Lambert–Eaton myasthenic syndrome

Signs and symptoms

The weakness in LEMS typically affects the proximal muscles of the arms and legs, with leg involvement more prominent than arm involvement. This makes climbing stairs and rising from a seated position difficult. Weakness often improves temporarily after exertion or physical exercise, while high temperatures can worsen it. Bulbar muscles (mouth and throat) are occasionally affected, but eye muscle weakness is uncommon; when double vision, drooping eyelids, or difficulty swallowing occur, they generally accompany leg weakness.

In advanced stages, respiratory muscle weakness may develop. Some individuals also experience coordination problems (ataxia). About three-quarters of people with LEMS have autonomic nervous system disruption, which may cause dry mouth, constipation, blurred vision, impaired sweating, orthostatic hypotension, and sometimes a metallic taste. On examination, strength improves with repeated testing (Lambert's sign), reflexes are typically reduced at rest but increase with muscle use, and the pupillary light reflex may be sluggish.

In LEMS associated with small-cell lung cancer, most have no cancer symptoms at the time, though LEMS symptoms can appear up to five years before the cancer diagnosis.

Mechanism

In normal neuromuscular transmission, a nerve impulse opens voltage-gated calcium channels (VGCC) at the nerve terminal, allowing calcium influx that triggers fusion of synaptic vesicles containing acetylcholine. The released acetylcholine stimulates muscle receptors, causing contraction. In LEMS, antibodies against VGCC—particularly the P/Q-type and possibly the N-type—reduce calcium entry into the nerve ending, decreasing acetylcholine release.

This explains both the muscle weakness and the autonomic symptoms, since the autonomic nervous system also relies on acetylcholine. P/Q-type VGCC are also present in the cerebellum, which may account for coordination problems. Antibodies bind especially to the domain III S5–S6 linker peptide of the receptor, and some individuals have antibodies against synaptotagmin, the calcium sensor for vesicle fusion. Many people with LEMS also have antibodies against the M1 subtype of the acetylcholine receptor, which may impair compensation for weak calcium influx.

Additionally, disruption of active zone vesicle release sites occurs, likely antibody-dependent. With repeated stimuli over about ten seconds, sufficient calcium accumulates to increase muscle contraction to normal levels, a phenomenon demonstrable by needle electromyography.

Diagnosis

Diagnosis is typically made using nerve conduction study (NCS) and electromyography (EMG). NCS evaluates compound motor action potentials (CMAPs) of affected muscles; in LEMS, CMAPs show small amplitudes with normal latency and conduction velocities. With repeated impulses at 2 Hz, the decrease in CMAP amplitude is larger than normal, and the amplitude does not recover sufficiently. In response to exercise or a rapid burst of electrical stimuli (20 impulses per second for ten seconds), the CMAP amplitude increases greatly (over 200%), attributed to calcium influx.

Single-fiber EMG may show increased jitter and blocking. Blood tests help exclude other causes of muscle disease, such as elevated creatine kinase (myositis) or abnormal thyroid function (thyrotoxic myopathy). Antibodies against voltage-gated calcium channels are identified in 85% of people with EMG-confirmed LEMS. Once LEMS is diagnosed, a CT scan of the chest is usually performed to look for underlying lung tumors; about 50–60% are found immediately, and the remainder typically within two to four years.

Scans are often repeated every six months for the first two years. A positron emission tomography scan may also be used to search for an occult tumor, particularly of the lung.

Treatment

If LEMS is caused by an underlying cancer, treating the cancer—usually with chemotherapy and possibly radiation therapy—can relieve symptoms. Firdapse is the only FDA-approved treatment for LEMS; it works presynaptically to increase acetylcholine release and improve muscle function. Intravenous immunoglobulin (IVIG) has some evidence of benefit. Immune suppression with prednisolone (a glucocorticoid) and the steroid-sparing agent azathioprine may be used, though immune suppression is less effective than in other autoimmune diseases.

Plasma exchange can provide improvement in acute severe weakness but is less effective than in myasthenia gravis, and additional immunosuppressive medication is often needed. Pyridostigmine, 3,4-diaminopyridine (amifampridine), and guanidine aim to improve neuromuscular transmission. 3,4-Diaminopyridine delays nerve terminal repolarization, allowing more calcium accumulation; tentative evidence supports its use for at least a few weeks. Pyridostigmine decreases acetylcholine degradation.

Guanidine causes many side effects and is not recommended. 4-Aminopyridine (dalfampridine) also causes more side effects than 3,4-DAP and is not recommended. The FDA approved amifampridine for children six years and older with LEMS on November 28, 2018.

Did You Know?

• LEMS may also be associated with endocrine diseases such as hypothyroidism or diabetes mellitus type 1.
• HLA-DR3-B8 seems to predispose to LEMS.
• The first possible clinical case was mentioned by Anderson and colleagues from St Thomas' Hospital, London, in 1953.