Case 21

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Case 21

HISTORY AND PHYSICAL EXAMINATION

A 51-year-old, white, previously healthy woman noted a gradual onset of progressive fatigue and general weakness. At first this was attributed to depression, and she was treated in a psychiatric hospital with haloperidol without effect. Within 3 months, her weakness had worsened so that she was unable to walk more than a few steps and could not manage stairs. Weakness was variable, and was much less of a problem in the morning. When the patient was first seen by a neurologist, a diagnosis of myasthenia gravis was made. She was placed on pyridostigmine (Mestinon®), which resulted in some improvement. At that time, a computed tomography (CT) scan of the chest, obtained to look for thymoma, was reported as normal. On questioning, the patient complained of difficulty swallowing, related to dry mouth, intermittent horizontal double vision and drooping of eyelids, and “burning” of the arms and legs. She denied sphincteric symptoms, loss of weight, loss of appetite, or shortness of breath.

Medical history was relevant for long-standing hypertension and hiatal hernia. She underwent an aortic bypass graft for intermittent claudication, cholecystectomy for gallstones, and hysterectomy for fibroid tumor. She had a long history of heavy cigarette use, at least 70 pack-years. She was on pyridostigmine (Mestinon®), captopril (Capoten®), and ranitidine (Zantac®).

Neurologic examination revealed normal mental status. The patient was not in distress and she used a wheelchair. She had mild bilateral ptosis, which was fatiguable on sustained upgaze. Fundi, pupils, extraocular movements, visual fields, and visual acuity were all normal. There was no facial weakness or asymmetry. The tongue was normal. Muscle bulk and tone were normal. She had proximal weakness, worse in the legs (Medical Research Council [MRC] 4/5 in legs and 4+/5 in arms). Deep tendon reflexes were diffusely hypoactive (trace to 1/4). Neither strength nor reflexes were accentuated by brief exercise. Sensation and cerebellar examination were normal. Gait was slow and waddling. Romberg test was negative.

Electrodiagnostic (EDX) studies were performed 24 hours after discontinuation of pyridostigmine (Mestinon®).

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

QUESTIONS

1. The abnormalities seen on routine nerve conduction studies in this case are least often observed in:

A. Amyotrophic lateral sclerosis.
B. Myopathy.
C. Lambert-Eaton myasthenic syndrome.
D. Postpoliomyelitis syndrome.

2. Characteristics of this disorder include all of the following except:

A. It results from impaired release of acetylcholine from the presynaptic terminal.
B. It is caused by blockage of the voltage-gated calcium channel (VGCC) in the presynaptic terminal.
C. It usually manifests with generalized weakness and minimal extraocular muscle weakness.
D. It frequently is associated with thymoma.

3. Both myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS) result in:

A. Low-amplitude compound muscle action potentials (CMAPs).
B. Significant facilitation of CMAPs after brief exercise.
C. Decrement of CMAPs with slow repetitive stimulation.
D. Significant increment of CMAPs with rapid repetitive stimulation.

Case 21: Nerve Conduction Studies

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Case 21: Needle EMG

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EDX FINDINGS AND INTERPRETATION OF DATA

Relevant EDX findings in this case include:

1. Low CMAP amplitudes with normal distal latencies and conduction velocities throughout the upper and lower limbs.
2. Normal sensory nerve action potentials (SNAPs) throughout.
3. Normal needle EMG.
4. Prominent postexercise potentiation of all motor amplitudes (i.e., CMAPs) after a single stimulus following brief exercise (10 seconds). This facilitation was universal (i.e., it occurred when applied to all motor nerves studied) and ranged from 260 to 300%. These postexercise potentiation values are as follows:

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5. Prominent CMAP increment after rapid repetitive stimulation (30 and 50 Hz) of the left median nerve at 250% (Figure C21-2).
6. A decrement of the CMAP after slow repetitive stimulation of the left median nerve at 35%.
7. Normal needle EMG.
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Figure C21-1 Baseline compound motor action potentials (CMAPs) with superimposed postexercise CMAPs of the left median nerve, recording the abductor pollicis brevis (A), and the left ulnar nerve, recording the abductor digiti minimi (B). Note the prominent facilitation following 10 seconds of exercise (260% for median and 294% for ulnar).

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Figure C21-2 Rapid, repetitive stimulation (50 Hz) of the median nerve at the wrist, recording the abductor pollicis brevis in a normal control (top), and in this patient (bottom). Note the significant facilitation of compound motor action potential (CMAP) (250%) in the patient but not the control.

These findings are consistent with presynaptic neuromuscular junction blockade, such as that seen in LEMS. Classic electrophysiologic findings include low CMAP amplitudes, significant facilitation after brief exercise, and prominent increment after rapid repetitive stimulation.

DISCUSSION

Pathophysiology

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction, caused by autoantibodies against the presynaptic P/Q type voltage-gated calcium channels (VGCC). The block of VGCCs results in a decrease in calcium influx during depolarization of the presynaptic membrane, and interferes with the calcium-dependent release of acetylcholine (ACH) from its stores in vesicles into the synaptic cleft. Passive transfer of IgG of patients with LEMS to animals produces the same physiologic and morphologic changes as those seen in humans.

Lambert-Eaton myasthenic syndrome is paraneoplastic, associated with small-cell lung cancer (SCLC) in approximately 50% of patients. A significant predictor for developing SCLC in patients with LEMS is smoking at the time of diagnosis. SCLC is commonly detected soon after the onset of LEMS symptoms, but this latency rarely extends beyond five years. Cultured SCLC cells exhibit VGCC activity, suggesting that SCLC cells expresses VGCCs and initiate the autoimmune process. Serum IgG antibodies against P/Q type VGCCs are present in 90% of patients with LEMS with SCLC, and in 3% of patients with SCLC with no neurological symptoms. Other malignancies associated with LEMS are relatively rare, and most have been intrathoracic such lymphoma, thymoma, and carcinoid tumors. The remaining LEMS patients do not have cancer, are usually younger women, and have other autoimmune disorders such as systemic lupus erythematosus, pernicious anemia, and juvenile-onset diabetes mellitus.

Clinical Features

Lambert-Eaton myasthenic syndrome, also referred to as the myasthenic syndrome, affects primarily adults older than 40 years of age, with a slight predilection to men. Patients present with proximal muscle weakness (especially of the lower extremities) and minimal ocular and bulbar weakness, and are susceptible to fatigue. Deep tendon reflexes are characteristically absent or reduced. Autonomic complaints (especially dry mouth) and transient paresthesias may also occur. A helpful and distinctive clinical finding is muscle facilitation: after a brief period (∼10 seconds) of intensive exercise of a muscle, muscle power is much transiently stronger and the deep tendon reflex to that muscle is enhanced. Unfortunately, this sign cannot always be confirmed during bedside evaluation. Figures C21-3 and C21-4 show the common signs and symptoms of LEMS patients, based on series of 50 patients.

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Figure C21-3 Lambert-Eaton myasthenic syndrome. Symptoms during the course of illness in 50 cases.

(Adapted from O’Neil JH, Murray NMF, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome: a review of 50 cases. Brain 1988:11:577–596.)

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Figure C21-4 Lambert-Eaton myasthenic syndrome. Signs during the course of illness in 50 cases.

(Adapted from O’Neil JH, Murray NMF, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome: a review of 50 cases. Brain 1988;11:577–596.)

The disorder may be mistaken for myasthenia gravis or myopathy. However, the diagnosis of LEMS is highly dependent on the electrophysiologic characteristics of the neuromuscular junction defect. Also, anti-P/Q-type VGCC antibodies are detected in the serum of 90% of patients with LEMS who have SCLC and in less than 50% of patients with LEMS without cancer. Elevated titers are detected in more than 10% of patients with SCLC and paraneoplastic cerebellar degeneration with no LEMS manifestations. Low titers may also be present in patients with other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. All patients with LEMS should be screened for cancer, particularly lung cancer, by CT scan or magnetic resonance imaging (MRI) of the chest.

Treatment of LEMS is difficult. Treatment of the primary cancer is essential but seldom results in improvement of the neurologic symptoms. Figure C21-5 outlines a practical algorithmic treatment plan of weakness for patients with LEMS. Measures to combat weakness include:

1. Drugs, such as pyridostigmine (a choline esterase inhibitor), guanidine, or 3-4 aminopyridine. 3-4 Aminopyridine blocks voltage-sensitive potassium channels, thereby increasing evoked transmitter release by prolonging the action potential duration and increasing calcium influx at the nerve terminal. Potential side effects include paresthesias and seizures. It is available commercially in Europe but limited to research studies in the United States. Guanidine also enhances the release of ACH from presynaptic terminal, but its serious adverse effects, including hepatotoxicity and bone marrow suppression, are limiting factors.
2. Plasmapheresis and intravenous immunoglobulins produce short-term clinical improvement and repeated treatments are needed to maintain improvement of muscle power.
3. Immunosuppressive drugs, particularly oral corticosteroids, azathioprine, or cyclosporine, may be helpful.
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Figure C21-5 Suggested treatment plan in patients with Lambert-Eaton myasthenic syndrome (LES = Lambert-Eaton myasthenic syndrome; IV IG = intravenous immunoglobulin).

Electrodiagnosis

Nerve Conduction Studies

Nerve conduction studies (NCSs) in LEMS reveal normal sensory responses. However, motor NCSs disclose low or borderline-low CMAP amplitude in all motor nerves (discussed in a later section). These are usually associated with normal distal latencies, conduction velocities, and F wave latencies.

In general, low-amplitude CMAPs with normal SNAPs are infrequent findings in the EMG laboratory, especially when the findings are diffuse (i.e., every motor NCS has low CMAP, and every sensory NCS reveals normal SNAP). Figure C21-6 outlines the common site of pathology in patients manifesting low-amplitude CMAP responses in all or most motor nerves. These disorders are distinguished by a detailed needle EMG and repetitive nerve stimulation. Table C21-1 lists the common causes of such findings, as seen in the EMG laboratory.

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Figure C21-6 Algorithmic approach to diffusely low compound motor action potential (CMAP) amplitudes (with normal sensory nerve action potential [SNAPs]).

Table C21-1 Causes of Diffuse Low-Amplitude CMAPs (Compound Muscle Action Potentials) and Normal SNAPs (Sensory Nerve Action Potentials)

Anterior horn cell disease (e.g., amyotrophic lateral sclerosis and poliomyelitis)
Diffuse polyradiculopathies (e.g., concomitant cervical and lumbar spondylosis)
Pure motor axonopathy (e.g., acute motor axonal neuropathy (AMAN) and hereditary motor neuropathy)
Neuromuscular junction defect (e.g., Lambert-Eaton myasthenic syndrome and botulism)
Myopathy (severe; e.g., critical illness myopathy and advanced muscular dystrophy)

Repetitive Nerve Stimulation

Abnormal repetitive nerve stimulations (RNSs) are the hallmark of neuromuscular junction defects. Since calcium diffuses out of the presynaptic terminal within 100 to 200 ms after a single-action potential, repetitive nerve stimulations are separated into slow and rapid stimulations, based on the stimulus rate (number of stimuli per second = hertz) applied to motor nerves. Slow RNS is performed at a rate slower than the time required for calcium diffusion (an interstimulus interval of >200 ms, i.e., slower than 5 stimuli/second, usually 2–3 Hz), and rapid stimulation occurs at a rate faster than this diffusion (an interstimulus interval of <100 ms, i.e., faster than 10 stimuli/second, usually 20–50 Hz) (for more details, refer to Case 17).

RNS in Healthy Individuals

Slow or fast rates of motor nerve stimulation do not abolish any endplate potential (EPP); all remain above threshold because of the presence of a “safety factor” (many more quanta (vesicles) are released with a single stimulus than are needed to generate an EPP). Thus, the CMAP (= summated muscle fiber action potentials, MFAPs) does not change (no decrement). After rapid RNS or following brief exercise, there usually is a slight physiologic increment of the CMAP, which does not exceed 25% of the baseline CMAP. This physiologic post-tetanic facilitation is believed to be caused by increased synchrony of MFAPs after tetanic stimulation (Figures C21-7 and C21-8).

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Figure C21-7 Slow, repetitive stimulation effect on endplate potential (EPP), single-fiber action potential (SFAP), also referred to as muscle action potential (MAP), and compound muscle action potential (CMAP) in normal nerve, myasthenia gravis (MG), and Lambert-Eaton myasthenic syndrome (LEMS or ELS).

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

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Figure C21-8 Rapid, repetitive stimulation effect on endplate potential (EPP), single-fiber action potential (SFAP, also referred as muscle action potential [MAP]), and compound muscle action potential (CMAP) in normal nerve, myasthenia gravis (MG), and Lambert-Eaton myasthenic syndrome (LEMS or ELS).

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

RNS in Patients With Lambert-Eaton Myasthenic Syndrome

1. CMAP is low in amplitude. Many muscle fibers do not reach threshold after a single stimulus because of the inadequate release of quanta (vesicles). Thus, many muscle fibers will not generate an MFAP which results in a low-amplitude baseline CMAP at rest.
2. Slow RNS (<5/second, i.e., an interstimulus interval of >200 ms, usually 2–3 Hz) results in decrement of the CMAP. Acetylcholine (ACH) release is reduced because of depletion of the immediately available ACH stores. At this slow rate, the role of calcium (Ca2+) in ACH release is not enhanced because Ca2+ diffuses out of the terminal in 100 to 200 ms. Thus, subsequent stimuli result in further loss of many EPPs and MFAPs (see Figure C21-7).
3. Rapid RNS (>5–10/second, i.e., an interstimulus interval of <100 ms, usually 20–50 Hz, or following brief exercise CMAP) greatly enhances Ca2+ influx, which results in larger releases of quanta and larger EPPs. This results in many muscle fibers reaching the threshold required for the generation of EPPs. Thus, more MFAPs are summated; hence the increment of the CMAP (see Figure C21-8). The post-tetanic facilitation should exceed 50%, and preferably 100%, to be diagnostic. This marked postexercise facilitation of the CMAP is the electrical correlate of the clinical facilitation of muscle strength and reflexes sometimes seen after brief exercise.

RNS in Patients With Myasthenia Gravis (MG)

1. CMAP is normal. A single stimulus usually leads to normal EPPs and MAPs in all fibers, which results in normal CMAP. This occurs despite the loss of ACH receptors and is due to the effect of the safety factor (many more quanta (vesicles) are released with a single stimulus than are needed to generate an EPP).
2. Slow RNS (<5/second, i.e., an interstimulus interval of >200 ms, usually 2–5 Hz) results in the progressive loss of many muscle fiber EPPs, owing to their failure to reach threshold. This results in loss of MFAPs and in a decremental CMAP (summated MAPs) (see Figure C21-7).
3. With rapid repetitive stimulation (>5–10/second, i.e., an interstimulus interval of <100 ms, usually 20-50 Hz or following brief exercise CMAP), the depleted stores are compensated by the Ca2+ influx, resulting in no change of CMAP. In severe myasthenics, there is a decrement in CMAP because the increased ACH release cannot compensate for the marked postsynaptic neuromuscular block (see Figure C21-8).

Single-Fiber EMG

Single-fiber jitter analysis is abnormal with frequent blocking in LEMS, as well as in myasthenia gravis. It is difficult to distinguish MG from LEMS using recruited (voluntary) single-fiber EMG because both disorders lead to a prolonged jitter, with or without blocking (for details, refer to Case 17). However, with stimulation jitter techniques, one can differentiate LEMS from myasthenia. Using a rapid rate of stimulation (>10 Hz), block or jitter or both improve significantly in LEMS owing to enhancement of ACH release by the influx of Ca2+ into the presynaptic terminal (Figure C21-9). However, at this rate of stimulation, the jitter does not change or worsen in myasthenia gravis.

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Figure C21-9 The effect of stimulation rate on jitter and blocking in an endplate in the extensor digitorum communis in a patient with Lambert-Eaton myasthenic syndrome (LEMS). Single-fiber EMG 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 to 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.)

Needle EMG

Needle EMG in LEMS usually is normal; rarely, short-duration, low-amplitude motor unit action potentials (MUAPs) are recorded, when severe neuromuscular blockade exists.

Conclusion

The EDX findings in LEMS include low-amplitude CMAP, increment of CMAP after brief exercise, and increment of CMAP after rapid RNS. Table C21-2 summarizes the EDX findings in LEMS and myasthenia gravis.

Table C21-2 Electrodiagnostic Findings in Lambert-Eaton Myasthenic Syndrome and Myasthenia Gravis

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The diagnosis of LEMS must be considered and excluded in all patients whose nerve conduction studies show low or borderline-low baseline CMAP amplitudes at rest, with normal sensory responses. Low or borderline-low CMAP amplitudes at rest should be followed by a repeat distal nerve stimulation after 10 seconds of exercise to exclude the possibility of LEMS. Assessing CMAP after brief exercise in patients with suspected LEMS is as accurate as results obtained after rapid RNS. It has the advantage of being much less painful and thus can be done on many motor nerves. It is recommended that postexercise CMAP is performed on several motor nerves, as a screening, in patients with suspected LEMS. If postexercise facilitation is present, then one motor nerve (such as a median or ulnar nerve) is stimulated with a rapid train (20–50 Hz) to verify the diagnosis.

Patients with LEMS are often misdiagnosed as MG. This occurs when slow RNSs (2–3 Hz) are only performed and result in CMAP decrements that are frequent and common finding in MG and LEMS. Most of these patients have low amplitude or borderline CMAPs on NCSs that are overlooked. Repeating distal nerve stimulation after 10 seconds of exercise on all nerves with low amplitude or borderline CMAPs, which is often done prior to slow RNS, should exclude or confirm the diagnosis of LEMS. If postexercise facilitation is present, a rapid RNS would be then done for confirmation. Table C21-3 lists the common differentiating clinical and electrophysiologic features of LEMS and MG.

Table C21-3 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
Deep tendon 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 (>50–100%)*
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‡

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

* See Figure C21-1.

† See Figure C21-2 (bottom tracing).

‡ See Figure C21-9.

FOLLOW-UP

A review of the CT scan performed earlier revealed a small mass in the azygoesophageal recess. A barium swallow confirmed the presence of an extrinsic indentation of the lower esophagus. After an unrevealing bronchoscopy, a right thoracotomy was performed. The mass was consistent with SCLC, with 9 of 27 positive lymph nodes. An extensive search for distant metastases was negative. The patient underwent radiation therapy and a 6-month course of chemotherapy. Her muscle weakness did not respond despite 3 months of plasmapheresis (twice per week) and pyridostigmine, 120 mg every 3 hours. After the completion of chemotherapy, she was placed on guanidine, and the dose was increased to 500 mg qid, with no effect. Prednisone, 80 mg daily, was added, also with no beneficial result.

Eight months later, diarrhea developed increasingly. Pyridostigmine (Mestinon) was stopped, but the diarrhea became so severe that the patient required intravenous hyperalimentation. There was no clinical or radiologic evidence of SCLC recurrence. Then acute tubular necrosis developed, and the patient declined treatment with dialysis. She died 14 months after the onset of neurologic symptoms, 10 months after being diagnosed with LEMS and SCLC.

DIAGNOSIS

Lambert-Eaton myasthenic syndrome, associated with small-cell lung carcinoma.

ANSWERS

1. B; 2. D; 3. C.

SUGGESTED READINGS

Chalk CH, et al. Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology. 1990;40(10):1552-1556.

Eaton LM, Lambert EH. Electromyography and electric stimulation of nerves in diseases of motor unit: observations on myasthenic syndrome associated with malignant tumors. JAMA. 1957;163:1117-1124.

Hughes R, Katirji MB. The Eaton-Lambert (myasthenic) syndrome in association with systemic lupus erythematosus. Arch Neurol. 1986;43:1186-1187.

Jablecki C. Lambert-Eaton myasthenic syndrome. Muscle Nerve. 1984;7:250-257.

Katirji B. Lambert-Eaton myasthenic syndrome: a harbinger to transitional cell carcinoma of the urinary bladder. J Clin Neuromusc Dis. 2000;1:134-136.

Lambert EH, Eaton LM, Rooke ED. Defect of neuromuscular conduction associated with malignant neoplasms. Am J Physiol. 1956;187:612-613.

Lennon VA, et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med. 1995;332:1467-1474.

Leys K, et al. Calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Ann Neurol. 1991;29(3):307-314.

Maddison P, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro EB, editors. Neuromuscular disorders in clinical practice. Boston, MA: Butterworth-Heinemann; 2002:931-941.

Maddison P, Newsom-Davis J, Mills KR. Distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1998;65:213-217.

Maddison P, Newsom-Davis J, Mills KR, et al. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet. 1999;353:117-118.

McEvoy KM, et al. 3,4-Diaminopyridine in the treatment of Lambert-Eaton syndrome. N Engl J Med. 1989;321:1567-1571.

O’Neil JH, Murray NMF, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome: a review of 50 cases. Brain. 1988;111:577-596.

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

Tim RW, Saunders DB. Repetitive nerve stimulation studies in Lambert-Eaton myasthenic syndrome. Muscle Nerve. 1994;17:995-1001.

Ueno S, Hara Y. Lambert-Eaton myasthenic syndrome without anti-calcium channel antibody: adverse effect of calcium antagonist, diltiazem. J Neurol Neurosurg Psychiatry. 1992;55(5):409-410.

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