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