Myasthenia gravis

Definitions & Key takeaways

Myasthenia gravis is an autoimmune disease, specifically a type II hypersensitivity disorder, which is characterized by autoantibodies against nicotinic acetylcholine receptors on the surface of muscle cells.

The antibodies block the receptors which means the signal to contract isn't received. Those antibodies also activate the complement pathway which leads to muscle cell destruction.

Symptoms can range from mild to severe and may include drooping eyelids, difficulty speaking or swallowing, and muscle weakness in the arms and legs. Treatment involves immunosuppressive drugs like prednisolone, and acetylcholinesterase inhibitors like neostigmine. The purpose is to reduce the immune system's attack on the muscle and to increase muscle strength.

Chapters:

Watch video only

Introduction0:00–0:43

Myasthenia gravis comes from the Greek word myasthenia, meaning muscle weakness, and the Latin word gravis, meaning severe.
So myasthenia gravis is an autoimmune condition that causes serious muscle weakness. 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.

Causes0:43–0:57

The communication site between the lower motor neuron and the skeletal muscle fiber is known as the neuromuscular junction, which consists of three main parts.

Physiology0:57–1:25

First, there's the pre-synaptic 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 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.

Pathology1:25–3:05

Now, the arrival of the action potential at the axon terminal triggers the opening of voltage-gated calcium channels in the pre-synaptic membrane, allowing calcium ions to rush in.
This triggers 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.
In myasthenia gravis, the immune system produces antibodies that disrupt the normal function of nicotinic acetylcholine receptors.
Now, there are 3 types of autoantibodies. First, we have blocking antibodies, which bind and block acetylcholine receptors, so acetylcholine can't activate them.
Next, there are binding antibodies, which bind the receptors and activate the complement system, eventually destroying them.
Finally, the third type includes modulating antibodies, which bind the receptors and trigger the muscle cell to pull the entire receptor inside.
As more receptors are blocked, destroyed, or removed from the post-synaptic membrane, it becomes harder and harder for muscles to receive signals, leading to muscle weakness.

Symptoms3:05–3:20

But that's not all. Sometimes the immune system does not directly attack the acetylcholine receptors.
Instead, it targets other important proteins that help neuromuscular junctions work properly, like muscle-specific kinase and lipoprotein-related protein 4.

Treatment3:20–4:23

When they're disrupted, the connection between nerves and muscles becomes unstable or weak, making it even harder for signals to reach the muscle and causing further muscle weakness.
Now, several risk factors contribute to myasthenia gravis, including thymic abnormalities and genetics. In thymic hyperplasia, the thymus enlarges and forms reactive B cell follicles that produce autoantibodies.
Next up is thymoma, which is a tumor that arises from the epithelial cells of the thymus. Both conditions can cause the thymus to misguide the immune system into attacking acetylcholine receptors.
Next up, are genetic factors. Certain HLA subtypes, which are genes that help control the immune system, can make someone more likely to develop autoimmune conditions like Myasthenia gravis.
Moreover, myasthenia gravis often shows up alongside other autoimmune diseases, such as thyroiditis, lupus, or rheumatoid arthritis.

Review4:23–9:20

Now, moving to clinical manifestations. As the immune system blocks, destroys, or removes receptors from the post-synaptic membrane, muscles have a hard time receiving signals.
Ultimately, this leads to muscle weakness and fatigue, which is more pronounced in the proximal muscles. Remember when you were a kid and spent the whole day in the backyard shooting basketballs?
Imagine that after a few throws, your muscles started to feel weak. You'd have to stop and rest before you could keep playing.
Well, that's what it's like for someone with myasthenia gravis. Their muscles get tired quickly, even with simple things like brushing their teeth, or combing their hair.
Myasthenia gravis can be subdivided into ocular and generalized myasthenia. Ocular myasthenia affects the muscles that move the eyes, also called extraocular muscles.
This often leads to droopy eyelids, known as ptosis, and double vision, also called diplopia. On the flip side, generalized myasthenia affects many muscles throughout the body, not just the ones around the eyes.
Moreover, weakness primarily affects the proximal muscles, so the muscles closer to the center of the body, like the shoulders and thighs, are more affected than the distal muscles in the hands or feet.
Since proximal muscles are responsible for big movements, everyday activities like lifting arms, climbing stairs, or getting out of a chair, become challenging.
Generalized myasthenia can also affect the muscles in your mouth and throat, making it difficult to speak, which is called dysarthria, and hard to swallow, which is known as dysphagia.
In severe cases, weakness can spread and affect the respiratory muscles, causing breathing difficulties and even respiratory insufficiency.
This is known as myasthenic crisis, and can be triggered by things like infections, pregnancy, or certain medications, such as aminoglycosides, erythromycin, and beta-blockers.
Next up is diagnosis, which relies on several tests. The first test is the ice pack test.
When you put ice over a tautic eyelid, the cold temporarily slows down the breakdown of acetylcholine in the synaptic cleft.
In myasthenia gravis, this gives acetylcholine more time to stimulate the muscle, which can temporarily improve the eyelid's movement.
Next is the Tensilon test, in which edrohonium is injected into the patient. This medication works by inhibiting acetylcholinesterase, thereby increasing the amount of acetylcholine in the synaptic cleft.
In patients with myasthenia gravis, this results in temporary improvement in muscle strength, highlighting the underlying deficiency in acetylcholine action at the neuromuscular junction.
Next, it's important to check for autoantibodies in the blood. Most people with myasthenia gravis will have antibodies against acetylcholine receptors, but in some cases, the immune system targets other proteins instead, like muscle-specific kinase or lipoprotein-related protein 4.
Sometimes, there will be no antibodies, which is known as seronegative myasthenia gravis. Another helpful technique is single fiber electromyography.
In myasthenia, repeated muscle stimulation shows a decrease in the action potential amplitude, which is a clear sign of impaired neuromuscular transmission.
Finally, a CT scan can help identify conditions like thymic hyperplasia and thymoma. The good news is that there are effective treatments for myasthenia gravis.
Acetylcholinesterase inhibitors, like neostigmine or pyridostigmine, inhibit the acetylcholinesterase, preventing the breakdown of acetylcholine.
As a result, acetylcholine accumulates in the synaptic cleft, which helps counteract the effects of acetylcholine receptor antibodies.
Next, immunosuppressive medications like prednisone can calm the immune system and reduce the production of harmful antibodies.
Finally, surgical removal of the thymus can reduce muscle weakness, likely because the thymus harbors B cells that produce antibodies against acetylcholine receptors.
All right, as a quick recap. In myasthenia gravis, the immune system produces autoantibodies that block, destroy, or remove acetylcholine receptors at the neuromuscular junction, causing muscle weakness.
Some individuals develop antibodies against other key proteins, such as muscle-specific kinase and lipoprotein-related protein 4, which disrupts the nerve muscle connection.
Finally, keep in mind that myasthenia gravis is more common with thymic conditions like thymic hyperplasia and thymoma.