Pulmonary Medicine

Neuromuscular Disorders Affecting the Thorax: Myasthenia Gravis

What every physician needs to know

Myasthenia gravis (MG) is an autoimmune disorder in which antibodies to acetylcholine receptors (AChR) or to muscle-specific receptor tyrosine kinase (MuSK) lead to weakness. Clinical forms include generalized myasthenia and ocular myasthenia; about half of patients with ocular MG will develop generalized disease within two years of onset.

The clinical course is characterized by "crises," including myasthenic crises in which an exacerbation of MG may be severe enough to result in respiratory failure that requires mechanical ventilation (occurs in 15-20% of patients with MG) and "cholinergic crises" that are characterized by worsening of weakness that is due to overdose with anticholinesterase medications and resultant depolarizing blockade at the myoneuronal junction.

Thymomas, which may exist concurrently with MG (in 10% of patients), are associated with a more fulminant course; thymomas are present in a third of those with a myasthenic crisis. MG is present in up to half of patients with thymomas. MG may also be associated with small-cell lung cancer, Hodgkin's lymphoma, and autoimmune disorders, such as autoimmune thyroid disease (in 3-8%), rheumatoid arthritis, and systemic lupus erythematosus.

Classification

Not applicable.

Are you sure the patient has myasthenia gravis? What should you expect to find?

A constellation of clinical findings is seen in the typical presentation of MG. Fluctuating weakness of involved voluntary muscles, with limb proximal muscle weakness greater in the arms than the legs, is typical. Muscle weakness improves with rest or use of anticholinesterase agents. Ocular, facial, or neck muscle involvement is common. Ocular symptoms include ptosis, diplopia, and blurred vision, but the pupils are spared. Facial symptoms include an expressionless appearance. Neck symptoms are evident as difficulty holding up the head.

Bulbar symptoms, which may be the presenting symptoms (in 15%), include fatiguable chewing, dysarthria, dysphagia, and aspiration. Respiratory muscle weakness may occur in the absence of limb weakness and may constitute the initial clinical presentation of MG. A third of patients have respiratory muscle weakness that presents late in the course of the disease. While myasthenic crises may develop spontaneously, precipitating factors include infections, tapering of immunosuppressives, and surgery.

Physical examination demonstrates fatigability with repetitive muscle activity. Bedside testing includes the Tensilon (edrophonium) test, which should be used if significant ptosis is present. Tensilon, a short-acting acetylcholinesterase inhibitor, is given at a dose of 2 mg intravenously every sixty seconds until positive results in the form of transient improvement in muscle weakness are observed or until a total dose of 10 mg has been administered. A positive test suggests MG, but positive results are also seen in Lambert-Eaton myasthenic syndrome, botulism, and ALS. Muscarinic side effects may be seen, including symptomatic bradycardia and bronchospasm. Atropine should thus be available when the test is conducted.

The "ice pack test" may also be used in patients with ptosis, as neuromuscular transmission is improved at lower temperatures. In the ice pack test, an ice pack is placed on the patient's closed eyelids and removed after two minutes. A positive result is improvement in the degree of ptosis; the test is 80% sensitive in those with prominent ptosis.

An alternative diagnosis should be entertained when muscarinic symptoms (e.g., hypersalivation, sweating, increased secretions, nausea, vomiting, and diarrhea) are present, when symptoms worsen with a Tensilon test, when upper motor neuron signs are noted, when symptoms improve with exercise, and when pupillary involvement is seen.

Beware: there are other diseases that mimic myasthenia gravis.

A number of disorders may mimic MG, including generalized fatigue, amyotrophic lateral sclerosis (ALS), Lambert-Eaton myasthenic syndrome, botulism, penicillamine-induced myasthenia, and congenital myasthenic syndromes.

How and/or why did the patient develop myasthenia gravis?

The pathogenesis of myasthenia gravis is based on an antibody-mediated, T-cell-dependent, and autoimmune mechanism. Antibodies directed at proteins in the postsynaptic membrane of the neuromuscular junction result in destruction of acetylcholine receptors and impaired transmission of neural impulses across the neuromuscular junction.

Which individuals are at greatest risk of developing myasthenia gravis?

MG is the most common disorder of neuromuscular transmission, occurring with an incidence of 10-20 cases per million persons and a prevalence of 100-200 cases per million persons. Women of childbearing age are affected twice as often as men. Thymic tumors are present in 10% of patients with MG. Although the disease may occur at any age, a bimodal age distribution has been described, with an early peak in the second to third decades (and a female predominance) and a late peak in the sixth to eighth decades (and a male predominance).

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Assessment for antibodies to acetylcholine receptors (AChR) or to muscle-specific receptor tyrosine kinase (MuSK) is key to diagnosis. Eighty percent of those with generalized MG (and 60% with ocular MG) have detectable antibodies to AChR. The concentration of antibodies does not correlate with disease severity. AChR antibodies have also been found in Lambert-Eaton myasthenic syndrome and in systemic lupus erythematosus.

Anti-muscle-specific kinase (MuSK) antibodies are present in a subgroup of patients with MG who demonstrate a higher incidence of bulbar weakness and respiratory failure.

In electrodiagnostic tests not specific for MG, 77% demonstrate a 10-15% decrease in amplitude of action potentials during slow repetitive stimulation, while 92% have single-fiber EMG abnormalities. EMG is the most sensitive test for MG.

What imaging studies will be helpful in making or excluding the diagnosis of myasthenia gravis?

No imaging studies are helpful in diagnosis but once MG is confirmed, a chest CT should be obtained to look for an associated thymoma.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of myasthenia gravis?

Pulmonary function testing usually reveals a decreased vital capacity (VC) and decreases in inspiratory and expiratory muscle strength, which improve after administration of mestinon.

What diagnostic procedures will be helpful in making or excluding the diagnosis of myasthenia gravis?

Not applicable.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of myasthenia gravis?

Not applicable.

If you decide the patient has myasthenia gravis, how should the patient be managed?

General Management

Plasmapheresis (5 exchanges over 7-14 days) or intravenous immunoglobulin (IVIG, 2 g/kg over 2-5 days) is central to management. No clear difference in response has been demonstrated between plasmapheresis and IVIG, but the onset of action with plasmapheresis may be faster. Prednisone may be used at an initial dose of 60-80 mg/day. Other immune-modulating treatments include azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and tacrolimus. The anticholinesterase agent, pyridostigmine bromide, can be titrated to effect.

Rituximab has also been studied for the treatment of MG. It can be efficacious in MG patients with muscle-specific tyrosine kinase and acetylcholine receptor antibodies and is often used as salvage therapy for severe resistant MG. Predictors of response include less severe disease and younger age at the point of treatment. It is usually reserved for patients with thymomas whose symptoms are under relatively good control. Thymectomy in patients without thymomas remains controversial, but it may be used in those with generalized MG.

Management of Myasthenic Crisis

The patient should be admitted to the intensive care unit for monitoring, including pulse oximetry, frequent measurement of VC (every 2-4 hours), pulmonary toilet, and non-invasive ventilation and/or intubation with mechanical ventilation, if necessary. Immune suppression should not be used in a myasthenic crisis, as a response may not be seen for months. If the response to glucocorticoids is deemed inadequate, immune modulating treatments may be considered in chronic treatment.

Corticosteroids given in conjunction with plasmapheresis or IVIG may be effective in the short-term management of myasthenic crisis, although the time to onset of benefit from corticosteroids is 2-3 weeks. Transient worsening of symptoms may be seen with initiation of corticosteroids (in 10%), sometimes necessitating institution of mechanical ventilation. Corticosteroids and anticholinesterase agents should be started only after plasmapheresis.

Surgical treatment centers on thymectomy.

Emergency Respiratory Management of the Patient with Myasthenic Crisis

Signs of impending respiratory compromise include upper airway obstruction that is due to vocal cord paralysis, inability to handle oral or respiratory secretions, bilateral basal atelectasis, and weak cough. Hypercapnia is a late sign. An FVC of less than 15 mL/kg or a declining negative inspiratory force (NIF) usually indicate the need for intubation. Aggressive chest physiotherapy and pulmonary toilet are key in management.

Acute respiratory failure is generally treated with invasive mechanical ventilation; however, non-invasive ventilation may be attempted first. A PaCO2 greater than 45 mmHg predicts failure using non-invasive ventilation. Weaning trials may be attempted once the patient's respiratory status improves, as reflected in a maximal inspiratory pressure (MIP) greater than -20 cm H2O, a maximal expiratory pressure (MEP) greater than 40 cm H2O, and a forced vital capacity (FVC) greater than 10 mL/kg. Risk factors for extubation failure include male gender, a history of prior myasthenic crises, atelectasis, and duration of mechanical ventilation longer than ten days. Low arterial pH, low FVC, the presence of atelectasis, and the need for BiPAP use after extubation all predict the need for reintubation.

Predictors of post-operative respiratory failure following thymectomy include a low FVC, bulbar symptoms, high levels of AChR antibodies, and intraoperative blood loss.

What is the prognosis for patients managed in recommended ways?

The overall mortality in MG is under 5%. Weakness in MG generally peaks within a few years of symptom onset, and significant, albeit incomplete, improvement is expected with anticholinergic medications. Use of corticosteroids leads to remission in up to 80% of patients.

Thymectomy, with or without underlying thymoma, may improve survival and symptoms; 80% of those without thymoma will have (delayed) recovery.

What other considerations exist for patients with myasthenia gravis?

Not applicable.

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