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Myasthenia gravis is a neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy.

Ø Classification

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

Ø Signs and symptoms

Ptosis of the left eye.

The hallmark of myasthenia gravis is fatiguability. Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Often the physical examination is within normal limits.

The onset of the disorder can be sudden or rapid. Often symptoms are intermittent. The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable.

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 eyelids), 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 velar 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. Since the heart muscle is stimulated differently, it is never affected by MG.

Ø Pathophysiology

The thymus. Displayed thymus is relatively large, since it is a juvenile thymus.

Myasthenia gravis is an autoimmune disease: it features antibodies directed against the body's own proteins. While in various similar diseases the disease has been linked to a cross-reaction with an infective agent, there is no known causative pathogen that could account for myasthenia. There is a slight genetic predisposition: particular HLA types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to 75% of patients have an abnormality of the thymus; 25% have a 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 protein (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 suffer from co-existing autoimmune diseases at a higher frequency than members of the general population. Of particular mention is co-existing thyroid disease where episodes of hypothyroidism may precipitate a severe exacerbation.

The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research in which might eventually lead to new treatment options.

Ø Diagnosis

Myasthenia can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders. A thorough physical examination can reveal easy fatiguability, with the weakness improving after rest and worsening again on repeat of the exertion testing. Applying ice to weak muscle groups characteristically leads to improvement in strength of those muscles. Additional tests are often performed, as mentioned below. Furthermore, a good response to medication can also be considered a sign of autoimmune pathology.

Ø Physical examination

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
• "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show.

Ø Neurophysiology

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.

Ø Edrophonium test

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) or neostigmine (Prostigmin), drugs that block 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.

Ø Imaging

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.

Ø Pulmonary function test

Spirometry (lung function testing) may be performed to assess respiratory function if there are concerns about a patient's ability to breathe adequately. The forced expiratory volume in one second (FEV1) or the peak expiratory flow rate (Pefr) 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.