Myasthenia Gravis

The term myasthenia gravis has Latin and Greek  origin. It  literally means “grave muscle weakness.”

Myasthenia Gravis  is a chronic autoimmune neuromuscular disease that results in by varying degrees of weakness of the skeletal  muscles of the body.

This weakness increases during periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often, but not always, involved in the disorder. The muscles that control breathing and neck and limb movements may also be affected.

Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects young adult (under 40) and older (over 60), but it can occur at any age. In former case there is female preponderance and in later case it is more common in males.

In children other types of myasthenia gravis are also found.

The disease  is more common in families with other autoimmune diseases. A familial predisposition is found in 5% of the cases.

Thyroid disorders may be seen in as many as 10% of patients with myasthenia gravis, and symptoms of hyperthyroidism or hypothyroidism  may be present.

Myasthenia Gravis is associated with various autoimmune diseases, including:

  • Thyroid diseases, including Hashimoto’s thyroiditis and Graves’ disease
  • Diabetes mellitus type
  • Rheumatoid arthritis
  • Lupus
  • Demyelinating central nervous system diseases

Pathophysiology

Myasthenia gravis is caused by a defect in the transmission of nerve impulses to muscles. It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junction. A neuromuscular junction is the place where nerve cells connect with the muscles they control.

Under normal circumstances, when impulses travel down the nerve, the nerve endings release a neurotransmitter substance called acetylcholine. Acetylcholine travels through the neuromuscular junction and binds to acetylcholine receptors which are activated and generate a muscle contraction.

In myasthenia gravis, antibodies are  produced by the body’s own immune system. These autoantibodies  are directed most commonly against the nicotinic acetylcholine receptor (nAChR) , the receptor in the motor end plate for the neurotransmitter acetylcholine that stimulates muscular contraction. Some forms of the antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors.

Recent research has shown that been realized that a second category of myasthenia gravis occurs  to auto-antibodies against the muscle specific kinase [MusK protein], a tyrosine kinase receptor which is required for the formation of the neuromuscular junction.

Thymus gland abnormalities are frequently found (Up to 75%)  in this condition.

In myasthenia gravis, it contains certain clusters of immune cells indicative of lymphoid hyperplasia  similar to found in the spleen and lymph nodes during an active immune response. Some individuals with myasthenia gravis develop thymomas or tumors of the thymus gland. Generally thymomas are benign, but they can also be malignant.

The relationship between the thymus gland and myasthenia gravis is not yet fully understood. It is believed that  the thymus gland may give incorrect instructions to developing immune cells, ultimately resulting in autoimmunity and the production of the acetylcholine receptor antibodies, thereby setting the stage for the attack on neuromuscular transmission.

myasthenia gravis

Defect in Myasthenia Gravis -Image Credit:Chop

Symptoms and Signs of Myasthenia Gravis

The hallmark of myasthenia gravis is fatiguability. Muscles become progressively weaker during periods of activity and improve after periods of rest. The onset of the disorder can be sudden.

Often symptoms are intermittent.

The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable.

Most commonly affected muscles are one that control eye and eyelid movement, facial expression, and swallowing are most frequently affected.

Usually the first noticeable symptom is weakness of the eye muscles in most of the cases. This may result in drooping of eyelids [ptosis], blurring of vision or double vision [diplopia]. Some of the patients may present with difficulty in swallowing and slurred speech.

Other symptoms may be unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression depending upon the muscle group involved.

The severity of the symptoms vary ranging from a localized form, limited to eye muscles (ocular myasthenia), to a severe or generalized form in which many muscles – including respiratory [That control breathing]  are affected.

Myasthenic crisis is caused by paralysis of the respiratory muscles and necessitates assisted ventilation to sustain life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress.

Heart muscle is generally unaffected by myasthenia gravis.

Some drugs like macrolides, fluoroquinolones, aminoglycosides, tetracycline, and chloroquine, Beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide, trimethaphan, diphenylhydantoin, lithium, chlorpromazine, muscle relaxants, levothyroxine, adrenocorticotropic hormone (ACTH), and, , corticosteroids may worsen the symptoms of Myasthenia gravis. Therefore it is prudent to get a detailed clinical history.

Classification of Myasthenia Gravis

The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America Clinical Classification

Class I

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

Class II

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

  • Class IIa: Predominantly limb or axial muscles
  • Class IIb: Predominantly bulbar and/or respiratory muscles

Class III

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

  • Class IIIa: Predominantly limb or axial muscles
  • Class IIIb: Predominantly bulbar and/or respiratory muscles

Class IV

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

  • Class IVa: Predominantly limb or axial muscles
  • Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation

Class V

Intubation needed to maintain airway

Diagnosis of Myasthenia Gravis

Because the symptoms are intermittent and patients are absolutely fine in between two episodes and the symptoms may overlap with other conditions, the diagnosis of  myasthenia gravis is usually delayed.

A detail history can raise the clinician’s suspicion. A detailed examination is done to check for neuromuscular system.

Muscle fatigability

It can be tested by repetitive use of muscles. For example

  • Looking upward and sidewards for 30 seconds
  • Looking at the feet while lying on the back for 60 seconds
  • Keeping the arms stretched forward for 60 seconds
  • 10 deep knee bends
  • Walking 30 steps on both the toes and the heels
  • 5 sit ups, lying down and sitting up completely

Peek sign indicates involvement of ocular muscles. After complete initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show.

Lab Investigations

Antibodies against the acetylcholine receptor may be found in the serum.The test has a reasonable sensitivity of 80–96%.  When myasthenia gravis limited to the eye muscles, the test may be negative in up to 50% of the cases. A proportion of the patients without antibodies against the acetylcholine receptor may show antibodies against the MuSK protein.

No laboratory tests are available in a time frame that is useful to confirm the emergency diagnosis of myasthenia gravis (MG).  An arterial blood gas determination can help guide respiratory management.

Imaging

Chest radiography is indicated to determine the presence of aspiration or other pneumonias, which commonly occur in patients with myasthenia gravis. CT scan or MRI of the chest is highly accurate in detecting thymoma.

Special Tests

Tensilon (edrophonium) challenge test

This approach requires the intravenous administration of edrophonium chloride or Tensilon(r), a drug that blocks the degradation (breakdown) of acetylcholine and temporarily increases the levels of acetylcholine at the neuromuscular junction.

This test is also used to differentiate between myasthenia crisis from cholinergic crisis.

A positive response is not completely specific for myasthenia gravis because several other conditions (eg, amyotrophic lateral sclerosis) may also respond to edrophonium with increased strength.

Once the patient’s airway and ventilation are secured, an initial test dose of edrophonium is given. Some patients may respond noticeably to a small dose (1 mg).

If no adverse reaction occurs following the test dose, another dose (3 mg) of edrophonium should produce noticeable improvement in muscle strength within 1 minute.6 If no improvement occurs, an additional dose of 5 mg can be administered to total no more than 10 mg.

Patients who respond generally show dramatic improvement in muscle strength, regaining facial expression, posture, and respiratory function within 1 minute.  During this procedure, the patient must be monitored carefully because edrophonium can cause significant bradycardia, heart block, and asystole.

Patients with a cholinergic crisis may respond to edrophonium challenge by increasing salivation and bronchopulmonary secretions, diaphoresis, and gastric motility. If muscle strength fails to improve following the maximum dose of edrophonium, the patient is having a cholinergic crisis or has another cause of weakness that is unrelated to myasthenia gravis.

Ice pack test

In a patient with myasthenia gravis who has ptosis, placing ice over an eyelid will lead to cooling of the lid, which leads to improvement of the ptosis. This occurs because cooling improves neuromucular transmission. This test has a pooled sensitivity and specificity of 82% and 96%, respectively.

Neurophysiology

Standard electromyography, single-fiber electromyography, repetitive nerve stimulation can be used  to confirm the diagnosis of myasthenia gravis.

Electromyography, in which single muscle fibers are stimulated by electrical impulses, can also detect impaired nerve-to-muscle transmission. EMG measures the electrical potential of muscle cells. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated electrical stimulation compared to muscles from normal individuals.

Spirometry

Lung function testing  may be performed to assess respiratory function if there are concerns about a patient’s ability to breathe adequately.

Muscle biopsy

Only performed if the diagnosis is in doubt and a muscular condition is suspected.

Treatment of Myasthenia Gravis

In emergency situations, the patient should be transferred to the hospital setting as soon as possible. Patients in frank respiratory arrest should be intubated and ventilated and managed i emergency situation.Infection should be ruled out. Any cause for exacerbation should be found and managed. Acetylecholine inhibitors should be given to control muscle weakness.

Patients in outpatient department can be managed by oral medications and other modalities as required.

Acetylcholinesterase inhibitors

Neostigmine and pyridostigmine can improve muscle function by slowing the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor.. Pyridostigmine is a short-lived drug with a half-life of about 4 hours.

Immunosuppressive drugs

Immunosuppressive drugs suppress the immunity of a person. Steroids, cyclosporine, mycophenolate mofetil and azathioprine may be used to suppress the levels of antibodies. These drugs can be used in conjunction with cholinesterase inhibitor. Treatments with some immunosuppressives take weeks to months before effects are noticed.

Plasmapheresis and Intravenous immunoglobulins

If the myasthenia is serious , plasmapheresis can be used to remove the putative antibody from the circulation. Intravenous immunoglobulins  can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits

Thymectomy

Thymectomy, the surgical removal of the thymus, is essential in cases of thymoma in view of the potential neoplastic effects of the tumor. Most of these patients show significant improvement after the thymus is removed.

Role of removal of thymus is not very clear in patients who do not have an abnormality of thymus.

Prognosis

With treatment, the outlook for most patients with myasthenia gravis is bright with a normal life expectancy, except for those with a malignant thymoma. Quality of life can vary depending on the severity and the cause. Except for those who get remissions following thymectomy,  most patients need treatment for the remainder of their lives, and their abilities vary greatly.

Myasthenia gravis is not usually a progressive disease. The symptoms may come and go, but the symptoms do not always get worse as the patient ages.

Complications

  • The most common severe complication of myasthenia gravis is respiratory failure, which often presents with the rapid deterioration of respiratory effort that ultimately results in apnea.
  • Pneumonia is a common complication in patients with myasthenia gravis and often is the cause of death in fatal cases.
  • Chronic respiratory insufficiency
  • Excessive use of cholinesterase inhibitors can result in a cholinergic crisis.
  • Chronic use of corticosteroids can result in a large number of serious complications, including opportunistic infection, GI bleeding, hyperglycemia, osteoporosis, aseptic necrosis, and cataract formation.
  • Other immunosuppressive medications increase the incidence of opportunistic infections, renal insufficiency, and hypertension.

Myasthenia Gravis In Children

Myasthenia gravis most commonly affects adults and elderly, but it has been known to occur at any age.Presentation and causes of myasthenia like picture in children differ from adults.

Three types of myasthenic symptoms in children can be distinguished.

Neonatal Myasthenia Gravis

It occurs in 12% of the pregnancies with a mother with myasthenia gravis. In such cases the mother passes the antibodies to the infant through the placenta causing neonatal myasthenia gravis.

The symptoms will start in the first two days and disappear within a few weeks after birth.

Congenital Myasthenic Syndrome

Children of a healthy mother can, very rarely, develop myasthenic symptoms beginning at birth. This is called congenital myasthenic syndrome.  It is not caused by an autoimmune process, but due to synaptic malformation, which in turn is caused by genetic mutations.

Thus, CMS is a hereditary disease. More than 11 different mutations have been identified and the inheritance pattern is typically autosomal recessive.

The types of CMS are classified into three categories: presynaptic, postsynaptic, and synaptic.

Presynaptic symptoms include brief stops in breathing, weakness of the eye, mouth, and throat muscles. These symptoms often result in double vision and difficulty chewing and swallowing.

Postsynaptic symptoms in infants include severe muscle weakness, feeding and respiratory problems, and delays in the ability to sit, crawl, and walk. Onset symptoms for all ages may include droopy eyelids.

A particular form of postsynaptic CMS (slow-channel CMS) includes severe weakness beginning in infancy or childhood that progresses and leads to loss of mobility and respiratory problems in adolescence or later life.

Synaptic symptoms include early childhood feeding and respiratory problems, reduced mobility, curvature of the spine, and weakness, which causes a delay in motor milestones..

Juvenile Myasthenia Gravis

It is myasthenia occurring in childhood but after the peripartum period.


 

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