Lambert-Eaton myasthenic syndrome

Abstract

Lambert-Eaton myasthenic syndrome is a disorder of neuromuscular transmission in which an autoantibody is directed against the pre-synaptic calcium channel. It presents with proximal limb weakness, greater in the legs, with or without peripheral and autonomic neuropathy. Bulbar involvement is rare and fatigueability is not a feature.

BACKGROUND

The term “myasthenia” comes from the Latin “myos” meaning muscle, and the Greek asthenes, meaning a- (without) + sthenos (strength), and so it literally means muscle weakness, not fatiguable weakness. In common parlance, however, the term “myasthenic weakness” is used to describe the fatiguability which is a cardinal feature of myasthenia gravis, an acquired, autoimmune, post-synaptic disorder. In 1956 Lambert, Eaton and Rooke described a novel acquired pre-synaptic neuromuscular transmission disorder which has become referred to as the Lambert–Eaton myasthenic syndrome or LEMS. Indeed, it is described as a “myasthenic” syndrome in textbooks alongside myasthenia gravis but, potentially confusingly, it is not usually characterised by prominent complaints of fatiguable weakness and the clinical picture is unlike conventional myasthenia gravis. This commonly leads to diagnostic delay in a treatable disorder.

CASE PRESENTATION

A woman presented at the age of 32 years. She gave a four-year history of bilateral knee pain and had thought this was the explanation for her decreasing mobility requiring her to resort to sticks to walk, and for the past six months the use of a wheelchair out of doors. She had a past history of chondromalacia patellae and presumed this to be the cause of her pain. She did not give any story of variability in muscle strength or fatiguability. There was no upper limb weakness, or bulbar features. She had difficulty rising from a chair and was unable to get out of a bath. There were no sensory symptoms. She was referred from orthopaedics querying a diagnosis of a myopathy. On examination she was slim. Upper limb and cranial nerve examination was normal. There was predominantly proximal weakness of the lower limbs grade 4 MRC with no wasting. Reflexes were absent in the lower limbs and present only with reinforcement in the upper limbs.

INVESTIGATIONS

Serum CK was 865 IU/l (normal range up to 180). Neurophysiological studies demonstrated small compound muscle action potentials (CMAP) in upper and lower limb muscles. Three per second repetitive stimulation elicited a reduction in amplitude. However, 15 seconds of maximal voluntary contraction of her right abductor pollicis brevis (APB) resulted in a 300% increase in CMAP highly suggestive of LEMS (fig 1). Sampling of muscle showed occasional fasciculations and infrequent fibrillations. There was a full interference pattern, with motor unit potentials (MUPs) of normal amplitude. A variable configuration of potentials was noted suggesting a disorder of neuromuscular transmission. Sensory studies were normal. Her voltage gated calcium channel antibodies were strongly positive at 1369 pmol (normal range up to 45). CT chest was normal. She was started on 3, 4 diamino-pyridine (3, 4 DAP) with some improvement in muscle power. Immunosuppression with steroids and azathioprine has resulted in her regaining mobility without aids and a return to work.

Figure 1. Left median compound muscle action potential (CMAP) to thenar muscles of unexpectedly small amplitude (upper trace).

Muscles exercised for 20 seconds and CMAP amplitude increments by 300% (lower trace).

TREATMENT

The weakness responds to 3, 4 DAP which blocks potassium channels at the motor nerve terminal, so increasing the duration of the action potential which leads to increased calcium influx and, thus, greater acetylcholine release. Daily doses range from 10 mg qds to 20 mg qds, and rarely more. Toxicity includes perioral or distal paraesthesias, insomnia and seizures. The drug is contraindicated in patients with epilepsy. The evidence base for other therapies is poor.² Guanidine is a very toxic alternative potassium channel blocker. Pyridostigmine offers very little additional benefit to 3, 4 DAP. Conventional wisdom would recommend immunosuppression with steroids or azathioprine with intravenous immunoglobulin or plasma exchange for severe disease, exacerbations, or in those unable to tolerate steroids or other immunosuppressants. The approach and doses recommended are the same as in myasthenia gravis. There are reports of disease regression in cases of LEMS associated with lung cancer after the cancer is successfully treated.

DISCUSSION

Lambert–Eaton myasthenic syndrome is rare with a prevalence of about 1 per 100,000, equally common in men and women. The onset is mostly over the age of 50 although it can affect children. It is associated with small cell lung tumours, lymphoproliferative disorders and rarely with other malignancies. It has been suggested that LEMS may be more common than is generally believed among patients with lung cancer, with many having undiagnosed disease. Overall, tumours are identified in about 50% of cases, and there are also reports of an association with sarcoidosis. In the remainder there is evidence of an association with other autoimmune disorders including vitiligo, and there is an association with HLA-B8 and DR3. Authors have recommended CT thorax at diagnosis and that a paraneoplastic aetiology be considered for up to five years from symptom onset.

The weakness is usually more prominent in lower limbs but bulbar features and diplopia (transient in up to 40%) are less common and less severe than in myasthenia gravis. The sensory neuropathy is distal and symmetrical and may be a prominent feature. The associated autonomic neuropathy causes dry eyes, impotence and a dry mouth. The serum CK is normal in over 80% of cases.

In tumour and autoimmune and other cases, LEMS is caused by an IgG antibody mediated autoimmune attack on pre-synaptic voltage gated calcium channels. This reduces calcium entry on depolarisation, reducing the numbers of vesicles fusing with the terminal membrane, thus reducing acetylcholine release and the safety factor of neuromuscular transmission

At first presentation LEMS does not sound like a pure neuromuscular disorder and, despite the name, it is not usually characterised by complaints of fatiguability. Indeed the main thrust of this article is that the picture is unlike myasthenia gravis. The weakness is usually proximal, lower limb before upper limb, and does not often involve the extraocular muscles or produce dysarthria. Additional features which are often present if sought include complaints of numbness or tingling in hands and feet, a dry mouth and erectile failure. These features, along with the absence or depression of reflexes may lead to the investigation of a possible “neuropathy” while the story suggesting fixed weakness may lead to the investigation of a “myopathy”.

The diagnosis depends on a combination of detection of the serum antibody and neuro-physiological studies;¹ both requiring the diagnosis to be thought of; EMG studies without repetitive stimulation at appropriate frequencies may well be non-specific. The usual finding at rest is of small MUPs which may provide the clue to LEMS, but if the diagnosis is not considered the EMG will not be diagnostic. In this case the diagnosis was also supported by the variable morphology of the MUPs consequent on variable blocking of transmission from a proportion of the terminal neuromuscular junctions within a single motor unit.

LEARNING POINTS

• The diagnosis of LEMS is often delayed and it may need “rebranding” or renaming to downplay the “myasthenic” label.

• The current label may lead to the diagnosis only being considered in patients who look as though they may have myasthenia, whereas the presentation is more often like proximal lower limb myopathy.

• Fatigue is not a major feature, unlike the more common myasthenia gravis.

• The clinician referring the patient for an EMG often has not suggested the diagnosis and diagnostic studies are performed only after the observation of unexpectedly small motor unit potentials.

• The diagnostic EMG abnormalities are only seen with appropriate stimulation techniques and mild or difficult cases will be missed unless the clinician has considered and queried the diagnosis.