Lambert-Eaton myasthenic syndrome

With Lambert-Eaton myasthenic syndrome, or LEMS for short, “myasthenia” refers to muscle weakness, and Lambert-Eaton refers to Edward Lambert and Lealdes Eaton, the two physicians who first described the condition. So, Lambert-Eaton myasthenic syndrome is a rare autoimmune condition that attacks the peripheral nervous system, causing muscle weakness, weak or absent reflexes, and autonomic dysfunction.

First, let's focus on physiology and how muscles normally work. Whether you’re reaching for a slice of pizza or sinking that perfect shot in basketball, it all starts in the brain. The upper motor neuron of the cerebral cortex fires an action potential down the spinal cord to activate lower motor neurons. Next, lower motor neurons pick up these signals and pass them along their axons toward terminal branches and axon terminals, all the way to skeletal muscle fibers.

This communication site between the lower motor neuron and the skeletal muscle fiber is known as the neuromuscular junction, which consists of three main parts. First, there’s the presynaptic membrane, which is the axon terminal of the lower motor neuron packed with acetylcholine vesicles. Acetylcholine is actually the neurotransmitter that enables muscle contraction. Next, there’s the postsynaptic membrane, which is the membrane of the skeletal muscle fiber, rich in nicotinic acetylcholine receptors.

Finally, this tiny space between two membranes is called the synaptic cleft and contains the enzyme acetylcholine esterase.

Now, when the action potential reaches the axon terminal, it opens voltage-gated calcium channels called P/Q type channels. Next, calcium rushes in through these channels, triggering the acetylcholine vesicles to fuse with the presynaptic membrane and release acetylcholine into the synaptic cleft. Once inside the cleft, acetylcholine moves across to bind nicotinic acetylcholine receptors on the postsynaptic membrane. Eventually, this binding triggers the muscle cell to depolarize, setting off a chain of intracellular events that lead to contraction. Once the contraction is over, acetylcholine is broken down by acetylcholine esterase, allowing the muscle to relax and prepare for the next signal.

This subdivision of the peripheral nervous system that controls voluntary movements is known as the somatic nervous system. There is also the autonomic nervous system, which controls involuntary actions like heart rate, breathing, and digestion. Thanks to the autonomic nervous system, you don’t have to worry about your digestion or heart rate while you’re shooting basketballs with your friends.

Now, in Lambert-Eaton myasthenic syndrome, the immune system produces antibodies that disrupt the P/Q-type voltage-gated calcium channels. So, when an action potential arrives at the axon terminal, not enough calcium can get through the presynaptic membrane. Without calcium, the neuron cannot release acetylcholine into the synaptic cleft. And without acetylcholine, the nicotinic receptors remain quiet, leaving the muscle fiber without the signal to contract.

The good news is that with repeated impulses from the brain, some calcium enters the presynaptic membrane through the few functional channels. Often, that’s enough to release acetylcholine and finally trigger the muscle fiber to contract. (VO long pause)

These autoantibodies don’t just target motor neurons of the somatic nervous system. They also disrupt P/Q-type calcium channels throughout the body, including the peripheral nerves of the autonomic nervous system. As a result, these individuals also have autonomic dysfunction.

Now, there are several reasons why the immune system turns against these channels. The most common is paraneoplastic syndrome, mainly caused by small-cell lung carcinoma. These cancer cells tend to express the same calcium channels found on motor and autonomic neurons. So, as the immune system is producing antibodies to fight the cancer cells, it mistakenly attacks the calcium channels on peripheral neurons, leading to Lambert-Eaton myasthenic syndrome.

Genetics can also play a role, since certain HLA subtypes increase the risk of autoimmune conditions. That’s why Lambert-Eaton myasthenic syndrome often shows up alongside other autoimmune conditions, like vitiligo or autoimmune thyroid conditions.