Approach to differentiating lesions (neuromuscular junction): Clinical sciences

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Introduction0:00–0:44

Neuromuscular junction disorders are characterized by muscle weakness due to abnormal synaptic neurotransmission of acetylcholine.
The underlying pathology can be at the presynaptic membrane, such as impaired vesicular release of acetylcholine; within the synaptic cleft itself, such as decreased breakdown of acetylcholine; or at the postsynaptic membrane, such as a reduction in acetylcholine receptors.
Some important conditions associated with abnormal synaptic neurotransmission of acetylcholine include myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulism, and organophosphate toxicity.
Now, if your patient presents with a chief concern suggestive of a neuromuscular junction disorder, first perform an ABCDE assessment to determine if they are unstable or stable.

Unstable Patient0:44–2:10

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.
Now, here’s a clinical pearl to keep in mind! Patients with a neuromuscular junction disorder may have diaphragm weakness, which can lead to respiratory failure.
In this case, be sure to perform bedside pulmonary function tests, which will reveal reduced vital capacity, which is the amount of air someone can exhale after a maximum inhalation.
Also, you will notice reduced maximal inspiratory pressure, which is known as negative inspiratory force, and reduced 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 consider intubating the patient.
This is known as the 20, 30, 40 rule to guide intubation timing in patients with neuromuscular weakness. Okay, let’s go back to the ABCDE assessment and take a look at stable patients.

Stable2:10–3:12

If your patient is stable, first obtain a focused history and physical exam, and labs, including complete blood count, comprehensive metabolic panel, creatine kinase, and thyroid stimulating hormone.
History will typically reveal painless muscle weakness and ocular symptoms, such as double vision and eyelid drooping. Additionally, the patient will often report symptoms associated with bulbar involvement, like change in their voice, slurred speech, and difficulty chewing or swallowing.
Next, the physical exam will reveal cranial nerve palsies, such as ptosis, impaired extraocular movements, and facial weakness.
Also, you will notice neck and limb weakness with a normal sensory exam. Finally, the complete blood count, comprehensive metabolic panel, creatine kinase, and thyroid stimulating hormone will be normal.

Neuromuscular junction disorder3:12–3:33

These findings are highly suggestive of neuromuscular junction disorder, so your next step is to assess whether there are fluctuations in weakness.
If fluctuating weakness is present, assess the patient further to determine whether the underlying cause is myasthenia gravis or Lambert-Eaton myasthenic syndrome.

Myasthenia Gravis3:33–5:44

First, let’s focus on myasthenia gravis, which is associated with muscle weakness that is worse with repeated use, and at the end of the day, but improves after rest.
The physical exam will reveal ocular, facial, and bulbar muscle weakness that is worse 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, you will find proximal greater than distal limb weakness, such as shoulder abduction weakness, which worsens when the patient repeatedly raises their arms over their head.
Deep tendon reflexes will be normal. Finally, if there is ptosis, perform an ice pack test by applying a bag of ice to the eyelid for 2 minutes, since cold temperature can improve neuromuscular transmission.
If the symptoms improve, the ice pack test is positive. With these findings, you should consider myasthenia gravis and test for serum antibodies that affect the postsynaptic transmission of acetylcholine.
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 myasthenia gravis. However, 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 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 myasthenia gravis even in the absence of antibodies.
Next, let’s take a look at individuals with Lambert-Eaton myasthenic syndrome! In this case, history will reveal muscle weakness that is better with repeated use and improves at the end of the day.

Lambert-Eaton Myasthenic Syndrome5:44–8:02

The patient might report symptoms consistent with autonomic dysfunction, such as dry eyes and mouth, constipation, and urinary incontinence.
Also, history might reveal active cancer, particularly small cell lung cancer, but other types of malignancy are possible as well.
On exam, patients will present with orthostatic hypotension, proximal greater than distal limb weakness that is better with repeated use and decreased or absent deep tendon reflexes.
They might also have dilated and poorly reactive pupils. With these findings, suspect Lambert-Eaton myasthenic syndrome.
Next, order voltage-gated calcium channel antibodies, which block presynaptic calcium channels, leading to decreased release of acetylcholine from presynaptic vesicles into the synaptic cleft.
In addition, order a nerve conduction study and electromyography. If voltage-gated calcium channel antibodies are positive, particularly against the P/Q voltage-gated calcium channels, nerve conduction study with repetitive nerve stimulation shows an incremental response in the compound muscle action potential after briefly exercising the muscle being tested, and electromyography shows normal or small compound muscle action potentials, diagnose Lambert-Eaton myasthenic syndrome.
Here’s another clinical pearl! Lambert-Eaton myasthenic syndrome is strongly associated with malignancy, so remember to do a neoplastic workup once you diagnose this condition.
The treatment for Lambert-Eaton myasthenic syndrome includes medications that increase acetylcholine levels at the neuromuscular junction, such as amifampridine phosphate and pyridostigmine, and therapies that target the voltage-gated calcium channel antibodies, such as intravenous immunoglobulin and plasma exchange.
However, if you identify malignancy as well, don't forget chemotherapy! Now, switching gears and moving on to individuals with no fluctuations in weakness.

Botulism8:02–11:17

In this case, assess your patient further to determine whether the underlying cause is botulism or organophosphate toxicity.
First, let’s discuss botulism, which is caused by botulinum neurotoxin produced by the Clostridia genus of bacteria, mainly Clostridium botulinum.
The neurotoxin cleaves SNARE proteins, which mediate acetylcholine-containing vesicles to fuse with the presynaptic membrane so that acetylcholine can reach the synaptic cleft.
In botulism, progressive weakness starts in the face and subsequently spreads downwards to the arms, and then the legs. Next, the patient might report autonomic symptoms, such as dry eyes and mouth, constipation, and urinary incontinence.
They might also have shortness of breath. Additional history may reveal home canning practices and ingestion of spoiled food with subsequent diarrhea, nausea, and vomiting.
Also, they might report injection substance use, particularly subcutaneously, a recent skin wound, or medical uses of botulinum toxin.
On exam, you will find orthostatic hypotension; dilated and poorly reactive or nonreactive pupils; flaccid tone; and generalized muscle weakness.
In this case based on the physical and history, you should consider botulism. Be sure to test the patient for botulinum toxin as well as neurotoxin-producing species of Clostridium in cultures.
If the transmission is foodborne, you can test the stool, gastric aspirates, and food items. If you suspect wound botulism, be sure to sample the wound as well.
In addition to botulism-specific labs, perform a nerve conduction study and electromyography. If botulinum toxin or Clostridium culture is positive, nerve conduction study with repetitive nerve stimulation shows incremental response to repetitive nerve stimulation, and electromyography shows normal or small compound muscle action potentials, diagnose botulism.
Here’s a high-yield fact! Botulism symptoms usually present within 12 to 36 hours after exposure.
Treatment includes supportive care and botulism antitoxin. You should give botulism antitoxin as soon as you suspect the diagnosis because test results might take several days.
Also, every case of botulism should be reported to the Department of Health. And here’s a clinical pearl to keep in mind!
If the patient is an infant, ask their guardian about ingestion of raw honey, as babies are much more susceptible to botulism from ingesting bacteria spores, which can subsequently produce the toxin.
This is why caregivers should avoid honey in infants less than a year old. Infants with botulism will present with a decreased muscle tone, sometimes described as a “floppy baby”, weak suck and cough, ptosis, and sluggish or nonreactive pupils.
Finally, let’s talk about organophosphates, which work by inhibiting acetylcholinesterase, subsequently increasing acetylcholine levels within the synaptic cleft, causing a cholinergic crisis.

Organophosphate toxicity11:17–13:12

In this case, your patient will report progressive weakness and muscle twitching, as well as gastrointestinal distress, including nausea, vomiting, diarrhea, and abdominal pain.
History will also reveal excessive sweating, tearing, drooling, and urination, but also shortness of breath and wheezing due to bronchial spasms.
You can use the mnemonic SLUDGE to remember many of these symptoms, which stands for Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress, and Emesis.
Lastly, the patient will report exposure to pesticides, which is especially common among agricultural workers. Also, they might report exposure to herbicides or chemical warfare, such as with sarin nerve gas.
The physical exam will reveal an abnormal heart rate and blood pressure; diaphoresis; sialorrhea, which refers to increased salivation; and miosis, as well as generalized muscle weakness and fasciculations.
With these findings, diagnose organophosphate toxicity. Here’s another high-yield fact to keep in mind!
Organophosphate poisoning can affect both muscarinic receptors and nicotinic receptors. Depending on the type of receptor that’s more affected, the heart rate and blood pressure can either drop or increase.
Finally, if you suspect organophosphate toxicity, administer atropine, which is a muscarinic receptor antagonist, as well as pralidoxime, which can reactivate acetylcholinesterase.

Review13:12–13:55

Alright, as a quick recap… Neuromuscular junction disorders are characterized by muscle weakness due to abnormal synaptic neurotransmission of acetylcholine.
Once you suspect neuromuscular junction disorder, assess for fluctuating weakness. If present, think of myasthenia gravis, which is characterized by weakness that worsens with repeated muscle use, or Lambert-Eaton myasthenic syndrome, which is associated with weakness that can improve with repeated muscle use.
On the other hand, if the weakness is not fluctuating, think of botulism, which is characterized by descending weakness, or organophosphate toxicity, which is the only one of these disorders that causes