Myasthenia gravis: Newer therapies offer sustained improvement

Testing for antibodies

Testing for circulating AChR antibodies, MuSK antibodies, or both is the first step in the laboratory confirmation of myasthenia gravis.

There are three AChR antibody subtypes: binding, blocking, and modulating. Binding antibodies are present in 80% to 90% of patients with generalized myasthenia gravis and 50% of those with ocular myasthenia gravis. Testing for blocking and modulating AChR antibodies increases the sensitivity by less than 5% when added to testing for binding antibodies.

AChR antibody titers correlate poorly with disease severity between patients. However, in individual patients, antibody titers tend to go down in parallel with clinical improvement.

MuSK antibody is detected in nearly half of myasthenia gravis patients with generalized weakness who are negative for AChR antibody.

Electrophysiologic tests

Electrophysiologic tests can usually confirm the diagnosis of seronegative myasthenia gravis. They are also helpful in seropositive patients who have unusual clinical features or a poor response to treatment.

Repetitive nerve stimulation studies use a slow rate (2–5 Hz) of repetitive electrical stimulation. The study is positive if the motor response declines by more than 10%. However, a decremental response is not specific for myasthenia gravis, as it may be seen in other neuromuscular disorders such as motor neuron disease or Lambert-Eaton myasthenic syndrome.

This test is technically easier to do in distal muscles than in proximal muscles, but less sensitive. Therefore, proximal muscles such as the trapezius or facial muscles are usually also sampled to maximize the yield. To further maximize the sensitivity, muscles being tested should be warm, and acetylcholinesterase inhibitors should be withheld for 12 hours before.

Repetitive nerve stimulation studies in distal muscles are positive in approximately 75% of patients with generalized myasthenia gravis and in 30% with ocular myasthenia gravis.²⁶

Single-fiber electromyography is more technically demanding than repetitive nerve stimulation and is less widely available. It is usually performed with a special needle electrode that can simultaneously identify action potentials arising from individual muscle fibers innervated by the same axon.

Variability in time of the second action potential relative to the first is called “jitter.” Abnormal jitter is seen in more than 95% of patients with generalized myasthenia gravis and in 85% to 90% of those with ocular myasthenia gravis.^26,27 However, abnormal jitter can also be seen in other neuromuscular diseases such as motor neuron disease or in neuromuscular junctional disorders such as Lambert-Eaton myasthenic syndrome.

Imaging studies

Chest computed tomography or magnetic resonance imaging with contrast should be performed in all myasthenia gravis patients to look for a thymoma.

TREATMENT OF MYASTHENIA GRAVIS

Acetylcholinesterase inhibitors

As a reasonable first therapy in mild cases of myasthenia gravis, acetylcholinesterase inhibitors slow down the degradation of acetylcholine and prolong its effect in the neuromuscular junction, but they are not disease-modifying and their benefits are mild.

Pyridostigmine is the usual choice of acetylcholinesterase inhibitor. Its onset of action is rapid (15 to 30 minutes) and its action lasts for 3 to 4 hours. For most patients, the effective dosage range is 60 mg to 90 mg every 4 to 6 hours. A long-acting form is also available and can be given as a single nighttime dose.

Immunomodulating therapy

Patients who have moderate to severe symptoms require some form of immunomodulating therapy.

Plasmapheresis or intravenous immune globulin is reserved for patients with severe or rapidly worsening disease because their beneficial effects can be seen within the first week of treatment.

Longer-acting immunotherapies (corticosteroids, azathioprine, mycophenolate mofetil and others) have a slower onset of responses but provide sustained benefits. Which drug to use depends on factors such as comorbidity, side effects, and cost.

Drugs to avoid

A number of medications can exacerbate weakness in myasthenia gravis and should be avoided or used with caution. The list is long, but ones that deserve the most attention are penicillamine, interferons, procainamide, quinidine, and antibiotics, including quinolones and aminoglycosides. A more comprehensive list of medications that may exacerbate myasthenia gravis symptoms can be found in a review by Keesey.²

RAPID INDUCTION IMMUNOTHERAPIES : PLASMAPHERESIS, IMMUNE GLOBULIN

Both plasmapheresis and intravenous immune globulin act quickly over days, but in most patients their effects last only a few weeks. Both are used as rescue therapies for myasthenic crises, bridging therapy to slow-acting immunotherapeutic agents, or maintenance treatment for poorly controlled cases.

Several retrospective studies have confirmed the efficacy of plasmapheresis in more than 80% of patients with generalized symptoms.^28,29

In a randomized trial in patients with generalized therapies, intravenous immune globulin improved muscle strength in the group of patients with severe symptoms.³⁰ The effective dosage of intravenous immune globulin varies from 1 to 2 g/kg without observed difference between doses.³¹ Trials comparing the efficacy of intravenous immune globulin and plasmapheresis in acute and severe myasthenia gravis did not reveal a difference in efficacy.^32,33 Intravenous immune globulin at a minimal dose of 0.4 g/kg every 3 months has been successfully used as a long-term maintenance monotherapy, and such a role could be expanded to more patients with further studies.³⁴

The choice between plasmapheresis and intravenous immune globulin is often based on the ability of a patient to tolerate each treatment and on the availability of the plasmapheresis procedure. Intravenous immune globulin is easier to administer, is associated with fewer adverse events related to vascular access, and is therefore more appropriate than plasmapheresis in some centers.

CHRONIC MAINTENANCE IMMUNOMODULATING TREATMENT

Corticosteroids

Prednisone, the most commonly used agent, leads to remission or marked improvement in 70% to 80% of patients with ocular or generalized myasthenia gravis.³⁵ It may also reduce the progression of ocular myasthenia gravis to the generalized form.³⁶

The effective dose of prednisone depends on the severity and distribution of symptoms. Some patients may need up to 1.0 mg/kg/day (usually 50 to 80 mg per day). In patients with mild to moderate symptoms, a lower maximal dosage such as 20 to 40 mg per day can be sufficient.

Within 1 to 2 weeks after starting high-dose prednisone, up to 50% of patients may develop a transient deterioration, including possible precipitation of a myasthenic crisis.³⁷ For this reason, high-dose prednisone is commonly started only in hospitalized patients who are also receiving plasmapheresis or intravenous immune globulin. Otherwise, an outpatient dose-escalation protocol can be used to achieve a target dose over several weeks.

Prednisone tapering can begin after the patient has been on the maximal dose for 1 to 2 months and significant improvement is evident. A monthly tapering of 5 to 10 mg is preferred, then more slowly after the daily dose reaches 30 mg. The usual maintenance dose averages about 5 mg daily.

Common side effects of prednisone include weight gain, cushingoid features, easy bruising, cataracts, glaucoma, hypertension, diabetes, dyslipidemia, and osteoporosis. Patients are advised to take supplemental calcium (1,500 mg per day) and vitamin D (400 to 800 IU per day). For those most at risk of osteoporosis, treatment with a bisphosphonate should be considered.

Other immunotherapeutic agents are often needed, either to replace the corticosteroid or to permit use of lower doses of it. Because of their delayed onset of action, starting such corticosteroid-sparing agents early in the course is often necessary. These agents are often initially combined with high-dose prednisone, with an eventual goal of weaning off prednisone entirely. This strategy offers the advantage of relatively rapid induction while avoiding the long-term adverse effects of corticosteroid treatment.

Azathioprine

Azathioprine doesn’t begin to show a beneficial effect in myasthenia gravis for 6 to 12 months, and it often reaches its maximal efficacy only after 1 to 2 years of treatment.³⁸

In a study of 78 myasthenia gravis patients, 91% improved when treated with azathioprine alone or together with prednisone.³⁹ In another study using azathioprine and prednisolone for generalized myasthenia gravis, nearly two-thirds of patients came off prednisolone while maintaining remission for 3 years.³⁸

A typical maintenance dose is 2 to 3 mg/kg/day. Common side effects are nausea, vomiting, and malaise. Less frequent side effects include hematologic abnormalities, abnormal liver function, and pancreatitis. Monthly monitoring of complete blood cell counts and liver function tests is warranted for the first 6 months, then less often.

One in 300 people in the general population is homozygous for a mutant allele in the thiopurine methyltransferase (TPMT) gene. Patients with this genotype should not receive azathioprine because of the risk of life-threatening bone marrow suppression.⁴⁰ A slightly increased risk of various forms of lymphoma has been documented.⁴¹