In normal neuromuscular function, a nerve impulse is carried down the axon (the long projection of a nerve cell) from the spinal cord. At the nerve ending in the neuromuscular junction, where the impulse is transferred to the muscle cell, the nerve impulse leads to the opening of voltage-gated calcium channels (VGCC), the influx of calcium ions into the nerve terminal, and the calcium-dependent triggering of synaptic vesicle fusion with plasma membrane. These synaptic vesicles contain acetylcholine, which is released into the synaptic cleft and stimulates the acetylcholine receptors on the muscle. The muscle then contracts. In LEMS, antibodies against VGCC, particularly the P/Q-type VGCC, decrease the amount of calcium that can enter the nerve ending, hence less acetylcholine can be released from the neuromuscular junction. Apart from skeletal muscle, the autonomic nervous system also requires acetylcholine neurotransmission; this explains the occurrence of autonomic symptoms in LEMS. P/Q voltage-gated calcium channels are also found in the cerebellum, explaining why some experience problems with coordination. The antibodies bind particularly to the part of the receptor known as the "domain III S5–S6 linker peptide". Antibodies may also bind other VGCCs. Some have antibodies that bind synaptotagmin, the protein sensor for calcium-regulated vesicle fusion. Many people with LEMS, both with and without VGCC antibodies, have detectable antibodies against the M1 subtype of the acetylcholine receptor; their presence may participate in a lack of compensation for the weak calcium influx. Apart from the decreased calcium influx, a disruption of active zone vesicle release sites also occurs, which may also be antibody-dependent, since people with LEMS have antibodies to components of these active zones (including voltage-dependent calcium channels). Together, these abnormalities lead to the decrease in muscle contractility. Repeated stimuli over a period of about 10 seconds eventually lead to sufficient delivery of calcium, and an increase in muscle contraction to normal levels, which can be demonstrated using an electrodiagnostic medicine study called needle electromyography by increasing amplitude of repeated compound muscle action potentials. The antibodies found in LEMS associated with lung cancer also bind to calcium channels in the cancer cells, and it is presumed that the antibodies originally develop as a reaction to these cells. It has been suggested that the immune reaction to the cancer cells suppresses their growth and improves the prognosis from the cancer.
Lambert–Eaton myasthenic syndrome
Botulism
Congenital myasthenic syndrome
Guillain–Barré syndrome
Tension myositis syndrome
De Quervain syndrome
Nemaline myopathy
Inclusion body myositis