Myasthenia gravis

A.      Description

 Weakness and progressive fatigue with exercise are the hallmarks of generalized myasthenia gravis. However, diplopia may be the only symptom of ocular myasthenia, and the pupil is never involved. Muscle wasting may occur late, but it is not prominent. The course is variable and marked with remissions and exacerbations, which makes evaluation of the therapy difficult. Most patients reach maximum severity of their disease within 1 year, but a few progress over several years. Classification into several general groups helps to predict the course and to determine the type of therapy. Choice of therapy depends on the individual case; some respond easily to a single modality, whereas others require all modalities used in tandem or together.

1.       Group I. About 14% of patients have ocular myasthenia only.

2.       Group IIA. Mild generalized myasthenia with ocular signs.

3.       Group IIB. Moderately severe generalized myasthenia, with mild bulbar and ocular involvement.

4.       Group III. Acute severe myasthenia, with bulbar and respiratory complications. Tracheostomy is required.

5.       Group IV. Late severe myasthenia, usually developing from other groups within 2 years.

B.      D

iagnostic tests

1.       Edrophonium (Tensilon) test

a.       Initial diagnosis. When there is a defect that is easily observed, such as grip strength, neck power, extraocular muscle function, ptosis, diplopia, swallowing, vital capacity, and occasionally changes on EMG, edrophonium chloride can cause transient improvement and support the diagnosis of myasthenia gravis. The edrophonium test is not used in patients with respiratory distress.

2.       For best results a placebo control is used, and the trial is done double-blind. The placebo can be nicotinic acid (100 mg/10 mL of saline), which gives a systemic response, or saline alone. Atropine (0.4 mg) is often used both as a control and to protect against excessive muscarinic side effects, such as:

a.       Excessive sweating.

b.      Excessive salivation.

c.       Lacrimation.

d.       Diarrhea.  

e.      Abdominal cramps and nausea.

f.        Incontinence of stool and urine.

g.       Bradycardia.

h.      Hypotension.

i.   Small pupils (less than 2 mm).

3.       Edrophonium, 10 mg, is used in the adult (0.2 mg/kg in children). To begin, 2 mg is infused into a secure IV line, and the patient is observed for excessive muscarinic side effects. If there are no severe effects, the remaining drug is infused in about 30 seconds.

4.       The patient is observed for improvement. The duration of action is 2 to 20 minutes; however, occasionally, in patients treated with prednisone, it may be longer (up to 2 hours). The clinical improvement should coincide with the drug’s expected duration of action.

b.      Smaller doses of edrophonium (1 mg) are used to diagnose cholinergic crisis. If there is no improvement, more drug is infused 1 mg at a time, up to 5 mg. Improvement is judged clinically, as in the diagnostic test. Respiratory function must be assessed carefully before the test; if edrophonium causes apnea, facilities for tracheal intubation must be at hand.

c.       Evaluation of oral anticholinesterase therapy can be done in some patients by infusing edrophonium, 2 mg, 1 hour after the last oral dose and watching for improvement and side effects. If there is improvement and there are no increased side effects, the oral dose is increased by 25% to 50%. If there is no change in the patient’s power but there are mild side effects, the dose is kept the same. When the side effects are prominent and the patient’s power is worse following the edrophonium, the oral dose is reduced by 25 to 50%.

2.  Neostigmine test. If the duration of the action of edrophonium is too short to permit evaluation of the patient’s response, the anticholinesterase neostigmine (Prostigmin) may be used. Neostigmine, 0.04 mg/kg, is injected IM and reaches its maximum activity in 1 to 2 hours. The effect is gone at 3 to 4 hours. Pretreatment with atropine can prevent muscarinic side effects.

3.  EMG. If a nerve is stimulated at 3 to 10 impulses/second repeatedly and an EMG is recorded, the amplitude of contraction is temporarily diminished in myasthenia gravis. When myasthenia patients are relaxed so that several muscles (at least one of which is proximal) are rested, 95% will show a pathognomonic EMG pattern. In myasthenia, a decrement in response is followed by a plateau or an increment, whereas in other disorders that may show a decrement (myotonia, poliomyelitis, amyotrophic lateral sclerosis, neuropathies, and McArdle disease), the decrement is continuous. Single-fiber EMG recording often shows abnormalities characteristic of neuromuscular junction disease.

5.       Acetylcholine receptor antibody assay is positive in 50% of patients with ocular myasthenia and in 80% to 90% of patients with generalized myasthenia. The antibody level reflects the severity of disease in untreated patients.

Evaluation of thymus

a.       About 75% of patients with myasthenia gravis have abnormal thymus glands. The most common abnormality is hyperplasia, but 15% have thymoma.

b.      CT scan of the mediastinum is highly reliable in identifying thymoma. CT scan is sometimes normal in patients with thymic hyperplasia.

C.      Treatment

1.       General measures

a.       Patients with generalized myasthenia should be hospitalized and kept at rest while anticholinesterase medication is begun.

b.      Contraindicated medications. Drugs that have mild neuromuscular blocking effects and sedatives, which may cause respiratory depression, are contraindicated. Common drugs of this type are:

1. Quinine.

2. Quinidine.

3. Procainamide.

4. Propranolol.

5. Lidocaine.

6. Aminoglycoside antibiotics.

7. Polymyxin.

8. Viomycin.

9. Colistin.

10. Morphine.

11. Barbiturates.

12. Other tranquilizers.

c.       The goals of therapy in myasthenia vary with the severity of the illness. Improvement in strength or increased time spent out of the hospital are goals in more severe cases. However, complete remission can occur with steroid therapy.

d.      Thyroid abnormalities occur in association with myasthenia gravis, and antithyroid antibodies and antimuscle antibodies have been detected in some myasthenics. However, no clinical correlation between the abnormalities and these antibodies has been made. In thyrotoxic patients, thyrotoxic myopathy is more common than myasthenia gravis. However, in patients with myasthenia, thyrotoxicosis must be treated before the myasthenia gravis will improve.

e.      Ephedrine, 25 mg t.i.d., or other stimulant drugs occasionally improve strength in patients on anticholinesterase therapy.

2.       Respiratory care

a.       Acute generalized myasthenia is a medical emergency, and even when the patient appears to have normal respiratory function, rapid decompensation can occur. Thus, myasthenics with generalized disease are kept under close observation in an intensive care unit until treatment is seen to be effective.

b.      Measurement of maximum voluntary ventilation (patient breathes as rapidly and as deeply as possible for 15 seconds while expired gases are collected and analyzed) gives the best indication of effects of myasthenia on respiratory muscles. Measurement of vital capacity with a hand spirometer is also a satisfactory way of following respiratory function.

c.       Ocular myasthenia (group I) is a benign illness. It is not associated with respiratory failure.

3.       Anticholinesterase therapy remains the initial choice when myasthenia is diagnosed. It is used in conjunction with corticosteroid therapy to treat the disease definitively.

a.       Pharmacology

1.       Anticholinesterase drugs inhibit the destruction of acetylcholine and allow its accumulation at the synapse. Therefore, the effects of the drug are limited to the cholinergic synapse. The motor end-plate is the primary therapeutic target, but autonomic cholinergic synapses are also affected and produce side effects. The drugs used do not cross the blood-brain barrier, so there are insignificant central effects. The parasympathetic postganglionic effects predominate because the ganglionic sites are less sensitive to inhibition. Both the dose of drug given and the level of activity at the synapse determine the degree of the parasympathetic activity.

2.       Side effects may be reduced by avoiding factors that increase parasympathetic activity (e.g., motion). Atropine, 0.4 to 0.8 mg PO, may be useful in reducing side effects in certain circumstances, but chronic use is usually not helpful because of atropine toxicity. However, patients should have atropine on hand for occasional use.

3.       Smaller doses of anticholinesterase, taken more frequently, or doses taken with food to delay absorption may help to reduce side effects. The patient often becomes tolerant of the side effects with prolonged therapy.

4.       The common anticholinesterase drugs are listed in Table 16-4.