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Global view of a neuromuscular junction:<BR>1 Axon <BR>2 Motor end-plate<BR>3 Muscle Fiber <BR>4 Myofibril
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(sometimes abbreviated MG; from the
Acetylcholine . Myasthenia is treated with
Immunosuppressants ,
Cholinesterase Inhibitor s and, in selected cases,
Thymectomy .
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 to maintain airway
The hallmark of myasthenia gravis is
Muscle Weakness that increases during periods of activity and improves after periods of rest. Muscles that control eye and eyelid movement, facial expression,
Chewing ,
Talking , and
Swallowing are especially susceptible. The muscles that control
Breath ing and neck and limb movements can also be affected. Often the physical examination is within normal limits.
3
The onset of the disorder can be sudden or rapid. Often symptoms come and go over time. The diagnosis of myasthenia gravis is often initially missed.
In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in MG varies greatly among patients, ranging from a localized form, limited to eye muscles (
Ocular Myasthenia ), to a severe or generalized form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in type and severity, may include asymmetrical
Ptosis (a drooping of one or both
Eyelid s),
Diplopia (double vision) due to weakness of the muscles that control eye movements, unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression,
Dysphagia (difficulty in swallowing), shortness of breath and
Dysarthria (impaired speech, often nasal due to weakness of the pharyngeal muscles).
In ''myasthenic crisis'' a
Paralysis of the respiratory muscles occurs, necessitating
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.
4 Since the
Heart Muscle is stimulated differently, it is never affected by MG.
Myasthenia gravis is an types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to 25% have a concurrent
Thymoma , a tumor (either benign or malignant) of the
Thymus , and other abnormalities are frequently found. The disease process generally remains stationary after thymectomy (removal of the thymus).
In MG, the autoantibodies are directed most commonly against the
Acetylcholine Receptor (
Nicotinic Type ), 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, either by
Complement fixation or by inducing the muscle cell to eliminate the receptors through
Endocytosis .
The antibodies are produced by plasma cells, that have been derived from B cells. These plasma cells are activated by T-helper cells, which in turn are activated by binding to acetylcholine receptor antigenic peptide sequences (epitopes) that rest within the histocompatibility antigens of antigen presenting cells. The thymus plays an important role in the development of T-cells, which is why myasthenia gravis is associated with thymoma. The exact mechanisms are however not convincingly clarified.
In normal
Muscle Contraction , cumulative activation of the ACh receptor leads to influx of
Sodium and
Calcium . Only when the levels of these electrolytes inside the muscle cell is high enough will it contract. Decreased numbers of functioning receptors therefore impairs muscular contraction.
It has recently been realized that a second category of gravis is due to auto-antibodies against the
MuSK Receptor (Muscle Specific Kinase), a
Tyrosine Kinase receptor which is required for the formation of the
Neuromuscular Junction . Antibodies against MuSK inhibit the signaling of MuSK normally induced by its nerve-derived ligand,
Agrin . The result is a decrease in patency of the neuromuscular junction, and the consequent symptoms of MG.
People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of MG, but both the symptoms and the titer disappear when drug administration is discontinued.
MG is more common in families with other autoimmune diseases. A familial predisposition is found in 5% of the cases. This is associated with certain genetic variations such as an increased frequency of HLA-B8 and DR3. People with MG also have an increased risk of developing another autoimmune disease.
Myasthenia can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders.
5 A patient may have visited the
ENT Doctor , the
Ophthalmologist and even the
Psychiatrist and waited for years for the right diagnosis.
A thorough
Physical Examination can reveal easy fatiguability, with the weakness improving after rest and worsening again on repeat of the exertion testing. Though this is not often performed, applying
Ice to the weak muscle groups characteristically improves the weakness. Additional tests are often performed, as mentioned below. Furthermore, a good response to medication can also be considered a sign of autoimmune pathology.
Muscle fatigability can be tested for many muscles. A thorough investigation includes
- looking upward and sidewards for 30 seconds: Ptosis and Diplopia .
- 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 situps, lying down and sitting up completely
If the diagnosis is suspected,
Serology can be performed in a
Blood Test to identify
Antibodies against the
Acetylcholine Receptor . The test has a reasonable
Sensitivity of 80–96%, but in MG limited to the eye muscles (ocular myasthenia) the test may be negative in up to 50% of the cases. About half of the patients without antibodies against the acetylcholine receptor have antibodies against the
MuSK Protein . Often, parallel testing is performed for
Lambert-Eaton Syndrome , in which other antibodies (against a voltage-gated
Calcium Channel ) can be found. Also the thyroid function should be tested.
Muscle fibers of patients with MG are easily fatigued, and thus do not respond as well as muscles in healthy individuals to repeated stimulation. By repeatedly stimulating a muscle with electrical impulses, the fatiguability of the muscle can be measured. This is called the repetitive nerve stimulation test. 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 a muscle to record the electric potentials of individual muscle fibers. By finding two muscle fibers belonging to the same motor unit and measuring the temporal variability in their firing patterns (i.e. their 'jitter'), the diagnosis can be made.
The "edrophonium test" is infrequently performed to identify MG; its application is limited to the situation when other investigations do not yield a conclusive diagnosis. This test requires the
Intravenous administration of
Edrophonium Chloride (Tensilon®, Reversol®), a drug that blocks the breakdown of acetylcholine by
Cholinesterase and temporarily increases the levels of acetylcholine at the
Neuromuscular Junction . In people with myasthenia gravis involving the eye muscles, edrophonium chloride will briefly relieve weakness.
A
Chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton due to a lung tumor) and comorbidity. It may also identify widening of the
Mediastinum suggestive of
Thymoma , but
Computed Tomography (CT) or
Magnetic Resonance Imaging (MRI) are more sensitive ways to identify thymomas, and are generally done for this reason.
Spirometry (lung function testing) may be performed to assess respiratory function if there are concerns about a patient's ability to breathe adequately. The FEV1 (forced expired volume in one second) or the PEFR (peak expiratory flow rate) may be monitored at intervals in order not to miss a gradual worsening of muscular weakness. Severe myasthenia may cause
Respiratory Failure due to exhaustion of the respiratory muscles.
Immunofluoresence shows IgG antibodies on the neuromuscular junction. (Note that it is not the antibody which causes myasthenia gravis that fluoresces, but rather a
Secondary Antibody directed against it.) Muscle electron microscopy shows receptor infolding and loss of the tips of the folds, together with widening of the synaptic clefts. Both these techniques are currently used for research rather than diagnostically.
Myasthenia gravis can usually be controlled with medication. Medication is used for two different endpoints:
- Direct improvement of the weakness
- Reduction of the autoimmune process
Muscle function is improved by cholinesterase inhibitors, such as neostigmine and pyridostigmine. These slow the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor. Usually doctors will start with a low dose, eg 3x20mg pyridostigmine, and increase until the desired result is achieved. If taken 30 minutes before a meal, symptoms will be mild during eating. Side effects, like perspiration and diarrhea can be countered by adding atropine. Pyridostigmine is a short-lived drug with a half-life of about 4 hours.
Immunosuppressive drugs such as prednisone, cyclosporine, mycophenolate mofetil and azathioprine may be used. It is common for patients to be treated with a combination of these drugs with a cholinesterase inhibitor. Treatments with some immunosuppressives take weeks to months before effects are noticed.
If the myasthenia is serious (myasthenic crisis), plasmapheresis is used to remove the putative antibody from the circulation. Similarly, intravenous immunoglobulins (IVIg) is used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits, typically measured in weeks.
Thymectomy, the surgical removal of the thymus gland (which is abnormal in myasthenia gravis patients), improves symptoms in more than 50 percent of patients. Some patients are cured by thymectomy, suggesting that the thymus plays a significant role in the pathogenesis of myasthenia, but it is not considered a definitive cure for the disease. The positive effects from a thymectomy may be seen within weeks to as much as 3–5 years after surgery. Thymoma is relatively rare in younger (<40) patients, but paradoxically especially younger patients with generalized MG without thymoma benefit from thymectomy. Of course resection is also indicated for those with a thymoma, but it is less likely to improve the MG symptoms.
With treatment, patients have a normal life expectancy, except for those with a malignant thymoma (whose lesser life expectancy is on account of the thymoma itself and is otherwise unrelated to the myasthenia). Quality of life can vary depending on the severity and the cause. The drugs used to control MG either diminish in effectiveness over time (
Cholinesterase Inhibitors ) or cause severe side effects of their own (
Immunosupressants ). A small percentage (around 10%) of MG patients are found to have tumors in their
Thymus , in which case
Thymectomy is a very effective treatment with long term remission. However, most patients need treatment for the remainder of their lives, and their abilities vary greatly. It should be noted that MG is not a progressive disease. The symptoms may come and go, but the symptoms usually don't get worse as the patient ages. For some, the symptoms decrease after 3–5 years.
Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects women under 40 and people from 50 to 70 years old of both sexes, but it can occur at any age. Younger patients rarely have thymoma. The prevalence in the
United States is estimated at 20 cases per 100,000 in the USA.
6 Risk factors are female gender, age 20–40, familial myasthenia gravis, D-penicillamine ingestion (drug induced myasthenia) and other autoimmune disease.
Three types of myasthenia symptoms in children can be distinguished:
# Neonatal: In 12% of the pregnancies with a mother with MG, she 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. With the mother it is not uncommon for the symptoms to even improve during pregnancy, but they might worsen after labor.
# Congenital: Children of a healthy mother can, very rarely, develop myasthenic symptoms beginning at birth. This is called
Congenital Myasthenic Syndrome or CMS. Other than Myasthenia gravis, CMS 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 congenital myasthenias cause muscle weakness and fatigability similar to those of MG. The symptoms of CMS usually begin within the first two years of life, although in a few forms patients can develop their first symptoms as late as the seventh decade of life. A diagnosis of CMS is suggested by the following:
- Onset of symptoms in infancy or childhood.
- Weakness which increases as muscles tire.
- A decremental EMG response, on low frequency, of the compound muscle action potential (CMAP).
- No anti-AChR or MuSK antibodies.
- No response to immunosuppressant therapy.
- Family history of symptoms which resemble CMS.
The symptoms of CMS vary from mild to severe, depending on the form. It's also common for patients with the same form, even members of the same family, to be affected to differing degrees. In most forms of CMS weakness does not progress, and in some forms symptoms may diminish as the patient gets older. Only rarely do symptoms of CMS become worse with time.
# Juvenile myasthenia gravis: Myasthenia occurring at a young age.
- Baets, MH de, Oosterhuis HJGH. Myasthenia gravis. Boca Raton: DRD Press, 1993
- Rowland LP, ed: Merritt's textbook of Neurology. 10th Ed. Philadelphia, Lippincott, Williams & Wilkins, 1995
- Cavel-Greant, D, Nicolle, MW ed; You, Me and Myasthenia Gravis Third ed. Ku:Reh Press, 2006
