Myasthenia gravis: Clinical sciences

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Introduction 0:00–1:04

Myasthenia gravis is a progressive autoimmune neuromuscular junction disorder characterized by fatigable weakness in skeletal muscles.
In myasthenia gravis, antibodies can bind to postsynaptic acetylcholine receptors, as well as to muscle-specific kinase and low-density lipoprotein receptor-related protein 4.
Once bound, antibodies activate the classical complement pathway, which triggers local inflammation, eventually reducing the number of functioning acetylcholine receptors and flattening the postsynaptic folds.
Ultimately, this impairs neuromuscular transmission and results in progressive weakness that worsens with repeated activity.
Myasthenia gravis can be limited to the ocular muscles, or generalized, affecting the bulbar, axial, limb, and respiratory muscles as well.
In severe cases, a person can present with respiratory failure, which is also known as a myasthenic crisis. Now, if your patient presents with chief concerns suggestive of myasthenia gravis, perform an ABCDE assessment to determine if they are unstable or stable.

Unstable Patient 1:04–1:36

If unstable, stabilize their airway, breathing, and circulation. At this point, you might need to provide noninvasive positive pressure ventilation or mechanical ventilation.
Next, obtain IV access, and don’t forget to put your patient on continuous vital signs monitoring, including heart rate, blood pressure, and pulse oximetry.
Next, obtain a focused history and physical exam, order arterial blood gas analysis, and assess your patient’s respiratory status by obtaining bedside pulmonary function tests, which include vital capacity, maximum inspiratory pressure, and maximum expiratory pressure.

Focused H&P 1:36–5:33

Your patient will report rapidly worsening painless weakness, shortness of breath, and difficulty swallowing or choking when eating.
Most patients will have a known history of myasthenia gravis, but some individuals might present for the first time in a crisis.
Additionally, history might reveal conditions associated with a weakened immune system, including active infections as well as recent surgical operations and postpartum state.
The patient might also report tapering of their immunosuppressants. Another possible trigger of myasthenic crisis is the use of medications known to exacerbate myasthenic symptoms, such as magnesium, botulinum toxin injections, paralytics, beta-blockers, and certain antibiotics, including aminoglycosides, fluoroquinolones, and macrolides.
Next, the physical exam will show shallow breathing and increased respiratory rate. With time, your patient will tire out, so their respiratory rate can subsequently drop.
The patient might have hypophonia, which is a weak voice, as well as drooling and dysarthria because of bulbar weakness.
They may also be using accessory muscles for respiration. However, in severe cases, the generalized weakness is too severe for the patient to recruit accessory muscles, so the absence of it should not reassure you!
Additionally, there may be paradoxical breathing, which occurs as a result of diaphragm weakness and results in inward abdominal movement on inspiration instead of outward.
Next, arterial blood gas analysis will usually be normal, but there might be hypercarbia and hypoxemia. Keep in mind that hypercarbia and hypoxemia are “late” clues, so, if there are signs of severe respiratory and bulbar weakness, you should not wait for these findings to intubate the patient.
Finally, bedside pulmonary function tests will show a reduced vital capacity, which is the amount of air exhaled after a maximum inhalation.
There will also be reduced maximal inspiratory pressure, which is known as negative inspiratory force, and maximal expiratory pressure.
If vital capacity is less than 20 milliliters per kilogram, maximal inspiratory pressure is less than 30 centimeters of water, and maximal expiratory pressure is less than 40 centimeters of water, you should probably intubate the patient.
This is known as the 20, 30, 40 rule to guide intubation timing in a patient with neuromuscular weakness. With these findings, diagnose myasthenic crisis and begin treatment immediately with plasmapheresis or intravenous immunoglobulin.
Corticosteroids should be started carefully, because of the potential to transiently worsen weakness. Finally, don’t forget to address the provoking condition, such as treating an underlying infection.
Now, here’s a clinical pearl to keep in mind! Cholinergic crisis presents similarly to myasthenic crisis and can be tricky to diagnose, because it can be due to overdose with acetylcholinesterase inhibitors, which are medications commonly used to treat myasthenia gravis!
It can also occur as a result of organophosphate poisoning, such as pesticides. You can use the mnemonic SLUDGE for the symptoms of a cholinergic crisis, which stands for Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress, and Emesis.
Another sign that would point to a cholinergic crisis as opposed to a myasthenic crisis is pupillary constriction. Okay, now, let’s go back to the ABCDE assessment.

Stable/suspect ocular myasthenia gravis 5:33–6:56

If your patient is stable, first obtain a focused history and physical exam, which is going to help you differentiate ocular from generalized myasthenia gravis!
First, let’s focus on the ocular type! These individuals typically report intermittent double vision or eyelid drooping that worsens with sustained and repeated muscle activity, such as reading or looking up.
Also, these symptoms will worsen at the end of the day and improve with rest. The exam will show worsening ptosis with sustained upgaze, worsening double vision with a fixed gaze, and weak eye closure.
Finally, if there is ptosis, perform an ice pack test by applying a bag of ice to the eyelid for 2 minutes because cold temperature can improve neuromuscular transmission.
If the symptoms improve, the ice pack test is positive. With these findings, you should suspect ocular myasthenia gravis!
Here’s a clinical pearl to keep in mind! Patients with ocular myasthenia do not have muscle weakness in non-ocular muscle groups.
However, many myasthenia patients present initially with isolated ocular symptoms and later progress to generalized myasthenia.
Switching gears and moving on to generalized myasthenia gravis! In addition to fluctuating ocular symptoms, such as double vision and eyelid drooping, these patients will also report symptoms associated with bulbar involvement, like a change in their voice, slurred speech, and difficulty chewing or swallowing.

Suspect generalized myasthenia gravis 6:56–8:26

Also, the patient will report fluctuating neck and limb painless muscle weakness that worsens with repeated movement. Again, symptoms will worsen at the end of the day and improve after rest.
Physical exam reveals weakness of the ocular, facial, and bulbar muscles that worsens with repeated use. For example, you will notice ptosis with sustained upgaze, reduced ability to keep cheeks puffed with air, and dysarthria or hypophonia when counting from 1 to 50.
Next, there will be proximal greater than distal limb weakness, such as shoulder abduction weakness, which worsens when the patient repeatedly raises their arms over their head.
Additionally, there will likely be a weakness in neck flexion and extension. Since this condition is limited to the neuromuscular junction, the sensory exam and deep tendon reflexes will be normal.
As in ocular myasthenia gravis, if there is ptosis, the ice pack test will likely be positive. With these findings, you should suspect generalized myasthenia gravis.
Once you suspect ocular or generalized myasthenia gravis, your next step is to test for disease-specific antibodies in the serum.

Myasthenia gravis 8:26–10:08

These include anti-acetylcholine receptor antibodies, anti-muscle-specific kinase antibodies, and anti-low-density lipoprotein receptor-related protein 4 antibodies.
If any of these antibodies are positive, diagnose ocular or generalized myasthenia gravis depending on the history and physical exam findings.
Keep in mind that individuals with ocular manifestations are less likely to test positive for disease-specific antibodies.
On the other hand, if these antibodies are negative, order a nerve conduction study with repetitive nerve stimulation and a single-fiber electromyography.
A nerve conduction study measures how well an electrical signal is traveling through a motor or sensory nerve, while electromyography evaluates the electrical activity generated by muscles, both at rest and with activation.
If the nerve conduction study and single-fiber electromyography are normal, consider alternative diagnoses. However, if the nerve conduction study reveals a decremental response in the amplitude of compound muscle action potentials to repetitive nerve stimulation, and the single-fiber electromyography shows increased jitter, which is increased asynchronous firing of muscle fibers innervated by the same motor neuron, diagnose ocular or generalized myasthenia gravis even in the absence of antibodies.
Once you diagnose myasthenia gravis, proceed with initial treatment, which mainly consists of acetylcholinesterase inhibitors, most commonly pyridostigmine, and immunosuppressants, such as corticosteroids and nonsteroidal immunosuppressants.

Treatment 10:08–11:16

Important nonsteroidal immunosuppressants include azathioprine, mycophenolate, methotrexate, cyclosporine, cyclophosphamide, tacrolimus, and rituximab.
In severe, refractory myasthenia gravis with acetylcholine receptor antibodies, you can consider complement inhibitors, such as eculizumab.
However, if your patient is not tolerating immunosuppressants, proceed with plasmapheresis or intravenous immunoglobulin.
Finally, since there’s a high incidence of thymomas in myasthenia gravis, all patients should have chest imaging because all thymomas should be removed unless surgery is contraindicated.
Also, regardless of the thymoma presence, consider early thymectomy in individuals with generalized myasthenia gravis and positive acetylcholine receptor antibodies.
Alright, as a quick recap…Myasthenia gravis is an autoimmune neuromuscular junction disorder characterized by fatigable weakness in skeletal muscles.

Review11:16–11:54

Based on the severity, myasthenia gravis can be limited to the ocular muscles, or generalized, affecting the bulbar, axial, limb, and respiratory muscles as well.
Treatment consists of acetylcholinesterase inhibitors and long-term immunosuppression, sometimes in combination with thymectomy.
In severe cases, the patient might present with myasthenic crisis and respiratory failure, which require immediate treatment with plasmapheresis