Myasthenia Gravis (MG) is an autoimmune disorder, meaning it is caused by the body’s immune system mistakenly identifying normal parts of the body as foreign and mounting an immune response against them. The identification of self peptides as foreign by helper T-cells leads to B-cells production of autoantibodies (antibodies against self) to a variety of proteins involving ACh transmission at the NMJ (figure XYZ). This interrupts acetylcholine action at the neuromuscular junction (NMJ), preventing the neural control of voluntary motor movement.  The following are the kinds of autoantibodies associated with Myasthenia Gravis

1: Anti AChR Autoantibodies

This is the most common presentation of MG and most MG patients with autoantibodies against other proteins will also test positive for AChR autoantibodies. The AChR autoantibodies are thought to block transmission through the NMJ by three mechanisms:

a) Autoantibodies competitively antagonize AChR therefore inhibiting ACh binding

b) Promoting endocytosis (internalization) of AChR into the muscle fibre so it is no longer at the cell surface.

c) Activate complement. The complement cascade outlined here chapter XYZ (add hyperlink) will inevitably lead to the creation of the membrane attack complex, which will bring about the lysis of the postsynaptic membrane.

2: MuSK Autoantibodies

MuSK is a protein expressed only in our skeletal muscle, it is thought to play a key role in presentation of high density of AChR at the NMJ. Thus antibodies against MuSK will result in less receptors on the muscle to start initiation of contraction.

3: LRP-4 Autoantibodies

LRP-4 acts upstream in regulation of AChR clustering much like MuSK, and regulation of presynaptic membrane organization.[4]

4: Agrin autoantibodies

Agrin is a protein responsible for the activation of MuSK

5: Cortactin autoantibodies

Cortactin is involved in regulation of both synaptic and post synaptic membranes at the NMJ [5]

In summation

As a result of inhibition destruction of any of these structures by autoantibodies, communication between the muscle and motor neuron is blocked or impaired, leading to fluctuating muscle weakness.

Clinical presentation

MG appears more frequently either before the age of 30 or at 50 yrs and older.  MG has a higher frequency in females less than 30 years of age, which is typical of autoimmune disorders.

Patients with MG most commonly present with symptoms involving the fatiguing of ocular muscles. This often presents as ptosis, a characteristic “drooping” of the eyelid figure XYZ.

There are two kinds of MG: ocular (localized in eye muscles) and generalized. As mentioned, patients most often present with only eye symptoms.  Ocular MG presents with signs and symptoms isolated only to the eye(s) and vision.  Ocular MG presents with ptosis, decreased movement of the eyeball, and weakness of the eyelids.  Ocular MG can progress to generalized MG.  Patients with generalized MG may also have ocular symptoms.

Patients with MG often have muscle weakness that gets worse throughout the day. When disease spreads to different muscle groups it can cause a host of different problems including trouble regulating swallowing (dysphagia), trouble speaking (dysarthria), and reduced facial expression. Patients’ dysphagia might cause them to need to be put on special diets. Patients may reduce their oral intake because of fatigue of chewing and swallowing muscles. In the appendages patients will have muscle weakness. This generally affects proximal muscles (closer to the torso) more than distal ones. In extreme cases, severe weakness of respiratory muscles can cause respiratory failure requiring mechanical ventilation.

Diagnostic Tests

To determine whether ocular symptoms are caused by MG vs other neuromuscular pathologies, a series of clinical exams for fatigue of eye muscles during gaze and unsynchronized eyelid movements. ice and rest test   Cogan Lid Twitch

 In addition to clinical presentation, diagnosis can be made by investigating the presence of autoantibodies to AchR. A serum sample is taken and tested for Myasthenia Gravis antibodies

[9]

Treatment of MG

Acetylcholinesterases break acetylcholine down into acetate and choline in the synaptic cleft of an NMJ. Therefore inhibition of acetylcholinesterase will lead to an increase of acetylcholine available in the NMJ which will compensate for a reduction in the number of active receptors

 Immunosuppressants inhibit the production and release of interleukin II which reduces proliferation and activity of T-cells and B-cells (which produce antibodies)

Corticosteroids suppress the immune and inflammatory response  Immunosuppressant medications that reduce the expression and activity of immune cells in the body. [7]

Complement interruption:

Drugs that act as antibodies which can block or even signal for the destruction of complement proteins. Blocking the correct complement proteins, such as C5, can effectively stop the complement cascade. [8]

Thymectomy:

Removal of the thymus gland can reduce autoimmunity, as the thymus is where T-cells mature.

Plasmapheresis:

Machine filtration of autoantibodies out of blood. This however does not prevent the production of new autoantibodies, and is therefore only a temporary treatment

Intravenous immunoglobulin:

Influx of detectable antibodies in the body reduces the production of autoantibodies.

[6]

References

1. M. K. Hehir – Generalized Myasthenia Gravis
2. Thieme E-Journals – Seminars in Neurology / Full Text (thieme-connect.com)
3. The use of botulinum toxin type A in cosmetic facial procedures – ScienceDirect
4. Lrp4 low density lipoprotein receptor-related protein 4
5. Cortactin Is a Regulator of Activity-Dependent Synaptic Plasticity Controlled by Wingless
6. Myasthenia Gravis
7. Cyclosporine – Lexicomp
8. Deculizumab – Lexicomp
9. Myasthenica Gravis Diagnostics – Lexicomp

Review Questions:

1: True or false, Patients will present with either AChR autoantibodies, or Anti MuSK antibodies but usually not both

2: Recall what we know about the immune system (link to textbook chapter). What causal factor (error in the system) might have allowed for the production of autoantibodies against AChR?

3: True or False, a patient with MG should be encouraged to rest as much as possible

Answers:

1: False, only a small percentage of MuSK MG patients present without AChR Autoantibodies

2: During T-cell negative selection auto-reactive t-cells are selected for apoptosis when their t-cell receptors recognize self peptide. The cells that produce and present self peptides are called mTEC cells, failure of mTEC’s to present AChR peptides will result in autoreactivity. Treg cells are a later line of defence against autoreactivity and are supposed to supress the actions of autoreactive T-cells.

3: False, A patient with MG will benefit from movement just as much as any other patient. Exercise will help prevent muscle atrophy, improve overall health, and combat the potential negative sideaffects of being bedridden such as pressure ulcers.