 8% of patients with MG, all patients should have thyroid function tests at the time of diagnosis. Other autoimmune disorders, such as systemic lupus erythematosus and rheumatoid arthritis, may coexist with myasthenia; screening for these should be performed by obtaining at least antinuclear antibodies and rheumatoid factor.

Therapy for MG has improved dramatically over the past 30 years, and the current mortality from this disorder is near zero. Treatment consists of one or more of several modalities, often used separately or in combination (Table C17-4). Treatment choices are usually individualized to the patient depending on severity of illness, age, life style and career, associated complicating disorders, and the risk and benefit of various therapies.

Table C17-4 Therapeutic Modalities in Myasthenia Gravis

Therapy	Mechanism of Action
Cholinesterase inhibitors (e.g., pyridostigmine)	Enhances neuromuscular transmission
Corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide, etc.	Immunosuppression
Plasmapheresis	Removes antibodies from circulation
Intravenous immunoglobulins	Unknown (?downregulates antibody production)
Thymectomy	Unknown (?eliminates a source of antigenic stimulation [thymic myoid cells] and/or removes a reservoir of B lymphocytes)

Electrodiagnosis

Electrodiagnostic (EDX) abnormalities encountered in MG are related to the blockade of the NMJ at the postsynaptic membrane. Although the changes are observed most often with repetitive stimulation of motor nerves or single-fiber EMG, other less specific changes may be encountered on routine EMG examination.

Nerve Conduction Studies

Sensory conduction studies are normal in MG. Similarly, routine motor conduction studies are usually normal. However, on rare occasions, the CMAP amplitudes are borderline or slightly decreased. This occurs in patients with prominent weakness, such as that associated with a myasthenic crisis, and is explained by prominent neuromuscular blockade beyond the safety factor (see repetitive nerve stimulation). In these situations, many muscle fibers do not reach threshold with a single stimulus, as is used with routine motor conduction studies, resulting in a small summated CMAP. It should be noted again that this is an extremely rare finding in MG. In fact, a presynaptic disorder, such as LEMS and botulism, should always be considered and excluded when the CMAP amplitudes are low or borderline. A presynaptic disorder is confirmed by looking for a significant (>50–100%) increment of CMAP amplitude after brief exercise and/or rapid, repetitive stimulation (see repetitive stimulation). Compound muscle action potential increment after brief exercise and/or rapid, repetitive nerve stimulation is not a feature of MG.

Needle EMG Examination

Needle EMG results usually are normal in MG. Three changes may, however, be seen. These include:

1. Unstable MUAPs (moment-to-moment variation of MUAPs). In healthy subjects, individual MUAPs are morphologically stable between successive discharges with no variation in amplitude and configuration, since all muscle fibers of the motor unit fire with every discharge. The morphology of a repetitively firing MUAP may fluctuate in patients with MG, if individual muscle fibers intermittently block within the unit (Figure C17-6). Technically, MUAP variation is best achieved during recording of a single MUAP by minimal voluntary activation. Care should be taken to record from no more than a single MUAP because MUAP overlap can lead to an erroneous assumption of MUAP instability. This finding is, however, not specific because it is observed in other neuromuscular junction disorders as well as in neurogenic disorders associated with active reinnervation such as motor neuron disease, subacute radiculopathy, or polyneuropathy. During reinnervation, the newly formed endplates are immature and demonstrate poor efficacy of neuromuscular transmission.

2. Short-duration, low-amplitude, and polyphasic MUAPs. These MUAPs, which are observed primarily in proximal muscles, are similar to the MUAPs seen in primary myopathies. They are caused, in MG, by physiologic blocking and slowing of neuromuscular transmission at many muscle fibers during voluntary activation. This leads to exclusion of many muscle fiber action potentials (MFAPs) from the MUAP (hence the short duration and low amplitude) and to a delay in neuromuscular transmission of other fibers (hence the polyphasia).

3. Fibrillation potentials. These potentials are extremely rare in MG. Their presence should raise the question of another diagnosis, or an associated diagnosis. When observed, they are inconspicuous and present mostly in proximal muscles. Their exact mechanism in MG is not known, but they are believed to be the result of persistent transmission block, which causes “effective” denervation of some muscle fibers.

Figure C17-6 Moment-to-moment variation (i.e., instability) of a single motor unit action potential recorded from the deltoid muscle in a patient with generalized myasthenia gravis (sensitivity = 0.2 mV/division, sweep speed = 100 ms/division).

Repetitive Nerve Stimulation (RNS)

Basic Concepts

To comprehend the effects of repetitive stimulation of motor nerves in both healthy individuals and those with myasthenic conditions, one must review important facts regarding the transmission of action potential through the presynaptic terminal and the postsynaptic membrane. These physiologic facts dictate the type and frequency of repetitive nerve stimulation (RNS) and the type of single fiber EMG study utilized in the accurate diagnosis of NMJ disorders.

• Quantum. A quantum is the amount of ACH packaged in a single vesicle, which contains approximately 5000 to 10000 ACH molecules. Each quantum (vesicle) released results in a 1 mV change in postsynaptic membrane potential. This occurs spontaneously during rest and forms the basis of miniature endplate potential (MEPP).

• Acetylcholine release and stores. The number of quanta released after a nerve action potential depends on the number of quanta in the immediately available (primary) store and the probability of release, i.e., m = p × n, where m = the number of quanta released during each stimulation, p = the probability of release (effectively proportional to the concentration of calcium and typically about 0.2, or 20%), and n = the number of quanta in the immediately available store. In normal conditions, a single nerve action potential triggers the release of 50–300 vesicles (quanta) with an average of about 60 vesicles (quanta). In addition to the immediately available store of ACH, located beneath the presynaptic nerve terminal membrane, a secondary (or mobilization) store starts to replenish the immediately available store after 1–2 seconds of repetitive nerve action potentials. A large tertiary (or reserve) store is also available in the axon and cell body.

• Calcium influx into presynaptic terminal. After depolarization of the presynaptic terminal, VGCCs open, leading to calcium (Ca²⁺) influx. Through a calcium-dependent intracellular cascade, vesicles are docked into the active zones, where they open into the synaptic cleft and release their ACH content. When this process is completed, Ca²⁺ then diffuses slowly out of the presynaptic terminal in 100 to 200 ms. The different rates at which motor nerves are repetitively stimulated in the EMG laboratory is extrapolated from the Ca²⁺ diffusion rate (see below).

• Endplate potential (EPP). EPP is the potential generated at the postsynaptic membrane after a nerve action potential and neuromuscular transmission. In humans, its amplitude is equivalent to approximately 60 quanta (60 vesicles), which are released from the presynaptic terminal. This results in approximately a 60 mV change in membrane potential amplitude.

• Safety factor. In normal conditions, the number of quanta (vesicles) released at the junction after the arrival of the nerve action potential at the presynaptic terminal (approximately 60 vesicles) far exceeds the change in postsynaptic membrane potential that is required to reach the threshold needed to generate a postsynaptic muscle action potential (7 to 20 mV). The safety factor results in an EPP that always reaches threshold, results in an all-or-none muscle fiber action potential (MFAP), and prevents neuromuscular transmission failure despite repetitive action potentials. In addition to quantal release, several other factors contribute to the safety factor and EPP, including ACH receptor conduction properties, ACH receptor density, and acetylcholinesterase activity.

• Compound muscle action potential (CMAP). CMAP is the summation of all propagated MFAPs within a muscle. The value is obtained after supramaximal stimulation of the motor nerve during recording through a surface electrode that is placed over the belly of a muscle.

Electrophysiology

When repetitive stimulation is applied to a normal motor nerve, the amount of ACH released during the first several stimulations exceeds what is released during ensuing stimulations. Despite this decrease, the amount of ACH released continues to exceed the ACH required to reach action potential threshold because of the safety factor. The decline in ACH release also levels off to a constant amount because of mobilization of large amount of ACH from depot stores into the active zone. This allows indefinite release of ACH during prolonged stimulation at physiologic rates.

The rate at which motor nerves are stimulated dictates whether calcium plays a role in enhancing the release of ACH. Because Ca²⁺ diffuses out of the presynaptic terminal within 100 to 200 ms, a slow rate of stimulation (slower than every 200 ms) implies that the subsequent stimulus arrives long after calcium has dispersed. Thus, an interstimulus interval of greater than 200 ms, or a stimulation rate of less than 5 Hz, is considered a slow rate of repetitive stimulation. At this slow rate, the role of Ca²⁺ in ACH release is not enhanced. In contrast, with rapid repetitive stimulation (i.e., at an interstimulus interval of less than 200 ms, or a stimulation rate greater than 5–10 Hz), Ca²⁺ influx is enhanced greatly, which results in larger releases of ACH and a larger EPP.

In normal conditions (Figures C17-7 and C17-8), both rates of stimulation generate MFAPs in all muscle fibers since the EPPs remain above threshold because of the safety factor. Thus, at both stimulation rates, all muscle fibers generate MFAPs, and the CMAP (summated MFAPs) does not change (i.e., no decrement or increment).

Figure C17-7 Slow repetitive stimulation effect on endplate potential (EPP), single-fiber action potential (SFAP, also referred to as muscle fiber action potential [MFAP]), and compound muscle action potential (CMAP) in normal health, myasthenia gravis (MG), and Lambert-Eaton myasthenic syndrome (ELS).

(Adapted from Oh S. Clinical electromyography, neuromuscular transmission studies. Baltimore, MD: Williams and Wilkins, 1988, with permission.)

Figure C17-8 Rapid repetitive stimulation effect on endplate potential (EPP), single-fiber action potential (SFAP, also referred to as muscle fiber action potential [MFAP]), and compound muscle action potential (CMAP) in normal health, myasthenia gravis (MG), and Lambert-Eaton myasthenic syndrome (ELS).

(Adapted from Oh S. Clinical electromyography, neuromuscular transmission studies. Baltimore, MD: Williams and Wilkins, 1988, with permission.)

However, the postsynaptic disorders, such as MG, are characterized by the following (Tables C17-3 and C17-5):

• The CMAP is normal since a single stimulus usually leads to normal EPPs and MFAPs in all fibers due the presence of safety factor and despite ACH receptor blockade.

• Slow RNS (2–5 Hz) results in the decline of many muscle fiber EPPs which often fail to reach thresholds. This leads to a progressive loss of MFAPs and a decremental CMAP (see Figure C17-7).

• Rapid RNS (10–50 Hz) results in no change of CMAP since the depleted stores are compensated by the Ca²⁺ influx. In severe myasthenics, rapid RNS may result is CMAP decrement since the increased ACH release cannot compensate for the marked postsynaptic neuromuscular block (see Figure C17-8).

Table C17-5 Compound Muscle Action Potential and Repetitive Abnormalities Characteristic of Common Neuromuscular Junction Disorders

In contrast, the presynaptic disorders, such as Lambert-Eaton myasthenic syndrome, are characterized by the following (See Tables C17-3 and C17-5):

• The CMAP is low in amplitude since many muscle fibers do not reach threshold after a single stimulus due to the inadequate release of quanta (vesicles).

• Slow RNS (2–5 Hz) results in CMAP decrement since the decline in ACH release with subsequent stimuli results in lower amplitude EPPs and further loss of MFAPs (see Figure C17-7).

• Rapid RNS (10–50 Hz) results in CMAP increment due to the accumulation of Ca²⁺ in the presynaptic vesicles. This, in turn, significantly enhances ACH release, and results in many EPPs reaching the threshold required for the generation of MFAPs (see Figure C17-8).

Technical Considerations

Repetitive nerve stimulation often follows routine motor NCS. Electromyographers and nerve conduction technologists should master the various motor NCS and RNS techniques to avoid false positive and false negative results. There are certain prerequisites that are essential for performing reliable RNS and for increasing the sensitivity and specificity of the test in the diagnosis of RNS.

1. Limb temperature should be kept warm since neuromuscular transmission is enhanced in a cool limb which may mask a CMAP decrement. Warming the extremity studied is important because cooling improves neuromuscular transmission and can result in a false negative RNS. Hand skin temperature should be maintained greater than 32°C, and foot skin temperature greater than 30°C.

2. Patients on cholinesterase inhibitors (such as pyridostigmine) should be asked to withhold their medication for 12–24 hours before RNS, if medically not contraindicated.

3. The limb tested should be immobilized as best as possible. Particular attention should be given to the stimulation and recording sites. Movement at either site may result in CMAP amplitude decay or increment, potentially leading to a false diagnosis of an NMJ disorder.

4. Though a supramaximal stimulation (i.e., 10–20% above the intensity level needed for a maximal response) is needed to obtain a CMAP, unnecessary high intensity or long duration stimuli should be avoided to prevent movement artifact and excessive pain.

5. The choice of nerve to be stimulated and muscle to be recorded from depends on the patient’s clinical manifestations. The aim is to record from clinically weakened muscles, if these muscles are accessible. Easily tested and well-tolerated nerves for RNS are the median and ulnar nerves, recording abductor pollicis brevis and abductor digiti minimi respectively, since they are accompanied by minimal movement artifact and the upper limb is easily immobilized. However, since distal muscles are frequently spared in MG, recording from a proximal muscle is often necessary. Slow RNS of the spinal accessory nerve, recording the upper trapezius muscle, is the most common study of a proximal nerve. It is relatively well tolerated, less painful, and subject to less movement artifact when compared to RNS of other proximal nerves such as the musculocutaneous or axillary nerves, recording the biceps or deltoid muscles, respectively. Finally, facial RNS, recording orbicularis oris, is indicated in patients with suspected ocular MG, particularly when RNS recording proximal muscles are normal or equivocal. However, the facial CMAP is low in amplitude and often plagued by large stimulation artifacts. This renders measurement of decrement difficult and subject to error.

6. In addition to RNS at rest, it is very useful to perform slow RNS after exercise to try to achieve postexercise exhaustion, a finding that is often seen in patients with MG. This phenomenon is analogous to the clinical exhaustion that is observed in these patients after exercise. Postexercise RNSs are particularly useful in patients with suspected MG who show only equivocal CMAP decrement at rest (10%). Voluntary exercise is preferable to tetanic stimulation (30–50 Hz) since the latter is extremely painful. After performing slow RNS at rest, the patient is asked to activate the recorded muscle for 1 minute. Then, slow RNS is repeated every 30 to 60 seconds for 4 to 6 minutes looking for postexercise exhaustion, i.e., worsening of decrement compared to baseline decrement at rest. The postexercise study may also result in a phenomenon, known as postexercise facilitation. This manifests as improvement or reversal of CMAP decrement, during the first minute of stimulation after exercise (see Figure C17-1A, and compare train 1 to train 2).

Measurements

In MG, slow RNS results in a CMAP decrement. The greatest decrement in amplitude occurs between the first and second responses, while the maximal amplitude decrement is often between the first and or third fourth responses. By the fifth response, the decrement levels off (see Figures C17-1A and C17-2). For these reasons, a train of four or five stimuli at 2 Hz usually is satisfactory and is best tolerable. The decrement is calculated as follows:

CMAP decrement of greater than 10% is considered positive and eliminates the potential for a false-positive result. Technical artifacts, such as movement of stimulating or recording electrodes, can lead to CMAP changes that may be mistakenly interpreted as a decrement. These can be minimized by immobilizing the tested limb and securing the stimulating and recording electrodes.

Single-Fiber EMG

where MCD is mean consecutive difference, IPI is interpotential interval, and N is the number of discharges (intervals) recorded. In practice, an MCD should be calculated from at least 50 interpotential intervals. Analysis of 10 to 20 pairs frequently is needed for a mean MCD to be reported. Although the jitter can be measured using a mean and a standard deviation, it is measured more reliably by the MCD because of the potential change in the mean IPI over time. Jitter is best expressed as the mean MCD of approximately 10 to 20 muscle fiber pairs (Figure C17-9).

Figure C17-9 Normal jitter analysis of a muscle fiber pair, recording the extensor digitorum communis, from a 40-year-old woman with fatigue.

Neuromuscular blocking is defined as the failure of transmission of one of the potentials. Blocking represents the most extreme abnormality of the jitter. Blocking is calculated as the percentage of discharges of a motor unit in which a single-fiber potential does not fire. For example, during 100 discharges of the pair, if a single potential is missing 30 times, the blocking occurs at a rate of 30%. In general, blocking occurs when jitter values are significantly abnormal.

In patients with MG, abnormal jitter values are common and frequently are accompanied by blocking (Figure C17-10). This reflects the failure of one of the muscle fiber pairs to transmit an action potential because of the failure of the EPP to reach threshold. The results of SFEMG jitter study are expressed by: (1) the mean jitter of all potential pairs, (2) the percentage of pairs with blocking, and (3) the percentage of pairs with normal jitter.

Figure C17-10 Abnormal jitter analysis of a muscle fiber pair, recording the frontalis muscle, from a 70-year-old man with mild ptosis. Note the intermittent blocking of the slave (second) potential (33%).

Jitter analysis is highly sensitive, but it is not specific. It is frequently abnormal in MG and other neuromuscular junction disorders; however, it also may be abnormal in a variety of neuromuscular disorders, including neuropathy, myopathy, and anterior horn cell disorder. Thus, a diagnosis of MG obtained by jitter analysis must be considered in the context of the patient’s clinical manifestations, nerve conduction studies, and needle EMG findings.

Stimulation Single-Fiber EMG

Stimulation (axonal-stimulated) SFEMG records the jitter between a stimulus artifact and a single potential that is generated by stimulation of a motor unit near the endplate zone. It has the advantage of requiring no patient participation; thus, it may be performed on children, as well as uncooperative or comatose patients. It is performed by inserting another monopolar needle electrode near the intramuscular nerve twigs, and stimulating at a low current and constant rate. The electromyographer has to manipulate two electrodes, a stimulating and recording electrode, until one or more potentials are recorded. The IPI is calculated between the stimulus artifact and a single potential generated by stimulating a motor unit near the endplate zone. Since jitter (MCD) values are calculated on the basis of one endplate, the normal values are lower than those obtained by voluntary activation. To calculate the normal stimulation jitter value, the reference data for voluntary activation are multiplied by 0.80.

In addition to its relative ease in performing, the rate of stimulation can be adjusted from a slow rate (2–5 Hz) to a rapid rate (20–50 Hz). This is helpful in the differentiation of presynaptic and postsynaptic disorders because neuromuscular transmission, jitter and blocking improve significantly with a rapid rate stimulation in LEMS, but it does not change or it worsens in MG (Figure C17-11).

Figure C17-11 The effect of stimulation rate on the jitter and blocking in an endplate in the extensor digitorum communis of a patient with Lambert-Eaton myasthenic syndrome. Single-fiber electromyographic recordings were made during stimulation of an intramuscular nerve twig. Each trace represents the superimposition of ten consecutive responses. Eighty percent of responses are blocked at 5 Hz, compared with 50% at 10 Hz and none at 20 Hz. S = stimulus artifact.

(From Saunders DB. Lambert-Eaton myasthenic syndrome: clinical diagnosis, immune-mediated mechanisms and update on therapies. Ann Neurol 1995;37(S1): S63-S73, with permission.)