Myasthenia Gravis (MG)

Myasthenia Gravis (MG)

Myasthenia Gravis is a chronic neuromuscular disorder that leads to weakness and abnormally rapid exhaustion of voluntary skeletal muscle. It is considered to be an autoimmune disease because the immune system attacks the body itself and its targets are acetylcholine receptors (85% of MG cases), a substance that acts as a neurotransmitter in neuromuscular synapses, where the nerves are connected to the muscles. It is normally stored in small vesicles at the nerve endings and is released when a nerve pulse reaches these points. It then forms a bridge between its receptors and muscle and initiates some chemical reactions that lead to muscle contraction.

MG leads to the production of autoantibodies that abnormally attack these receptors by reducing their number and then decreases muscle contraction capacity.

Moreover, the targets of these antibodies could be the kinase specific for muscles (MuSK – 10% of the cases), inhibiting the function of neuromuscular junction, or the protein related to the lipoproteins 4 (LPR4), which also leads to the inhibition of MuSK and therefore the function of acetylcholine receptors.

Incidence is estimated to 5-30:1.000.000 and its prevalence around 10-20:100.000.

The production of these antibodies has been found to involve the thymus gland, a small gland below the chest. Normally, this gland secretes hormones that affect the transmission of signals to neuromuscular synapses and is involved in the normal function of the immune system. It is large in infancy and reaches the maximum in puberty, where it is then shrinking and has little functionality.

In patients with MG, however, it is abnormally large in size and in most cases presents abnormalities and develops tumors (thymomas), which are usually benign.

All of the above cause weakness and exhaustion of the muscles. It is rarely fatal, although it can become threatening if the respiratory muscles are affected.

 

Symptoms

Their onset may be sudden, with generalized and severe muscle weakness, but often the first symptoms vary and are subtle, which may delay the diagnosis. It affects people of all ages, although it is more common in women, ages 20-40, and in men it is mainly in their 40-60.

The rest of the symptoms are caused by muscular weakness of voluntary muscles, which are controlled by the 10 main brain stem nerves.

Often, there is firstly a weakness in the eye muscles, with ptosis of eyelids (1 or even 2 eyelids) and / or diplopia. In addition, there are symptoms of inability to swallow, chew, talk, breathing difficulty, influence on facial muscles or limb movement. They include severe exhaustion, unbalanced gait, upper limb weakness and in the palms and fingers.

Muscular weakness can be developed  within a few days or weeks or remain on the same level for a long time. Its severity varies from person to person or even to the same person per periods. It tends to worsen with exercise, with the coexistence of other diseases and towards the end of the day. Symptoms are more intense and serious during menstruation and pregnancy.

Diagnosis

Conducted by a neurologist or expert physician with a personal history and clinical examination that includes three basic tests, electromyography (EMG), intravenous administration of tensilon, a substance that blocks the decomposition of acetylcholine and temporarily increases its levels in the neuromuscular junction. Patients have a temporary neutralization of weakness, and immunological blood tests to find antibodies against acetylcholine receptors.

Management

There is still no cure, but avoiding anything that can cause a crunch, taking medication, surgical removal of the throat and plasmapheresis are helpful in managing the symptoms.

Medication includes administration of anti-cholinesterase or cholinesterase inhibitors, which improve the transmission of neuromuscular pulses and contribute to the proper functioning of the muscles by improving muscle weakness. A representative drug is pyridostigmine (Mestinon).

Immune modulating therapies could also be conducted with specific immunoglobins and plasmapheresis is actually included in this therapeutic category.

Immunosuppressants such as Azathioprine (Imuran) and mainly steroids such as prednisone are also being administered.

Surgical removal of the thymus gland has been shown to lead to remission of symptoms and plasmapheresis is performed to remove antibodies from the plasma, especially in cases of symptoms exacerbation or before surgical removal of the thymus.

Emerging Therapies

Εculizumab – Monoclonic C5 antibody, approved recently by FDA for other indications by also in clinical trials for MG.

Rozanolixizumab – Monoclonic FcRn antibody, designed to decrease autoantibodies IgG, in trials also.

Efrartigimod – monoclinic FcRn antibody, which has shown positive results in improving symptoms in daily life, with tolerance, decrease of autoantibodies in previous phases in clinical trials, and is moving forward to the next phases.

Μοnarsen – antisense oligonucleotide, designed to reduce acetylocholinesterase, with satisfying results in phase IIb of its clinical trial.

International Consensus Guidance for Management of Myasthenia Gravis

For connection with other Family groups and Patient Organisations:

https://myasthenia.org/Community-Resources/Support-Groups-MG-Friends

Information about clinical trials conducted globally: https://www.centerwatch.com/clinical-trials/listings/condition/104/myasthenia-gravis-chronic-weakness/ and https://clinicaltrials.gov/ct2/home

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