Myasthenia Gravis Management

Principles of Therapy

Treatment goals should focus on complete remission, or minimal manifestations, while causing the least possible side effects.

Pharmacological therapy

In addition to symptomatic therapy, disease-modifying immunotherapy should also be provided.

Anticholinesterase Agents (AChE-I)

These are the first-line symptomatic therapy for all forms of MG. Patients usually experience partial improvement. However, complete improvement may occur in few patients. It must be noted that there is no difference in the efficacy between the different anticholinesterase agents, and that they do not stop the natural progression of the disease state. The dose and frequency should be tailored to the patient's individual needs. The muscarinic effects (eg diarrhea, abdominal cramps, etc) associated with these agents may limit the tolerated dose. The drug Propantheline may be used to block unwanted autonomic side effects. While, Loperamide may be used to treat diarrhea.

Distigmine

This agent is longer-acting compared to other pharmacotherapy, but is rarely used for MG because of the increased risk of cholinergic crisis.

Neostigmine

Neostigmine is an analog of Pyridostigmine with therapeutic effect at approximately 4 hours. It has a shorter duration of action, less effective and with more muscarinic side effects.

Pyridostigmine

Pyridostigmine is the primary AChE-I used for the symptomatic therapy of all forms of MG. It may be used as a long-term treatment in patients with milder disease. The effect begins within 30 minutes, peaks at about 2 hours, and lasts for 3-4 hours. It may be preferable to Neostigmine because of its longer duration of action with less muscarinic side effects. 

Corticosteroids

Prednisolone (Prednisone)

Prednisolone generally results in improvement of weakness in MG patients, this is based on observational studies which showed remission or marked improvement that occurs in 70-80% of patients within 2-4 weeks. It is used with or without Azathioprine as first-line agents for immunosuppression. Prednisolone should be started at a low dose to avoid temporary worsening of MG, then increase the dose slowly until there is marked clinical improvement is seen. In moderate to severe generalized MG, early high-dose Prednisone may be considered. After which, maintain the dose for 1-3 months. When remission occurs, reduce the dose to a minimum effective dose that is given on alternate days. Note that patients need to be observed closely for adverse effects. 

Immunosuppressants

Immunosuppressants should be considered in patients with progressive MG symptoms. It must be noted that abrupt discontinuation of immunosuppressants in insufficiently stabilized disease may lead to recurrence of symptoms and progression to a myasthenic crisis.

Azathioprine

Azathioprine is used extensively as a steroid-sparing immunosuppressant. Azathioprine is the most widely used immunosuppressant agent. It is a widely used immunosuppressant therapy for MuSK-MG. It may be combined with corticosteroids to add therapeutic effect and/or allow the steroid dose to be reduced. It may take 4-12 months to see beneficial effects, with the maximum effect seen at 6-24 months. Long term treatment (≥10 years) is not recommended due to the risk of malignancy. 

Ciclosporin

Ciclosporin may be as effective as Azathioprine. It may be used alone but is usually combined with steroids to allow for a reduction of steroid dose. This drug is considered as a third-line therapy and should only be used in patients intolerant or unresponsive to corticosteroids or other immunosuppressants (eg Azathioprine). Beneficial effects of Ciclosporin are seen in 1-3 months.
 
Cyclophosphamide

It has been demonstrated to be effective in treatment-resistant MG cases. However, the risk of adverse effects limits its use.

Eculizumab

Eculizumab has been approved by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) for refractory generalized MG that is AChR antibody-positive. Eculizumab is a humanized monoclonal antibody that binds to C5 and inhibits the formation of C5b-induced membrane attack complex. It is used in addition with immunosuppressant therapy. In a double-blind trial, Eculizumab showed significant benefit in daily living, quality of life starting in the first 4 weeks of treatment. An extension study also showed a reduced exacerbation rate of 75% compared to the baseline rate before study entry. Lastly, discontinuation should be considered if no clinical improvement is observed after a 3-month treatment trial.  

Efgartigimod

Efgartigimod was recently approved by the US FDA for the treatment of generalized MG that is AChR antibody-positive. It is an antibody fragment that binds to the neonatal Fc receptor (FcRn), thereby preventing FcRN from recycling immunoglobulin G (IgG) back into the blood. Efgartigimod results in an overall reduction of IgG, including the abnormal AChR antibodies. A multi-center, randomized, double-blind study showed improvement of 67.7% in activities of daily living compared to placebo (29.7%).

Mychophenolate

Mycophenolate may be considered for long-term therapy if refractory to the first-line treatment. This drug has been shown in small studies to improve functional status or as a steroid-sparing agent. It may be better tolerated than other immunomodulators due to its relative lack of side effects. However, Mycophenolate is costly and its beneficial effects may take months before being seen.

Intravenous Immunoglobulin (IVIg)

IVIg may be used to treat MG crisis or to improve a patient’s condition prior to thymectomy or as an adjuvant to minimize side effects with long-term immunosuppressant therapy. It may be used as an alternative to plasmapheresis or immunosuppressive therapy in patients with refractory MG or as a preoperative treatment prior to thymectomy. Its use should be considered as continuous therapy in patients with comorbidities, recurrent infections, or intolerance reactions to other immunosuppressants. With IVIg, rapid improvement occurs in 70% of patients within 4-5 days of treatment. IVIg can be used in the presence of systemic infection, and its beneficial effects may last for months. However, this drug is notably expensive. 

Other Therapies

Methotrexate

According to randomized clinical trials, oral Methotrexate may be beneficial in generalized MG who cannot tolerate or do not respond to steroid-sparing agents.

Rituximab

In studies, Rituximab appears to be particularly effective in patients with MuSK-positive MG that often respond relatively poorly to first-line immunosuppressive therapies. A retrospective cohort study showed benefit in terms of clinical remission for new-onset generalized MG and refractory disease. Pneumocystis pneumonia prophylaxis should be considered for longer-term (>6 months) combination therapies with other agents. 

Tacrolimus

It is widely used in Japan for the management of MG in patients who underwent thymectomy and with poor response to steroid therapy.

Myasthenia Gravis_Management

Nonpharmacological

Lifestyle Modification

Sleep hygiene, a balanced diet, avoidance of excess alcohol consumption, and aerobic exercise are also recommended in patients with myasthenia gravis. Multiple studies show that aerobic exercise is safe, well-tolerated, and may enhance strength and functional capacity. For stable myasthenia gravis patients, 150 minutes per week of moderate intensity exercise is recommended.

Psychological Intervention

It is important to note that support groups along with optimal treatment increases the patient's level of function. Psychological support and referral to a psychologist should be offered to patients.

Plasmapheresis

Plasmapheresis may be used to treat MG crisis or to improve a patient’s condition prior to thymectomy. It is considered equivalent to IV IgG in the treatment of myasthenic crisis. With this, pathogenic antibodies are separated from the blood cells mechanically. It is useful in decreasing symptoms when starting immunosuppressive therapy. Around 5 exchanges are performed, with 3-4 liters per exchange, over a 2-week period. It showed rapid short-term clinical improvement in most patients due to reduction in anti-AChR antibodies. However, plasmapheresis is not recommended in patients with cardiac failure, sepsis, hypotension, and pregnancy. It is also not recommended as a treatment to obtain a continuous and lasting immunosuppression in MG. Lastly, it is also not considered to be a suitable procedure in pediatric patients.

Immunoadsorption

Immunoadsorption is considered equally effective as plasmapheresis in the treatment of MG. IgG is semi-selectively removed by protein binding as the plasma passes through protein A-columns or a tryptophan-polyvinyl gel matrix. This may be considered in pregnancy or hemodynamically unstable patients.

Surgery

Thymectomy

There is currently no consensus in place on which surgical method is the first line. However, based on a study, more severe cases of MG may benefit from thymectomy compared to patients with mild MG. It is advisable that the patient be stabilized with immunotherapy before undergoing thymectomy to reduce perioperative morbidity and mortality. Patients with AChR antibody-positive, early onset generalized MG with insufficient response to Pyridostigmine are suitable candidates for thymectomy. In a prospective randomized study, there was significant benefit for thymectomized patients with AChR antibody-positive MG in terms of symptoms, with a steroid- and immunosuppressant-sparing effect occurring 1-5 years after thymectomy. In seronegative MG, thymectomy may be justified after exhaustion of all non-surgical approaches. 

Video-assisted thoracoscopic surgery (VATS) may be considered in preference to the transsternal approach, with many papers demonstrating superior results of VATS in terms of hospital stay, operative blood loss, and patient satisfaction compared to the transsternal approach. This reduces the required dose of immunosuppressants, which helps extend the duration of treatment for immunotherapy.

Patients with thymomas must undergo thymectomy at any age regardless of disease severity. During the surgery, the tumor and adherent structures should be completely removed, and the chest cavity be inspected for tumor implants. If the patient with a suspected thymoma is not suitable for surgery, biopsy and conservative therapy (radiotherapy) must be performed. Around 66% of patients with MG and nonmalignant thymoma were found to be symptom-free at 6 months to 7 years after thymectomy and treatment with Prednisolone and/or Azathioprine.

In the absence of a tumor, thymectomy offers a possibility of long-term benefit for those with generalized MG and anti-AChR antibodies. Thymectomy in these cases may increase the probability of improvement or drug-free remission. Though studies showing improvement have conflicting differences in baseline characteristics of prognostic factors and confounding variables (eg age, severity of MG), most of these have found improvement or remission in patients undergoing thymectomy. However, the improvement is slow and may take months or years. Lastly, ophthalmic surgery may be done to correct ptosis and/or diplopia.