Watch the video The Neuromuscular Junction (Described Concisely) to review the neuromuscular junction.

Before we discuss spastic and flaccid paralysis, we will do a quick review of what you’ve learned from your previous anatomy and physiology classes about interaction of the nervous system with muscles. It is important to remember the relationship between upper motor neurons (UMNs) and lower motor neurons (LMNs). Upper motor neurons originate in the brain and travel down the spinal cord where they synapse with lower motor neurons. Lower motor neurons originate in the spinal cord and innervate muscles and glands throughout the body. The area where LMNs interact with muscle is called the neuromuscular junction. To generate muscle contraction, an action potential will travel down the LMN axon where it triggers the opening of calcium voltage-gated channels so that Ca²⁺ can enter the axon terminal. This Ca²⁺ triggers the release of acetylcholine (ACh) by the LMN into the neuromuscular junction. ACh binds to the ligand-gated Na⁺ channels on the postsynaptic membrane so they open and allow Na⁺ into the muscle cell. The influx of Na+ generates an action potential in the muscle cell and causes contraction. Acetylcholine is broken down by acetylcholinesterase so it does not remain in the synaptic cleft and cause continuous action potentials.

Flaccid Paralysis

Flaccid paralysis occurs when muscle cells are not stimulated and there is consequently no muscle contraction. This can be caused by:

• Curare: a neuromuscular blocker that blocks nicotinic type 1 receptors from being activated by ACh at the postsynaptic membrane of the neuromuscular junction.
• Botulinum toxin: blocks the release of ACh from the presynaptic terminal. “Botox injections” placed in the muscles of the face contain botulinum toxin.
• Aminoglycoside antibiotics: this class of antibiotics can interfere with voltage-gated calcium channels on the terminal end of motor neurons. Enough interference can cause flaccid paralysis of muscle fibers due to reduced release of ACh. Only some individuals are affected by these antibiotics in this way.

Spastic Paralysis

Spastic paralysis is when the muscle is overstimulated and cannot relax. A few of its causes include:

• Upper motor neuron damage: Spastic paralysis generally occurs when upper motor neuron damage occurs but lower motor neurons remain intact. While upper motor neurons conduct action potentials to lower motor neurons to recruit the stimulation of voluntary muscle contraction, they also are used to deliver inhibitory signals to muscles that must relax during movement as well. This means that there are likely as many inhibitory signals generated from upper motor neurons as there are stimulatory signals. In the environment of less inhibition as seen with damaged upper motor neurons, reflexes like the muscle spindle reflex continue to stimulate action potentials in lower motor neurons. This continued stimulation can cause muscle to develop increased resting tone and resistance to movement.
• Acetylcholinesterase inhibition: If acetylcholinesterase is inhibited, then excessive acetylcholine will remain in the synaptic cleft. This will cause a maintained excitement of ACh receptors that leads to excessive and unwanted muscle contraction. An example of an acetylcholinesterase inhibitor is organophosphate, which is used in many insecticides.
• Black widow spider toxin or alpha latrotoxin causes spastic paralysis because it can depolarize the presynaptic terminal of the neuromuscular junction by opening cation channels which results in a massive release of acetylcholine into the synaptic cleft.

Myasthenia Gravis

Myasthenia gravis is an autoimmune disease that affects skeletal muscle. The overall cause of myasthenia gravis is antibody-mediated loss of acetylcholine receptors. Myasthenia gravis is a type II hypersensitivity caused by autoantibodies that bind to nicotinic receptors on postsynaptic terminals in the neuromuscular junction. Women are affected more than men.

Three mechanisms seen in myasthenia gravis contribute to the loss of function of acetylcholine receptors in the neuromuscular junction:

1. Complement system activation of the classical pathway that causes injury to the postsynaptic muscle membrane.
2. Accelerated acetylcholine receptor degradation by receptor-specific antibodies.
3. Blockage/obstruction of ACh receptors by antibodies so that acetylcholine cannot attach.

Myasthenia gravis is commonly manifested by weakness in the extraocular muscles that control the movement of the eyes and eyelids that results in diplopia (double vision) and ptosis (drooping of the eyelids). These ocular symptoms often present early in the progression of the disease. Later on, patients will often show weakness of face muscles and axial and/or limb weakness can become a major symptom. Patients can differ widely in the severity and progression of symptoms. Muscle weakness manifests more strongly with repeated use of the muscles. This is why a period of rest or a good night’s sleep can help muscles feel strong again, but they tire quickly with use. A myasthenic crisis may occur if weakness extends to involve the respiratory muscles. If the respiratory muscles lose enough strength, the patient may require ventilatory assistance. A crisis is often triggered by infection, fever, an adverse reaction to medication, or emotional stress.

Diagnosis of myasthenia gravis includes a physical exam, electromyography to look for decremental muscle responses after repetitive motor neuron stimulation, imaging for possible thymoma, and blood tests for antibodies against proteins in the synaptic junction (including the acetylcholine receptors). Diagnostic procedures used to involve the administration of edrophonium, an acetylcholinesterase inhibitor. If the patient’s symptoms improved after the administration of this drug, it suggested myasthenia gravis. This drug has now been discontinued, largely because of the very dangerous bradycardia it could induce during testing (can you explain why?).

The two most common drugs for treatment of myasthenia gravis are neostigmine and pyridostigmine, which are acetylcholinesterase inhibitors that increase the concentration of acetylcholine in the synapse. The increased ACh leads to more muscle stimulation and improves muscle contraction. Corticosteroids may also be given as an immunosuppressant to help decrease autoimmune activity.

A thymectomy can be a possible treatment for myasthenia gravis. This is because the thymus gland seems to be a source of lymph tissue induction of lymphocytes and antibodies against acetylcholine receptors. The reason for this is not well known, but up to 60% of myasthenia gravis patients demonstrate some abnormality in the thymus tissue.

Plasmapheresis, which is the removal, treatment, and return of blood to the body, can be an effective treatment for myasthenia gravis because it removes antibodies from the circulation and provides short-term clinical improvement. In plasmapheresis, blood is removed from the body and separated into blood cells and plasma. After the plasma is separated, the blood cells are returned to the patient while the plasma is discarded and replaced with a plasma donation that is free of the autoimmune antibodies. Another possibility is that the patients’ plasma can be treated through chemical means or filtration to remove the patient’s own antibodies and then the treated plasma is returned to the body.