Lambert-Eaton myasthenic syndrome

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Introduction0:00–0:23

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.

Physiology0:23–1:43

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 post-synaptic 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.

Pathology1:43–3:14

Now, when the action potential reaches the axon terminal, it opens voltage-gated calcium channels called PQ type channels.
Next, calcium rushes in through these channels, triggering the acetylcholine vesicles to fuse with the pre-synaptic membrane and release acetylcholine into the synaptic cleft.
Once inside the cleft, acetylcholine moves across to bind nicotinic acetylcholine receptors on the post-synaptic 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's 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 hoops with your friends.
Now, in Lambert-Eaton Myasthenic syndrome, the immune system produces antibodies that disrupt the PQ type voltage-gated calcium channels.
So when an action potential arrives at the axon terminal, not enough calcium can get through the pre-synaptic 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.

Symptoms3:14–3:54

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. These autoantibodies don't just target motor neurons of the somatic nervous system, they also disrupt PQ type calcium channels throughout the body, including the peripheral nerves of the autonomic nervous system.

Diagnosis3:54–4:08

As a result, these individuals also have autonomic dysfunction. Now, there are several reasons why the immune system turns against these channels.

Treatment4:08–4:43

The most common is perineoplastic 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.

Review4:43–8:58

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.
Now, let's move on to clinical manifestations, which can be subdivided into muscle and autonomic manifestations. When it comes to muscle manifestations, Lambert-Eaton Myasthenic syndrome mainly causes symmetrical weakness in the proximal muscles.
It's important to note that the weakness usually follows a caudocranial pattern. It begins in the legs, particularly the thighs and hips, and then progresses upward to affect the shoulders.
Because of this, individuals often report difficulties climbing stairs or standing up. This is extremely important because Lambert-Eaton Myasthenic syndrome can be mistaken for myasthenia gravis, but the pattern is different.
Myasthenia gravis follows the craniocaudal pattern, meaning it typically begins with the extraocular muscles and spreads down to affect arms and legs.
Another key feature of Lambert-Eaton Myasthenic syndrome is the warming up phenomenon, where muscle strength improves with repeated use.
That's because repeated impulses eventually push enough calcium through the few remaining functional PQ type calcium channels to trigger muscle contraction.
Imagine shooting basketballs in your backyard. At first your arms feel weak, but as you keep shooting, your strength picks up, and you start landing shots.
That's how it feels for someone with Lambert-Eaton Myasthenic syndrome. In more severe cases, weakness can affect the respiratory muscles, leading to breathing difficulties and even respiratory failure.
On top of weakness, reflexes are often reduced or completely absent. So if you tap the patellar tendon, you might see a weak or missing knee-jerk response.
On the other hand, autonomic manifestations might include dry mouth, constipation, blurred vision, sexual dysfunction, and urinary problems.
Now, let's talk about diagnosis, which mainly depends on clinical features in the presence of voltage-gated calcium channel antibodies, or VGCCs for short.
Nerve conduction studies usually show reduced motor amplitudes with normal sensory responses. They also reveal an incremental increase in muscle response during repeated stimulation.
In other words, quick repeated nerve stimulation leads to a stronger muscle response, which matches the warming up effect.
Finally, don't forget to check for small cell lung carcinoma using a chest CT or PET scan. Treatment depends on the underlying cause.
If malignancy such as small cell lung cancer is the cause, treating the cancer becomes the main priority. In other cases, medications like Amihampradine can help boost the release of acetylcholine into the synaptic cleft.
Additionally, to calm down the immune system, we can use immunosuppressive medications or intravenous immunoglobulins. In severe cases, plasmapheresis can help remove harmful antibodies from the blood.
All right, as a quick recap. Lambert-Eaton Myasthenic syndrome is an autoimmune condition where the body's immune system produces antibodies that disrupt the PQ type voltage-gated calcium channels.
These channels are found on peripheral motor neurons and in the autonomic nervous system. As a result, people develop proximal muscle weakness that usually starts in the legs and moves upward.
Reflexes are often reduced or completely absent, and many also experience symptoms of autonomic dysfunction like dry mouth, constipation, and urinary problems.