Myasthenia Gravis Treatment & Management

Even though no rigorously tested treatment trials have been reported and no clear consensus exists on treatment strategies, myasthenia gravis (MG) is one of the most treatable neurologic disorders. Several factors (eg, severity, distribution, rapidity of disease progression) should be considered before therapy is initiated or changed.

Pharmacologic therapy includes anticholinesterase medication and immunosuppressive agents, such as corticosteroids, azathioprine, cyclosporine, plasmapheresis, and intravenous immune globulin (IVIg).

Plasmapheresis and thymectomy are also employed to treat MG. They are not traditional medical immunomodulating therapies, but they function by modifying the immune system. Thymectomy is an important treatment option for MG, especially if a thymoma is present. A cardiothoracic surgeon should be consulted whenever thymectomy is contemplated as part of treatment.

MG is a chronic disease that may worsen acutely over days or weeks (and on rare occasions, over hours). Treatment requires scheduled reevaluation and a close doctor-patient relationship. Patients with MG require close follow-up care in cooperation with the primary care physician.

Intubation and intensive care unit (ICU) transfer usually are reserved for patients in myasthenic crisis with respiratory failure. Rapid respiratory failure may occur if the patient is not monitored properly. Patients should be watched very carefully, especially during exacerbation, by measuring negative inspiratory force and vital capacity.

Acetylcholine esterase (AChE) inhibitors and immunomodulating therapies are the mainstays of treatment.

In the mild form of the disease, AChE inhibitors are used initially. These agents include pyridostigmine, neostigmine, and edrophonium. Pyridostigmine is used for maintenance therapy.^{[9, 26]} Neostigmine is generally used only when pyridostigmine is unavailable. Edrophonium is primarily used as a diagnostic tool to predict the response to longer-acting cholinesterase inhibitors (see Workup).^[27]

With AChE inhibitors, a wide variability exists in the effective dose, depending on the severity and current activity of the disease and the presence of other factors that influence cholinergic transmission (eg, certain antibiotics, antidysrhythmic medications, and impaired renal function).^{[28, 26]} Most patients are able to titrate the dosage of their medication to control disease symptoms, but severe exacerbations can occur in patients with previously well-controlled disease.^[26]

Most patients with generalized MG require additional immunomodulating therapy. Immunomodulation can be achieved by various medications, such as commonly used corticosteroids.

The corticosteroid regimen should be tailored according to the patient’s overall improvement. The lowest effective dose should be used on a long-term basis. Because of the delayed onset of effects, steroids are not recommended for routine use in the emergency department (ED). Patients who are taking long-term moderate or high doses of steroids may have suppressed adrenal function and may require stress doses (eg, hydrocortisone 100 mg IV in an adult) during acute exacerbations.^[26]

Limited evidence from randomized, controlled trials (RCTs) suggests that corticosteroid therapy provides a short-term benefit in MG; this supports the conclusions of previous observational studies, as well as expert opinion. A systematic review found no clear difference between steroids and IVIg or azathioprine; however, further trials are indicated because of the flaws in the trials reviewed.^[29]

Other medications that are used to treat more difficult cases include azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly.^{[30, 31, 32]}

The mainstay of therapy is still azathioprine, usually after an initial dose of corticosteroids. Cyclosporine A and occasionally methotrexate and cyclophosphamide are used for severe cases, while tacrolimus is under investigation.^[33] No evidence-based studies fully prove the usefulness of AChE inhibitors, corticosteroids, and other immunosuppressive agents in improving ocular symptoms. In addition, the effect of corticosteroids and azathioprine on the progression to generalized MG is still uncertain.^[34]

To date, most of the studies on immunomodulatory therapy have had few participants and have found it difficult to assess the efficacy of the addition of immunosuppressive therapy to the previous regimens of corticosteroids and AChE inhibitors. Furthermore, most of the RCTs were short-term and did not evaluate long-term usage of these drugs. As a result, good RCT data on the use of immunosuppressive agents as monotherapy or dual therapy with steroids are absent.^[35]

However, limited evidence indicates that cyclosporine and cyclophosphamide improve symptoms in MG and decrease the amount of corticosteroid usage. The more common drugs used in MG, such as azathioprine and tacrolimus, show no clear benefit in use.^[35]

IVIg is a more cost-effective and clinically superior alternative to plasmapheresis (see Plasmapheresis below). It appears to be a better treatment option for the elderly and those with complex comorbid diseases, such as acute respiratory failure.^[36] IVIg is recommended for MG crisis, in patients with severe weakness poorly controlled with other agents, or in lieu of plasma exchange at a dose of 1 g/kg.^{[7, 37, 38]}

IVIg is effective in moderate or severe MG worsening into crisis, but it does not exhibit value in mild disease.^[39] Studies reveal that patients who have moderate or severe MG (ie, who are not in crisis) do not show an improvement in function or a reduced need for steroids.^[7] Data neither support or rule out a role for IVIg in chronic MG.^[7] To be included in IVIg studies, patients have been required to be autoantibody-positive. Therefore, the use of IVIg in a seronegative patient is not supported by the literature.^[7]

Transient neonatal MG, in which MG is transmitted vertically from an affected mother to her fetus, occurs in 10-30% of neonates born to myasthenic mothers. It may occur any time during the first 7-10 days of life, and infants should be monitored closely for any signs of respiratory distress.

The syndrome of neonatal myasthenia is caused by transplacental transfer of maternal autoantibodies against the acetylcholine receptor (AChR). Infants affected by this condition are floppy at birth, and they display poor sucking, muscle tone, and respiratory effort. They often require respiratory support and intravenous (IV) feeding, as well as monitoring in a neonatal ICU. As the transferred maternal antibodies are metabolized over several weeks, symptoms abate and the infants develop normally.

Treatment with cholinesterase inhibitors is effective in this age group as well. However, the dosage must be carefully titrated to the clinical effect.

Long-term immunomodulating therapies may predispose patients with MG to various complications. Long-term steroid use may cause or aggravate osteoporosis, cataracts, hyperglycemia, weight gain, avascular necrosis of hip, hypertension, opportunistic infection, and other complications. Long-term steroid use also increases the risk of gastritis or peptic ulcer disease. Patients on such therapy should take an H₂ -blocker or antacid as well.

Some complications are common to any immunomodulating therapy, especially if the patient is on more than 1 agent. These would include infections such as tuberculosis, systemic fungal infections, and Pneumocystis carinii pneumonia. The risk of lymphoproliferative malignancies may be increased with chronic immunosuppression. Immunosuppressive drugs may have teratogenic effects.

Initial deterioration in weakness before improvement is a common and serious concern within the first 3 weeks of immunomodulatory therapy; this potential complication warrants initiation of high doses in a supervised setting.

Excessive use of cholinesterase inhibitors can result in a cholinergic crisis. Other immunosuppressive medications increase the incidence of opportunistic infections, renal insufficiency, and hypertension.

Plasmapheresis (plasma exchange) is believed to act by removing circulating humoral factors (ie, anti-AChR antibodies and immune complexes) from the circulation. It is used as an adjunct to other immunomodulatory therapies and as a tool for crisis management. Like IVIg, plasmapheresis is generally reserved for myasthenic crisis and refractory cases. Improvement is noted in a couple of days, but it does not last for more than 2 months.

Plasmapheresis is an effective therapy for MG, especially in preparation for surgery or as short-term management of an exacerbation. Improvement in strength may help to achieve rapid postoperative recovery and to shorten the period of assisted ventilation. Long-term regular plasmapheresis on a weekly or monthly basis can be used if other treatments cannot control the disease.

Complications are primarily limited to complications of intravenous (IV) access (eg, central line placement) but also may include hypotension and coagulation disorders (though less commonly).

Even though no controlled trial to assess the efficacy of thymectomy in MG has been reported, this procedure has become the standard of care and is indicated for all patients with thymoma and for patients aged 10-55 years without thymoma but with generalized MG. Thymectomy has been proposed as a first-line therapy in most patients with generalized myasthenia. Research is under way to determine whether thymectomy combined with prednisone therapy is more beneficial in treating nonthymomatous MG than prednisone therapy alone.

In ocular MG, thymectomy should be delayed at least 2 years to allow for spontaneous remission or the development of generalized MG. Whether thymectomy is to be performed for prepubescent patients or patients older than 55 years is still controversial. Reports tend to encourage surgical treatment for the latter group.

Thymectomy is not recommended in patients with antibodies to muscle-specific kinase (MuSK), because of the typical thymus pathology, which is very different from the more common type of MG characterized by seropositivity for AChR antibodies.^[40]

Patients often experience some transient worsening of symptoms early in the postoperative period. Improvement usually is delayed for months or years. Complete removal of thymic tissue is widely considered to be of the utmost importance, on the grounds that any small remnant might lead to recurrence.

Thymectomy may induce remission. This occurs more frequently in young patients with a short duration of disease, hyperplastic thymus, more severe symptoms, and a high antibody titer, although a high titer of antibody is not consistently linked to better outcome.^[41]

Remission rate increases with time: at 7-10 years after surgery, it reaches 40-60% in all categories of patients except those with thymoma. In the absence of a thymoma, 85% of patients experience improvement, and 35% of these patients achieve drug-free remission. In a study by Nieto et al, the rate of remission in the presence of thymic hyperplasia was 42% compared to 18% in patients with thymoma.^[42]

MGFA classification of thymectomy

Over the years, many different techniques have been employed to perform thymectomy. Although it is generally believed that complete removal of thymic tissue is better (see above), this is not an established fact. There is no consensus as to whether one technique is superior to another in achieving benefit or minimizing risks.

The Myasthenia Gravis Foundation of America (MGFA) has proposed a classification scheme for thymectomy, which is primarily based on techniques described in various published reports.^[12] A robotic minimally invasive approach to thymectomy has been used, though the advantages of this approach remain to be established.^[43]

The MGFA thymectomy classification is as follows:

• T-1 transcervical thymectomy – Basic; extended
• T-2 videoscopic thymectomy - Classic or VATS (video-assisted thoracic surgery) thymectomy; VATET (video-assisted thoracoscopic extended thymectomy)
• T-3 transsternal thymectomy – Standard; extended
• T-4 transcervical and transsternal thymectomy

Patients with MG may experience difficulty chewing and swallowing because of oropharyngeal weakness. It may be difficult for the patient to chew meat or vegetables because of masticatory muscle weakness. If dysphagia develops, it is usually most severe for thin liquids because of weakness of pharyngeal muscles. To avoid nasal regurgitation or frank aspiration, liquids should be thickened.

Educate patients about the fluctuating nature of weakness and exercise-induced fatigability. Patients should be as active as possible but should rest frequently and avoid sustained physical activity.