Neuromuscular junction disorders: Pathology review

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Case Study0:00–1:14

While doing your rounds, you see Kira, a 23-year-old female who presents with a series of recurrent symptoms that get worse as the day progresses.
These include slurring of speech, difficulty swallowing, and double vision. She also mentions that her head feels heavy and is hard to hold up.
She also complained that her arms are so weak she can’t even brush her hair. Additionally, she reports severe fatigue and shortness of breath.
On examination, sensation and reflexes are normal. Next, you see a 62-year-old man named Jonathan, who presents with a history of leg muscle weakness that prevents him from doing simple things like climbing stairs or standing up, which gets better the more he uses his legs.
He also reports shortness of breath, fatigue, dry mouth, impotence, and unintentional weight loss. Examination reveals a severely underweight man with dilated pupils.
Reflexes are initially absent, although these are obtainable after a brief period of exercise. Blood tests were obtained, detecting anti-acetylcholine receptor antibodies in Kira and anti-voltage-gated calcium channels antibodies in Jonathan.
Now, both seem to have some type of neuromuscular junction disease. But first, a bit of physiology.

Physiology1:14–1:59

In normal neuromuscular function, a nerve impulse is carried down the axon from the spinal cord, to the nerve endings, in the neuromuscular junction, where the impulse is transferred to the muscle cell.
Here, the nerve impulse leads to the opening of voltage-gated calcium channels, causing an influx of calcium ions into the nerve terminal, which triggers synaptic vesicle fusion with plasma membrane.
These synaptic vesicles contain a neurotransmitter called acetylcholine, which is released into the synaptic cleft. The neurotransmitter then binds to nicotinic acetylcholine receptors on muscle cell membranes and activates a chain reaction in the muscles that ultimately results in their contraction.Ok, so there are two commonly tested diseases affecting the neuromuscular junction.
First we have myasthenia gravis which is the most common. It’s an autoimmune disease that leads to varying degrees of skeletal muscle weakness, especially in women in their 20s and 30s and men in their 60s and 70s.

Myasthenia Gravis1:59–4:07

The cause of this odd “bimodal” distribution of age-of-onset is unclear. What’s clear, though, is that the disease is marked by an antibody-mediated type II hypersensitivity.
This begins when B cells get inappropriately activated, and they start making antibodies against the nicotinic acetylcholine receptors on the muscle cells.
The antibodies bind to these receptors, and once they do that, the receptors are unable to bind acetylcholine. Without acetylcholine, muscles don’t contract as they should when they receive the “contract” signal from the central nervous system.
Anti-acetylcholine receptor antibodies can also activate the classical pathway of the complement. The complement system is a family of small proteins that work in an enzymatic cascade to fight off pathogens.
The activation of complement causes inflammation and destruction of the muscle cells, reducing the number of acetylcholine receptors on the muscle cell surface, which impairs contraction even more.
Now, a minority of people with myasthenia gravis produces another type of antibody called muscle-specific receptor tyrosine kinase antibody, which attacks proteins inside myocytes instead of nicotinic acetylcholine receptors, and this leads to muscle cells impairment as well.The trigger for autoantibody production is unknown, but the disorder can be associated with other diseases.
For example, myasthenia gravis can present as a paraneoplastic syndrome, which is a condition that arises as a result of cancer elsewhere in the body.
The culprit is usually bronchogenic carcinoma or a thymic neoplasm, also called a thymoma, which generates an immune response that results in autoantibody production.
Other conditions associated with the disease include hyperthyroidism, thymus hyperplasia, and autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, and pernicious anemia.Regarding symptoms, the high-yield hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after rest.

Myasthenia Gr. Symptoms4:07–6:05

Manifestations also fluctuate in intensity over minutes, to hours, to days, and tend to get better in cold weather. Ok, so myasthenia can initially affect the muscles around the eyes, which might be the only signs of disease.
When this occurs, the disease is called ocular myasthenia gravis, and it typically evolves into generalized myasthenia after a few years.
These muscles control movement of the eye as well as the eyelids, so because they can’t contract, individuals might develop diplopia or double vision, as well as ptosis, or drooping eyelids.
Neck muscles can become weak too, and these individuals might feel their head is heavy and it’s hard to keep upright. When arm and leg muscles are involved, people might experience difficulties in walking, climbing stairs, and performing simple tasks such as hair combing and brushing their teeth.
In other cases, individuals might present with bulbar symptoms, which are caused by weakness in the muscles of the mouth and throat responsible for speech and swallowing.
These symptoms can include a change in voice and slurred speech, nasal regurgitation, difficulties chewing, choking, and dysphagia, or difficulty swallowing.
Finally individuals often exhibit chronic and severe fatigue. If certain muscles are affected, people can develop a myasthenic crisis, which is a life-threatening manifestation of the disease.
This can occur when there decreased function of the muscles that control breathing, like the intercostal muscles or the diaphragm, which can cause dyspnea and, in time, respiratory insufficiency.
Once respiratory insufficiency begins, respiratory failure may occur rapidly. Myasthenic crisis are often due to a supervening infection that reactivates the immune system.Diagnosis is usually based on suggestive symptoms and the presence of the anti-acetylcholine receptor antibody in the serum.

Myasthenia Gr. Diagnosis6:05–8:21

During a physical exam, they might have the milkmaid’s grip sign. This is where the individual is asked to squeeze the hand of the clinician and their handgrip may alternate between weak and normal, which resembles a milking motion.
A high yield fact to keep in mind is that sensation and deep tendon reflexes are normal. For lab tests, around a quarter of those affected have no antibodies to acetylcholine receptors in their serum; in these individuals, the muscle-specific receptor tyrosine kinase antibody should be tested.
Single-fiber electromyography, a test that uses repetitive electrical stimuli to assess muscle function, can be performed too, and it usually detects abnormal neuromuscular transmission.
Now, sometimes, treatment with long-acting acetylcholinesterase inhibitors like pyridostigmine can lead to a cholinergic crisis due to too much acetylcholine released at the neuromuscular junction which causes overstimulation.
Because a cholinergic crisis is almost identical to a myasthenic one, the edrophonium, or Tensilon test can be used to differentiate between them.
The test uses injections of edrophonium chloride, an acetylcholinesterase inhibitor, to briefly block the breakdown of acetylcholine and temporarily increases its levels at the neuromuscular junction.
In myasthenia gravis, this is enough to overcome the symptoms caused by the decreased number of available receptors, so the weakness will improve.
If symptoms get worse, a cholinergic crisis can be suspected.Thyroid function tests are indicated to rule out associated Graves disease or hyperthyroidism.
This is essential, especially in those with ocular myasthenia gravis, where concomitant hyperthyroidism is frequent. Similarly, once myasthenia is diagnosed, CT or MRI of the thorax should be done to check for thymic hyperplasia and thymoma.
Those with myasthenia crisis should be evaluated for an infectious trigger and for respiratory muscle weakness by pulmonary function tests.
Other high-yield triggers of myasthenia include surgery, pregnancy, and childbirth.Treatment consists of acetylcholinesterase inhibitors like neostigmine or pyridostigmine.

Myasthenia Gr. Treatment8:21–9:14

These drugs prevent acetylcholinesterase from degrading acetylcholine, which increases its concentration around muscle cells and, subsequently, counteract the effects of acetylcholine receptor antibodies.
Acetylcholinesterase inhibitors can cause adverse effects related to nicotinic and muscarinic overstimulation, the two receptors for acetylcholine.
This in turn, can be managed by using an antimuscarinic agent such as scopolamine. Next, severe cases of myasthenia gravis can also be treated with immunosuppressive drugs, like prednisone, which reduce the production of harmful antibodies.
Finally, a lot of people with myasthenia gravis undergo surgical removal of the thymus, or thymectomy, which can improve symptoms even in people that don’t appear to have any issue with the thymus gland itself.
Okay, let’s move on to Lambert-Eaton myasthenic syndrome, or LEMS for short. This is a rare autoimmune disease that attacks the peripheral nervous system, causing limb muscle weakness.

LEMS9:14–11:14

The peripheral nervous system includes the nerves that connect the central nervous system to muscles and organs. It can be divided into the somatic nervous system, which controls the voluntary movements of our skeletal muscles, and the autonomic nervous system.
The latter can be further divided into the sympathetic and parasympathetic, and they control the involuntary contraction of the smooth muscles and secretion from glands.
LEMS mostly affects the somatic nervous system, and to a lesser degree, the parasympathetic part of the autonomic nervous system.And just like myasthenia gravis, it is characterized by a type II hypersensitivity reaction.
In this case, B cells inappropriately make antibodies against the presynaptic voltage-gated calcium channels on the motor neurons.
As a consequence, the antibodies bind to and block the channels, leaving just a few that are viable. But these can only really generate a low level of calcium within the neuron, which is not enough to trigger the release of acetylcholine into the neuromuscular junction and cause the muscles to contract.
Although, with repeated stimulation by electrical impulses from the brain, enough calcium might finally make it through the few free calcium channels, resulting in acetylcholine release and muscle contraction.
This is why, unlike myasthenia, muscle weakness in LEMS tends to improve the more you use the affected muscles.Now, LEMS is typically associated with small cell lung cancer, which makes the condition a paraneoplastic syndrome.
Because small cell lung cancer cells express the same calcium channels that are found on motor neurons, when B cells generate antibodies against cancer cells, the antibodies can also mistakenly attack the presynaptic voltage-gated calcium channels on the motor neurons.
Other autoimmune diseases that LEMS can be associated with include Hashimoto’s thyroiditis and diabetes mellitus type 1, although the precise mechanism is unclear.Regarding symptoms, something high-yield about Lambert-Eaton myasthenic syndrome is that it is marked by a warming-up phenomenon, which is when symptoms are relieved temporarily after repeated use of the muscles.

LEMS Symptoms11:14–12:34

Most commonly, the disease leads to symmetrical weakness of the proximal muscles, which are the muscles closer to the trunk, like those in the shoulders, hips and thighs.
Compared with myasthenia gravis, the lower limbs are more likely to be affected. On your exams this is often presents as the individual having difficulties climbing stairs, standing up from a sitting position, and lifting their arm to brush their hair.
In the advanced stages of the disease, individuals can also develop weakness in the respiratory muscles, and that can cause respiratory failure, though this is not as common as in myasthenia gravis.
Apart from skeletal muscle, the autonomic nervous system also requires acetylcholine neurotransmission, which means most people with Lambert-Eaton myasthenic syndrome will also have autonomic symptoms.
These can include dry mouth, constipation, blurry vision, dilated pupils, and urinary and erection problems. Additionally, voltage-gated calcium channels are also found in the cerebellum, explaining why some experience problems with coordination.
Affected individuals can also experience increased fatigability and unintentional weight loss if lung cancer is involved.

LEMS Diagnosis12:34–13:16

Diagnosis in LEMS is based on suggestive symptoms and a series of tests. In contrast to myasthenia gravis, reflexes are often weak or absent but sensation is still intact.
Lab test can detect autoantibodies against the voltage-gated calcium channels in the individual’s serum; and electromyography showing an incremental response to repetitive nerve stimulation.
The Tensilon test can be used as well; unlike myasthenia, in LEMS there’s usually minimal improvement in muscle weakness but symptoms don’t worsen like in cholinergic crisis.
Once the diagnosis is confirmed, a chest CT scan is often done to look for evidence of an underlying small cell lung cancer.
Treatment of Lambert-Eaton myasthenic syndrome depends on the underlying cause. If there’s a small cell lung cancer, then treatment of the cancer is the main goal, usually by surgery or chemo and radiotherapy.

LEMS Treatment13:16–14:20

When there’s no associated lung cancer, however, treatment consists mostly of guanidine, which can increase the concentration of free intracellular calcium and acetylcholine concentrations at the neuromuscular junction, and of 3,4-diaminopyridine, which increases acetylcholine concentrations by blocking the cells from releasing potassium.
Now, 3,4-diaminopyridine can be used as monotherapy or in combination with guanidine but guanidine cannot be used by itself since is not as effective.
If necessary, immunosuppressive drugs like steroids and intravenous immunoglobulin therapy, can sometimes be used to bind and neutralize the autoantibodies.
Occasionally, more severe cases can be treated with plasma exchange, like plasmapheresis, which is when plasma proteins, like antibodies, are removed and replaced with plasma from a healthy donor.Alright, as a quick recap, myasthenia gravis is characterized by antibodies against the nicotinic acetylcholine receptors on the surface of muscle cells.

Review14:20–15:52

The hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after periods of rest.
When the eye is involved, individuals might develop diplopia and ptosis. Neck muscles weakness might make people feel like their head is heavy and hard to keep up right.
Arm and leg involvement leads to difficulties in walking, climbing stairs, and performing simple tasks. Bulbar symptoms can be present too, including slurred speech, nasal regurgitation, difficulties chewing, choking, and dysphagia.
Others might develop a myasthenic crisis where respiratory muscles are affected, leading to respiratory insufficiency. Diagnosis is based on suggestive symptoms and the presence of the anti-acetylcholine receptor antibodies in the serum.
Next, Lambert-Eaton myasthenic syndrome is caused by autoantibodies that target the voltage-gated calcium channels on motor neurons.
Typically, there’s symmetrical muscle weakness of the proximal muscles that improves temporarily after use. Classically, that can lead to difficulties in climbing stairs, standing up, and hairbrushing.
In contrast to myasthenia gravis, weakness affects the legs more than the arms and reflexes are weakened or absent. Autonomic symptoms include dry mouth, constipation, blurry vision, dilated pupils, and urinary and erection problems.
Diagnosis is based on suggestive symptoms and autoantibodies against the voltage-gated calcium channels in the individual’s serum.
Now back to our cases. Kira presents with a series of progressive symptoms that get worse throughout the day.

Summary15:52–16:58

These include slurring of speech, difficulty swallowing, double vision, and neck and arm weakness. Additionally, she reports severe fatigue and shortness of breath.
On examination, sensation and reflexes are normal. Now, these symptoms are suggestive of myasthenia gravis, especially since they worsen with use.
The diagnosis was confirmed by blood tests, which showed antibodies against acetylcholine receptors in Kira’s blood. Jonathan presents with leg muscle weakness that gets better the more he uses his legs.
He also reports dry mouth and impotence, which are autonomic symptoms, as well as unintentional weight loss. On examination, reflexes are initially absent.
Now, the fact that his leg weakness improves with muscle use, and that his reflexes are absent makes us think of Lambert-Eaton myasthenic syndrome while the weight loss suggests a possible malignancy.
The diagnosis was confirmed by the presence of anti-presynaptic voltage-gated calcium channel antibodies in Jonathan's blood.
A chest x-ray might be needed to look for lung cancer given that he lost a lot of weight and