Myasthenia gravis

1401

A long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness.

Associated with antibodies against muscle-specific tyrosine kinase.

The most commonly affected muscles are those of the eyes, face, and swallowing.

The weakness of the muscles involved in swallowing may lead to swallowing difficulty.

Some food may be left in the mouth after an attempt to swallow, or food and liquids may regurgitate into the nose rather than go down the throat.

Weakness of the muscles of mastication may cause difficulty chewing.

In individuals with MG, chewing tends to become more tiring when chewing tough, fibrous foods..

Difficulty in swallowing, chewing, and speaking is the first symptom in about one-sixth of individuals.

Weakness of the muscles involved in speaking may lead to dysarthria and hypophonia.

Speech may be slow, slurred, or have a nasal quality.

Presents with progressive or fluctuating weakness, and extraocular and other cranial muscles are commonly affected.

It can result in double vision, drooping eyelids, trouble talking, and trouble walking.

Due to weakness of the muscles of facial expression and muscles of mastication, facial weakness may manifest as the inability to hold the mouth closed, resulting in the “hanging jaw sign”, and as a snarling expression when attempting to smile.

The individual appear sleepy or sad, and have difficulty in holding the head upright.

Onset can be sudden.

The initial main symptom is painless weakness of specific muscles, not fatigue.

The muscle weakness becomes progressively worse during periods of physical activity and improves after periods of rest.

Typically, the weakness and fatigue are worse toward the end of the day.

Generally starts with ocular weakness.

In about two-thirds of individuals, the initial symptom is related to the muscles around the eye.

There may be eyelid drooping, ptosis due to weakness of levator palpebrae superioris, and double vision due to weakness of the extraocular muscles.

Eye symptoms tend to get worse when watching television, reading, or driving, particularly in bright conditions.

Some affected individuals choose to wear sunglasses.

It might then progress to a more severe generalized form, characterized by weakness in the extremities or in muscles that govern basic life functions.

The muscles that control breathing and limb movements can also be affected, but rarely do these present as the first symptoms of MG, but develop over months to years.

In a myasthenic crisis, a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life.

Crises may be triggered by various biological stressors such as infection, fever, an adverse reaction to medication, or emotional stress.

Monitoring is very important, as at least 20% of people diagnosed with it will experience a myasthenic crisis within two years of their diagnosis, requiring rapid medical intervention.

The most disabling period of MG might be years after the initial diagnosis.

Human leukocyte antigen (HLA) haplotypes are associated with increased susceptibility to myasthenia gravis and other autoimmune disorders.

Relatives of MG patients have a higher percentage of other immune disorders.

Myasthenia Gravis Foundation of America Clinical Classification

Class Description

I Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere

II Eye muscle weakness of any severity, mild weakness of other muscles

IIa Predominantly limb or axial muscles

IIb Predominantly bulbar and/or respiratory muscles

III Eye muscle weakness of any severity, moderate weakness of other muscles

IIIa Predominantly limb or axial muscles

IIIb Predominantly bulbar and/or respiratory muscles

IV Eye muscle weakness of any severity, severe weakness of other muscles

IVa Predominantly limb or axial muscles

IVb Predominantly bulbar and/or respiratory muscles

V Intubation needed to maintain airway

Affected patients often have a large thymus or develop a thymoma.

The thymus gland cells form part of the body’s immune system, and in those with myasthenia gravis, the thymus gland is large and abnormal.

Myasthenia gravis is an autoimmune disease caused by antibodies that block acetylcholine receptors, and is often associated with thymic hyperplasia.

The thymus sometimes contains clusters of immune cells which indicate lymphoid hyperplasia, and the thymus gland may give wrong instructions to immune cells.

Muscle-specific tyrosine kinase plays in important role at the post synaptic membrane in the formation and maintenance of the neuromuscular junction by inducing acetylcholine receptor clustering and differentiation of nerve terminals.

Myasthenia gravis is associated with acetyl receptor antibodies and with muscle specific tyrosine kinase antibodies.

Patients with muscle-specific tyrosine kinase antibodies are more often female and have an earlier on set of disease in the third or fourth decades than patients with acetylcholine receptor antibodies.

Ptosis and diplopia are more common with acetylcholine receptor antibodies and less common and mild or with muscle-specific tyrosine kinase antibodies.

Muscle-specific tyrosine kinase antibodies more commonly are associated with bulbar dysfunction, facial weakness, respiratory distress and overall conditions that often lead to crisis and hospitalization.

Disruption of the above pathway by autoantibodies bind to muscle-specific tyrosine kinase leads to a neuromuscular transmission defect.

For women who are pregnant and already have MG, in a third of cases experience an exacerbation of their symptoms, and in those cases it usually occurs in the first trimester of pregnancy.

Signs and symptoms in pregnant mothers tend to improve during the second and third trimesters.

Complete remission can occur in some mothers.

Immunosuppressive therapy is maintained throughout pregnancy, as this reduces the chance of neonatal muscle weakness, and controls the mother’s myasthenia.

About 10–20% of infants with mothers affected by the condition are born with transient neonatal myasthenia, producing feeding and respiratory difficulties that develop about 12 hours to several days after birth.

Affected neonates typically respond to acetylcholinesterase inhibitors, and the condition generally resolves over a period of three weeks as the antibodies diminish and generally does not result in any complications.

Very rarely, an infant can be born with arthrogryposis multiplex congenita, secondary to profound intrauterine weakness, due to maternal antibodies that target an infant’s acetylcholine receptors.

Three types of myasthenic symptoms in children can be distinguished:

Transient neonatal myasthenia occurs in 10 to 15% of babies born to mothers afflicted with the disorder, and disappears after a few weeks.

Congenital myasthenia, the rarest form, occurs when genes are present from both parents.

Congenital myasthenias cause muscle weakness and fatigability.

The signs of congenital myasthenia usually are present in the first years of childhood, although they may not be recognized until adulthood.

Juvenile myasthenia gravis is most common in females.

Usual onset form women is under 40, and men over 60.

Frequency 50 to 200 per million.

It is newly diagnosed in three to 30 per million people each year.

Diagnosis is becoming more common due to increased awareness.

Diagnosed when appropriate clinical features are present and tests show at least one of the following: pathologic antibodies, abnormal decrement in repetitive nerve stimulation, and an abnormal result of a single fiber electromyography.

Repetitive nerve stimulation may result in more than a 10% decrement in compound muscle action potential amplitude with low frequency stimulation and results differ by the type of myasthenia gravis.

Can be difficult to diagnose, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders.

It is uncommon in children.

With treatment, most of those affected lead relatively normal lives and have a normal life expectancy.

An autoimmune disease which results from antibodies that block or destroy nicotinic acetylcholine receptors at the junction between the nerve and muscle.

It is an autoimmune synaptopathy.

The antibodies attack a normal human protein, the nicotinic acetylcholine receptor, or a related protein called MuSK a muscle-specific kinase.

The test is for antibodies against the acetylcholine receptor has a reasonable sensitivity of 80–96%.

Acetylcholine receptor antibodies are found in about 80% of patients and muscle specific kinase antibodies are found in only one-10% of cases.

A proportion of the patients without antibodies against the acetylcholine receptor have antibodies against the MuSK protein.

Other less frequent antibodies are found against LRP4, Agrin and titin proteins.

This prevents nerve impulses from triggering muscle

Diagnosis is supported by blood tests for specific antibodies, the edrophonium test, or a nerve conduction study.

Edrophonium test requires the intravenous administration of edrophonium chloride or neostigmine, drugs that block the breakdown of acetylcholine by cholinesterase (acetylcholinesterase inhibitors).

This test is no longer typically performed, as its use can lead to life-threatening bradycardia which requires immediate emergency attention.

Production of edrophonium was discontinued in 2008.

Rarely, a similar condition known as congenital myasthenia can occur as an inherited genetic defect in the neuromuscular junction.

Muscle fibers of patients are easily fatigued, which the repetitive nerve stimulation test can help diagnose.

In single-fiber electromyography, which is considered to be the most sensitive, although not the most specific, test for MG, a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers.

Two muscle fibers belonging to the same motor unit are identified, and the temporal variability in their firing patterns is measured.

Frequency and proportion of particular abnormal action potential patterns, called “jitter” and “blocking”, are diagnostic.

Jitter is the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit.

Blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.

Ice test-Applying ice for two to five minutes to the muscles reportedly has a sensitivity and specificity of 76.9% and 98.3%, respectively, for the identification of MG.

The ice test is useful for ptosis.

An ice pack is applied to the affected upper eyelid for 2-5 minutes: positive test is the improvement of ptosis by > 2mm or more.

This transient improvement in ptosis is due to the cold decreasing the acetylcholinesterase break-down of acetylcholine at the neuromuscular junction.

In neonatal myasthenia, newborns of mothers with myasthenia may have symptoms during their first few months of life.

Respiratory failure can occur.

Facial and neck weakness are common.

Typically painless.

Typically there is normal CSF and neuroimaging studies.

Has a bimodal distribution, with a smaller early peak in the second and third decades of life, in mostly females, with another peak at 60 to 80 years.

Autoimmune disease characterized by muscular weakness and fatigue and thymectomy, immunosuppressives, anticholinesterase agents, plasmapheresis and immunoglobulin therapy are all included in management.

Plasmapheresis can be used to remove the putative antibodies from the circulation.

Intravenous immunoglobulins (IVIGs) can be used to bind the circulating antibodies.

Both of these treatments have relatively short-lived benefits, typically measured in weeks, and often are associated with high costs which make them prohibitive; they are generally reserved for when MG requires hospitalization.

Treatment is by medication and/or surgery.

Medication consists mainly of acetylcholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process.

Thymectomy is a surgical method to treat MG.

As thymomas are seen in 10% of all people with the MG, people are often given a chest X-ray and CT scan to evaluate their need for surgical removal of their thymus and any cancerous tissue that may be present.

Surgery to remove a thymoma, generally does not lead to the remission of MG.

Removal of the thymus, has no clear indication of beneficial except in the presence of a thymoma.

A 2016 randomized controlled trial, however, found some benefits to thymectomy.

The most sensitive serological marker is the presence of circulating acetylcholine receptor antibodies (AChR-Abs).

Acetylcholine receptor antibodies are present in 80-90% of patients with generalized disease, but less often in patients with ocular myasthenia of about 50%.

Striated muscle antibodies are present and up to 30% of patients and 80% of patients whose myasthenia is associated with a thymoma.

Acetylcholine receptor antibodies are false positive in about 10% of cases.

Thymectomy causes remission in 18%-55% of patients and clinical improvement occurs in the majority.

Myasthenia gravis is generally treated with medications known as acetylcholinesterase inhibitors such as neostigmine and pyridostigmine.

Acetylcholinesterase inhibitors can provide symptomatic benefit and may not fully remove a person’s weakness from MG.

Acetylcholinesterase inhibitors may allow a person the ability to perform normal daily activities.

Acetylcholinesterase inhibitors are started at a low dose and increased until the desired result is achieved.

Atropine, can reduce the muscarinic side effects of acetylcholinesterase inhibitors.

Pyridostigmine is a relatively long-acting drug with a half-life around four hours with relatively few side effects.

Generally, it is discontinued in those who are being mechanically ventilated as it is known to increase the amount of salivary secretions.

Immunosuppressants, such as prednisone or azathioprine, may also be used.

Steroid treatment is not the preferred method of treatment.

Other immune suppressing medications may also be used including rituximab.

Compared with placebo, a greater proportion of patients on rituximab met the primary end point of minimal disease manifestations at 16 weeks, and demonstrated favorable results on several secondary end points.

About 10% of people with generalized MG are considered treatment-refractory.

Autologous hematopoietic stem cell transplantation (HSCT) is sometimes used in severe, treatment-refractory MG.

Plasmapheresis and high dose intravenous immunoglobulin may be used during sudden flares of the condition.

If the breathing muscles become significantly weak, mechanical ventilation may be required.

10% patients have a thymoma.

About 15% of thymoma patients have myasthenia.

1-2% develop myasthenia during penicillamine treatment, usually for rheumatoid arthritis.

Secondary to penicillamine typically remits on withdrawal of the drug.

Patients susceptible to muscle relaxants, b-blockers, antimalarials, verapamil and aminoglycosides.

Up to 70% of myasthenia gravis patients present with ptosis, and 90% of these patients will eventually develop ptosis.

Patients that benefit the most from thymectomy are those without a thymoma, have a lower stage of disease, are of female gender and have short duration of symptoms between diagnosis and operation.

Annual incidence is between 0.25 and 2 people per 100,000, with an increased age-related frequency in those over 60, with a bias towards men.

Myasthenia gravis occurs in all ethnic groups and both sexes.

It most commonly affects women under 40 and people from 50 to 70 years old of either sex, but it has been known to occur at any age.

Younger patients rarely have thymoma.

The prevalence in the United States is estimated at between 0.5 and 20.4 cases per 100,000, with an estimated 60,000 Americans affected.

20% spontaneous remission rate.

20-30% will die without treatment within 10 years.

Lifetime risk greater than 500 per million.

In about 90% no specific cause can be identified.

Patients older than 60 years constitute 36% to 59% of patients.

In the early 1900s, the mortality associated with MG was 70%; now, that number is estimated to be around 3–5%, which is attributed to increased awareness and medications to manage symptoms.

Thymectomy mortality in myasthenia gravis is less than 1%.

Patients with MG should be educated regarding the fluctuating nature of their symptoms, including weakness and exercise-induced fatigue.

Exercise participation should be encouraged with frequent rest.

Evidence indicates a partial home program including training in diaphragmatic breathing, pursed lip breathing, and interval-based muscle therapy may improve respiratory muscle strength, chest wall mobility, respiratory pattern, and respiratory endurance.