The Neuromuscular Junction in Health and Disease

 

CASE 4

 

A 69-year-old woman became progressively weaker over a 3-month period. Her symptoms fluctuated during the day — at their worst when she awakened. Although her greatest difficulty was climbing stairs, she also had difficulty raising her arms. Patient denied pain, numbness, diplopia, difficulty swallowing, bladder abnormalities, and dark urine. She noted some dryness of her mouth. Her medical history included vascular insufficiency of her legs that required a shunt on the right, and diabetes mellitus that was treated orally. She had been a heavy smoker for many years.

Physical examination: There were not abnormalities of cranial nerve, cerebellar, or sensory function. Her weakness was diffuse and mild, with strength increasing on repeated effort. Deep tendon reflexes were absent, but after quadriceps exertion, knee jerk became obtainable. Plantar responses were flexor. Nerves were normal to palpation. There was no plantar hyperpathia and no calf tenderness.

 

Questions

1. What is the major diagnosis under consideration? Describe its main features.

2. What other condition(s) have features that seem to change with exercise?

3. What else could be considered in light of this patient’s history?

 

Answers

1. Patients with Lambert-Eaton myasthenic syndrome (LEMS) frequently complain of weakness maximal on arising. Their strength improves as they continue their activities. Other common features are hip weakness, absent or hypoactive reflexes, and dryness of the mouth. In addition, this patient’s heavy smoking history is significant, because LEMS is frequently associated with oat cell carcinoma of the lung.

2. Exercise, of course, is related too the weakness in myasthenia gravis. It also elicits symptoms in metabolic myopathies (such as Pompe’s disease) and can trigger cramps and myokymia. In addition, patients with spinal stenosis can experience claudication after walking. In mytonic states, the clinical and electrical myotonia can improve temporarily with exercise (warming up).

3. In view of the patient’s history of diabetes mellitus, the possibility of a diabetic polyneuropathy or polyradiculopathy must be considered. In addition, because proximal muscles are especially involved, a myopathy must be ruled out.

 

Electrodiagnostic Examination

Motor Conduction

Latency

(msec)

Conduction

Velocity

(M/sec)

Amplitude

Left median wrist/ abductor pollicis brevis

3.2 Normal

Elbow/wrist

52 Normal

Low

Left peroneal ankle/ extensor digitorum brevis

4.5 Normal

Knee/ankle

36 Slow

Markedly low

Right peroneal ankle/ extensor digitorum brevis

4.2 Normal

Knee/ankle

41 Low normal

Markedly low

Left tibial ankle/abductor hallucis

48.4 Normal

Knee/ankle

39 Low normal

Markedly low

Left FEDB

48 Normal

Sensory Nerve Action Potentials

Latency (msec)

Amplitude

Left median wrist/second digit

2.3 Normal

Normal

Left ulnar wrist/fifth digit

2.2 Normal

Normal

Repetitive Supramaximal Stimulation (RSS)

Repetitive supramaximal stimulation of the left ulnar nerve at 1- and 3-Hz stimulation rate did not elicit a significant change in the evoked CMAP. Stimulation of the left median nerve at 3 Hz elicited a 22% decrement. After exertion of the abductor pollicis brevis, there was a 400% increment. On RSS at 20 and 50 Hz, there was an increment of 150% and 250% respectively.

Electromyography

Left deltoid

Left biceps brachii

left first dorsal interosseous

Left paraspinal (upper to lower

lumbar)

Left tibialis anterior

Left quadriceps

Left extensor diditorum brevis

Silent at rest. Normal MUPs on volition. No variability of the MUPs was noted.

 

Questions

1. Does RSS at 3 per second distinguish between myasthenia gravis and LEMS? What else has to be considered?

2. What do the studies at 20 and 50 per second signify? Comment on the postactivation facilitation.

3. What routine study can alert you to the possibility of LEMS?

4. Comment on the nerve conduction studies.

5. What other electrodiagnostic features are found in LEMS?

Answers

1. Three-per-second RSS resulted in a progressive decrement in the amplitude of the evoked CMAP, which was maximal by the sixth response, and subsequently reversed (suggesting that recruitment was occurring). This finding, however, does not distinguish between myasthenia gravis and LEMS, inasmuch as this occurs with both presynaptic and postsynaptic deficits.

There are causes of decrements on RSS other than neuromuscular junction disorders. A decrement can be seen in hemiplegia, parkinsonism, poliomyelitis, cervical radiculopathy, myotonia congenita or dystrophica, myositis, systemic lupus, tick paralysis, some drug treatment, and polyneuropathy.

2. Lambert-Eaton myasthenic syndrome (LEMS) is identified by a significant facilitation at a higher stimulation frequency (greater than 10 per second). Normal subjects may show a similar increment, but it should not exceed 50%. In this patient, an increment of 250% was found using these higher frequencies.

In addition, the effect of tetany, either on volition or after RSS, can be studied. There is an immediate postactiviation facilitation, followed by a postactivation exhaustion several minutes later. In this case, a 400% increment followed 30 seconds of voluntary activity of the target muscle. This postactivation facilitation after exertion is probably the electrical correlate of the clinical improvement in strength and in the knee jerk noted after exercise.

3. In a patient with progressive weakness, especially in a proximal distribution, LEMS has to be considered. In addition, if routine motor nerve conduction studies reveal low-amplitude CMAPs, the examiner should consider LEMS. Other presynaptic abnormalities include botulinum toxicity and hypermagnesemia. Alternatively, low CMAPs can occur with dysfunction elsewhere, such as axonal polyneuropathies, or any lower motor neuron or myopathic process causing loss of muscle fibres.

4. The borderline values of the nerve conduction studies suggest a concomitant polyneuropathy, possibly related to the patient’s diabetes mellitus. Note: This is a possible cause of the decrement at slow rates on RSS.

5. On EMG, there may be variability of the MUPs from a motor unit. In addition, SFEMG may reveal increased jitter and frequent blocking, which probably correlate with the variation in MUPs. These abnormalities seem to reverse after rapid RSS.

Electrodiagnostic Interpretation

Studies are consistent with LEMS. In addition, there is a minimal polyneuropathy.

Follow-up

Normal blood tests included CPK, antinuclear antibodies, thyroid function, and test for acetylcholine receptor antibodies. There was evidence for diabetes mellitus.

Tensilon test was negative. Computerised tomography scan revealed a mediastinal mass that, on bronchoscopic biopsy, was found to be a small-cell carcinoma.

Significance

This is a case of LEMS suggested clinically (progressive proximal weakness, absent deep tendon reflexes, and dryness of the mouth in a long-term smoker), and electrically (decreased amplitude in the CMAPs). It was confirmed electrically by a decrement at low-frequency RSS and an increment at high-frequency RSS and after voluntary exercise.