Myasthenia gravis: what is behind the muscle weakness?

Myasthenia gravis is a chronic autoimmune disease associated with muscle weakness. Myasthenia is derived from the Greek words for muscle (mys) and disease (asthenia). Gravis is the Latin word for heavy. It mainly affects people in their fourth and seventh to eighth decades of life, with women being more likely to be affected at a younger age and men more likely as they get older. In many cases, the cause of the rare disease cannot be determined. Nowadays, an average life expectancy can be achieved through successful therapy, and the prognosis is correspondingly good. In the following, we present details on the disease’s symptoms, diagnostics, course and therapy.

What is myasthenia gravis?

Myasthenia gravis or myasthenia gravis pseudoparalytica is a neurological disease. It is caused by antibodies that the human organism produces itself. It belongs to the group of autoimmune diseases.

The body’s antibodies usually target foreign substances potentially harmful to the body, such as bacteria or viruses. However, antibodies against endogenous structures (autoantibodies) can be formed if the immune system malfunctions. This can lead to inflammatory reactions with corresponding symptoms.

What happens in the body with myasthenia gravis?

In myasthenia gravis, autoantibodies are formed against the so-called acetylcholine receptor at the synapse (point of contact) between nerve cells and muscles. This part of the muscle is also called the motor endplate.

Receptors are parts of a cell sensitive to certain stimuli, such as docking points for certain messenger substances (neurotransmitters). Acetylcholine receptors are receptors for the messenger substance acetylcholine. However, they occur not only on the motor endplate but also in many other places in the human body.

Acetylcholine is released by the nerve cells at the motor endplate and typically docks onto the acetylcholine receptors of the muscle cells. The receptor then opens, allowing sodium and potassium ions to flow into the muscle cell. This leads to the excitation of the muscle cell and its contraction. Simply put, the nerves send signals that reach the muscles via a messenger substance and a receptor, causing them to tense.

In myasthenia gravis, however, the autoantibodies block the receptors so that acetylcholine cannot dock, and there is no stimulation or contraction of the muscle cells. In the long term, the acetylcholine receptors are also destroyed with increasing muscle weakness.

Causes: how does myasthenia gravis develop?

How the acetylcholine receptor antibodies are formed, i.e., the actual cause of the disease, has yet to be fully clarified.

In most of those affected, pathological changes in the thymus (thymus gland) can be detected. The thymus is part of the lymphatic system and is involved in building the immune system. During puberty, it is no longer needed and regresses. In the case of myasthenia gravis, however, enlargement of the thymus (thymus hyperplasia) or even new formations (thymomas) are often detectable.

Myasthenia gravis is also associated with other autoimmune diseases such as Hashimoto’s thyroiditis (inflammation of the thyroid gland), rheumatoid arthritis (inflammation of the joints) and systemic lupus erythematosus (inflammation of various structures).

 

Symptoms: how does myasthenia gravis manifest itself?

The main symptom of myasthenia gravis is muscle weakness. This results in other symptoms that differ depending on the affected muscle group. The following forms are distinguished:

• ocular muscles:  drooping of the eyelid (ptosis) on one or both sides, seeing a double vision (diplopia), paralysis of eye muscles
• bulbar muscles:  difficulty speaking (dysarthria) and swallowing ( dysphagia ), sagging facial features (facies myopathic)
• Skeletal muscles:  weakness of the extremities, weakness of the head, and, in severe cases, weakness of the respiratory muscles with shortness of breath (dyspnea)

The symptoms occur in particular with repeated stress and increase during the day, with infections, menstruation and stressful situations. The disease can, therefore, progress in phases. Pain may occur, but pain is not usually a symptom. As the disease progresses, muscle mass may decrease (muscle atrophy).

It is essential to distinguish it from other neurological diseases because there are no disturbances in touch sensitivity (sensitivity) and reflexes.

Is myasthenia gravis dangerous?

It is a severe condition that requires treatment. It severely restricts those affected in their daily lives and reduces their quality of life. To alleviate the symptoms, it is often necessary to take medication for a lifetime – but without being able to cure the disease in this way. With the proper treatment, however, an average life expectancy can be achieved in many cases.

The danger comes from the critical deterioration of the symptoms in the context of a so-called myasthenic crisis. Causes for such an increase in symptoms can be drugs that affect neuromuscular transmission, infections, fever and anaesthesia during operations. The weakness of the respiratory muscles in connection with the inability of the lungs to absorb enough oxygen (respiratory insufficiency) and the risk of liquids or solids entering the lungs (aspiration) are at the fore in the myasthenic crisis.

To treat a myasthenic crisis, intensive medical therapy with securing the airways and administration of appropriate medication is necessary. The mortality rate of this clinical picture is two to three per cent despite intensive medical therapy.

Diagnosis of myasthenia gravis

If myasthenia gravis is suspected, different tests are carried out to make the diagnosis.

 

assessment of muscle function

The diagnosis begins with the physical examination of the patient. Particular attention is paid to muscle strength and fatigue with repeated stress. There are several tests to assess muscle function:

• Simpson’s test:  ptosis, as the eyelid droops, is provoked by looking upwards for one minute.
• Arm Hold Attempt: The victim cannot extend their arms straight out and hold them horizontally for 180 seconds.
• Leg hold attempt: The sufferer cannot hold the legs at a 45° angle for 45 seconds while lying down.
• Attempt to hold the head: The patient cannot hold the head at a 45° angle for 90 seconds while lying down.
• Facial expression test: assessing the closure of the eyelid depending on its strength.

Edrophonium-Test

Drug tests also check the effect of a cholinesterase inhibitor on the symptoms (edrophonium test, formerly Tensilon test). Edrophonium is administered intravenously to the patient. It is an inhibitor of the enzyme cholinesterase. Cholinesterase is responsible for breaking down the messenger substance acetylcholine.

If this enzyme is inhibited, there is a higher concentration of acetylcholine at the motor endplate and, thus, better muscle function. Accordingly, muscle weakness should improve within 30 to 60 seconds with edrophonium.

Injecting cholinesterase inhibitors has some risks and side effects and should only be performed by an experienced healthcare professional with emergency equipment.

Laboratory diagnostics, electrophysiological examination and imaging

The last pillar of diagnostics includes laboratory diagnostics, electrophysiological examination of the muscles and imaging:

• Antibodies against the acetylcholine receptor are detected in the laboratory. It can be detected via five different types of antibodies. In addition, routine parameters such as blood count, thyroid  ​​and inflammation values ​​are determined.
• The electrophysiological examination refers to the stimulation of nerves using electrical impulses. These stimulations usually result in muscle contraction, i.e., measured muscle tension. In myasthenia gravis, the muscle response decreases from stimulation to stimulation. This phenomenon is called decrement. A combination with the edrophonium test is possible. In this case, less or no decrement should be detectable after administration of the enzyme.
• The imaging methods computed tomography (CT) and magnetic resonance imaging (MRI) play a role in detecting a pathological change in the thymus.

 

Therapy: Which medications for myasthenia gravis?

The basis of therapy for myasthenia gravis is cholinesterase inhibitors to improve muscle function. The drug of choice is pyridostigmine. It can be taken in tablet form. The setting, i.e., determining the correct dose, should be carried out by a specialist with the appropriate experience. Patients must be informed about the correct intake and possible dangers and risks. Possible side effects include, above all, nausea, abdominal cramps, diarrhoea, profuse sweating and a slow heartbeat ( bradycardia ).

A regression of the symptoms with a cholinesterase inhibitor alone can only be achieved in about ten per cent of those affected. In most cases, a combination with a  drug that suppresses the immune system (immunosuppressant) is necessary. Glucocorticoids ( cortisone ), such as prednisolone, are primarily used. Also, side effects must be considered, especially with long-term use. The dosage should, therefore, be discussed with an experienced specialist. Another option is the immunosuppressant azathioprine. It can be used alone or in combination with prednisolone.

Many of those affected also benefit from the surgical removal of the thymus gland, regardless of whether it is pathologically changed or not. In individual cases, advice should be given by a doctor.

Those affected should generally ensure a healthy lifestyle and a balanced diet with sufficient vitamins, minerals and trace elements. In addition, accompanying therapies and aids can be helpful. These include, for example, speech therapy for speech disorders, a neck brace for poor head posture and walking aids (walker, wheelchair).

New therapies for myasthenia gravis

New approaches in the therapy of myasthenia gravis aim at a more targeted suppression of the immune reaction. For example, an antibody directed against specific defence cells in the body (B cells) is an option. It is Rituximab, which is already used in other diseases (including leukaemia and autoimmune diseases).

Eculizumab can also be used. This is an antibody against another part of the immune system called complement factor C5.

Which drugs are taboo?

Some medications should be avoided or used with extreme caution in myasthenia gravis. Every doctor treating you must be informed about your illness. Before taking any new medication, you should always consult a specialist. 

Among the “forbidden” drugs in myasthenia gravis include:

• some antibiotics of the group of aminoglycosides (streptomycin, neomycin, gentamicin), fluoroquinolones (levofloxacin, ciprofloxacin ), glycopeptides (vancomycin), lincosamides ( clindamycin ) and macrolides (erythromycin)
• Antidepressiva (Amitriptyline)
• Antikonvulsiva (Benzodiazepine, Carbamazepin, Gabapentin)
• Antimalariamittel (Chinin, Chloroquin)
• Anti-rheumatic drugs (D-penicillamine, chloroquine)
• Botulinumtoxin (Botox)
• Diuretika (Schleifendiuretika, Thiaziddiuretika)
• Interferon-a
• Calcium channel blockers
• Lithium
• The muscle relaxant
• magnesium supplements

 

Prognosis in myasthenia gravis

In most cases, medication is lifelong. This involves certain risks and side effects. However, the medication can achieve remission (regression) of the symptoms so that an average life expectancy and a good quality of life are possible.

The myasthenic crisis is particularly life-threatening if the symptoms worsen dramatically and breathing is impaired. Luckily, this emergency can be avoided with proper treatment.