Approach to differentiating lesions (neuromuscular junction): Clinical sciences

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. 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. 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.

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.

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. 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.