Myasthenia gravis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

A broad range of therapeutic strategies are available for the treatment of MG. Choice of therapy depends on the severity of the symptoms and the type of antibodies present. With optimal care, mortality is rare and the majority of patients lead normal lives.[22] However, there is a significant ongoing real-life burden of disease for some patients who show improvement premised on clinical scales used in studies.

Mild to moderate disease (classes I, II, and III)

Class I is ocular MG; classes II and III represent generalized disease. Patients with mild and occasional symptoms require no treatment.

Cholinesterase inhibitors

The cholinesterase inhibitor pyridostigmine is part of initial treatment for most patients with either ocular or generalized MG, with the dose depending on the severity of symptoms.[1][3][89][90][91] However, patients with antibodies to muscle-specific tyrosine kinase (MuSK) often respond poorly to cholinesterase inhibitors, with frequent adverse effects, and occasional worsening of symptoms.[1]

Corticosteroids

A corticosteroid (e.g., prednisone) is used for patients in whom pyridostigmine monotherapy is not effective.[1][90][91][92][93] Therapy is started with a low dose and gradually titrated up toward maximum dose. Results from one small randomized controlled trial (RCT) suggest that low-dose prednisone with gradual escalation may be effective in treating ocular MG and may avoid the adverse effects associated with higher doses of corticosteroids.[94] Some patients may experience worsening of MG, including the risk of precipitating myasthenic crisis, if corticosteroids are started at high dose.[91]

Once treatment goals are achieved, the dose should be tapered to establish a minimally effective dose.[1] One study concluded that rapid tapering of prednisone appears to be feasible, well tolerated, and associated with a good outcome in patients with moderate to severe MG.[95] Patients with generalized MG with moderate symptoms usually require chronic corticosteroid maintenance therapy or additional therapy such as thymectomy or addition of immunosuppressive or immunomodulatory therapy for their corticosteroid-sparing effect.[1][90][93]

Immunosuppressants

For patients in whom corticosteroids are contraindicated and patients requiring high doses of corticosteroids, other immunosuppressants may be considered. These other immunosuppressants may be used instead of a corticosteroid, or in combination in order to allow dose reduction (i.e., as a corticosteroid-sparing agent).[1]

Azathioprine is recommended as the first-line immunosuppressive treatment for MG, based on effectiveness and tolerability.[1][90][91][96]

Other immunosuppressive agents that may be considered include cyclosporine, tacrolimus, mycophenolate, and methotrexate.[1][3][90][97] Cyclosporine is effective, but use is limited due to potential serious adverse effects and drug interactions.[1] Tacrolimus also provides benefit, but is less widely used for MG outside Asia.[98] Evidence for the effectiveness of mycophenolate is equivocal, and RCT evidence for methotrexate is lacking; these options may be considered if other options are not tolerated or ineffective.[1][3][90][97][99][100]

Rituximab

Evidence suggests that rituximab (a monoclonal antibody that binds to the antigen CD20) is effective in patients with MuSK-MG. It should be considered as an early therapeutic option for patients with moderate MuSK-MG if the response to initial immunotherapy is inadequate. Efficacy for patients with acetylcholine receptor (AChR)-MG is uncertain.[3][101][102] Some patients may be able to taper and stop prednisone and/or other immunosuppressant agents when on rituximab.

Thymectomy

Thymectomy has been found to be effective in patients without thymoma who have mild or moderate generalized MG with AChR antibodies.[3][90][103][104][105] Thymectomy may be considered early in the disease course for patients ages 18 to 50 years, to minimize the need for immunosuppressants, including long-term corticosteroid treatment. Thymectomy should be strongly considered for all patients with generalized MG in whom a trial of immunosuppressants is ineffective or produces intolerable adverse effects.[3] There is evidence of less benefit for patients with late-onset MG.[106]

Patients with ocular AChR-MG with an insufficient response to cholinesterase inhibitors may be offered thymectomy if they have contraindications to, are refractory to, or prefer not to take immunosuppressive agents, although there is no large prospective RCT of thymectomy in this patient population.[3]

Thymectomy may be considered for patients without detectable AChR antibodies if immunosuppressants are ineffective or to minimize adverse effects. However, there is no evidence to support thymectomy in patients with MuSK, low-density lipoprotein receptor-related protein 4, or agrin antibodies without thymoma.[3]

If a patient has what appears to be thymoma on imaging studies, thymectomy is indicated independent of the type or severity of MG.[1][90]

In patients with mild disease who do not otherwise need corticosteroids or other immunosuppressants, treatment with these agents prior to thymectomy is not necessary. Thymectomy should be undertaken in an institution where the health professionals are experienced in anesthetic care and perioperative management of patients with MG. Techniques available range from robotic-assisted or video-assisted thoracotomy to thoracotomy using a transcervical or median sternotomy approach.[107][108][109][110] Less invasive approaches are reported to be as effective as more aggressive approaches.[107][108][110] It is generally accepted that the more complete the removal of thymus, the higher the rate of remission in MG symptoms. Surgical risks include injury to phrenic or recurrent laryngeal nerves, pleural effusion, pulmonary embolism, wound infection or delayed healing, and later sternal instability.

Risk factors for myasthenic crisis after thymectomy include preoperative history of myasthenic crisis, preoperative MG severity, preoperative bulbar symptoms, and high-dose pyridostigmine use.[111][112] One systematic review concluded that plasma exchange before surgery may reduce the risk of postoperative myasthenic crisis in patients with severe disease, but may have little or no effect in patients with mild disease.[113]

Severe (classes IV and V) or refractory disease

Patients will be treated with pyridostigmine and usually with an immunosuppressant.

Rituximab is effective for treatment of MuSK-MG, including MuSK-MG patients with an unsatisfactory response to immune‐based therapies.[3][101] Some patients with MuSK-MG may be able to taper and stop prednisone and/or other immunosuppressant agents when on rituximab.

For patients with AChR-MG, rituximab is recommended as an option if other immunosuppressant agents are ineffective or not tolerated; however, efficacy in this group is uncertain.[3][114][115][116][117]

Patients with AChR-MG should be considered for thymectomy if this has not already been carried out (see above for detailed information about thymectomy).[3][90][103][105]

Additional or alternative treatment options for severe or refractory disease include intravenous immune globulin (IVIG), plasma exchange, cyclophosphamide, eculizumab, ravulizimab, and efgartigimod alfa.

IVIG and plasma exchange

IVIG or plasma exchange may be an appropriate treatment in the following circumstances: for MG that is refractory to other treatment; as a short-term treatment for patients with MG with or at risk for myasthenic crisis (e.g., respiratory insufficiency or dysphagia); when a rapid response to treatment is needed; before starting corticosteroids if necessary to prevent or minimize exacerbations; and in preparation for surgery to avoid perioperative corticosteroids or other immunosuppressive drugs.[1] Each can be done intermittently (every 4-6 weeks) as an outpatient treatment.

Studies suggest that IVIG and plasma exchange are equally efficacious when compared at 2 weeks post-treatment, so choice of treatment depends on patient factors and availability.[1] The effects of both are temporary.

IVIG is easier to administer than plasma exchange.[118][119][120][121] Onset of response to IVIG is within 4 to 5 days, with maximal response apparent within 1 to 2 weeks. Plasma exchange also elicits a rapid response, with onset usually after 2 to 3 sessions.[81][119][122] IVIG appears to be less effective in MG patients with MuSK antibodies.[1][50] IVIG maintenance therapy may be considered for select patients.[1]

Cyclophosphamide

Cyclophosphamide is associated with significant risk of toxicity, including bone marrow suppression, opportunistic infections, bladder toxicity, sterility, and neoplasms. Therefore, it is used only for patients with severe refractory MG in whom other immunosuppressants are ineffective or not tolerated.[1][90]

Eculizumab

Eculizumab, a C5 complement inhibitor monoclonal antibody, is recommended as a treatment option for severe, refractory, generalized AChR-MG, if other immunotherapies result in an inadequate response or are not tolerated.[3] Studies indicate that eculizumab is an effective and tolerable immunotherapy for refractory severe MG.[123][124][125] Eculizumab may also be suitable for patients with refractory moderate disease, or earlier in the treatment course.

Ravulizumab

Ravulizumab, a long-acting C5 complement inhibitor monoclonal antibody, is approved in the US and Europe for treating generalized AChR-MG. In a phase 3 randomized, double-blind trial, ravulizumab was associated with significantly greater improvements in both patient- and clinician-reported outcomes than placebo, with an acceptable safety profile.[126]

Efgartigimod alfa

Efgartigimod alfa is a human immunoglobulin G1 (IgG1) antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels. It is available as an intravenous formulation and as a subcutaneous formulation (coformulated with hyaluronidase). Intravenous efgartigimod alfa was well tolerated and more efficacious than placebo in a phase 3 RCT of patients with generalized AChR-MG, and is approved in the US and Europe for treating generalized AChR-MG. Adverse effects included respiratory tract infections, headache, and urinary tract infections.[127][128][129] Subcutaneous efgartigimod alfa/hyaluronidase is approved in the US for the treatment of generalized AChR-MG.[130]

Myasthenic crisis

Approximately 15% to 20% of patients with MG will experience a myasthenic crisis (exacerbation necessitating mechanical ventilation), which usually occurs within 2 years of diagnosis.[23] A myasthenic crisis may be provoked by infections (particularly respiratory infections), aspiration, medications including high-dose corticosteroids, surgery, medications that are contraindicated or relatively contraindicated in MG, failure to adhere to medications, administration of immune checkpoint inhibitors as cancer therapy, or trauma.[3][57][58][60][81]

If myasthenic crisis is suspected, serial measurements of forced vital capacity (FVC) and negative inspiratory force (NIF) are taken. Indications for mechanical ventilation are FVC 15 mL/kg or less (normal ≥60 mL/kg) and/or NIF 20 cm H₂O or less (normal ≥70 cm H₂O). Physicians should not wait for abnormal arterial blood gas (ABG) as it occurs late in the course after clinical decompensation.

Initial therapy consists of optimized ventilatory settings to facilitate respiratory muscle relaxation, removal of provoking factor(s), and acute therapy for the recovery of transmission across neuromuscular junction with either IVIG or plasma exchange.[118][119] High-dose corticosteroids may be initiated concurrently with IVIG or plasma exchange, as they reach their maximal effectiveness at the time when the effects of IVIG or plasma exchange are waning.[131][132]

Supportive care includes deep venous thrombosis prophylaxis, ulcer prophylaxis, adequate nutrition and hydration, and avoidance of infections and drugs that may worsen myasthenia symptoms.

Maintenance therapy options once the patient is stabilized are described under "Severe (classes IV and V) or refractory disease" above.

MG in pregnancy

Pregnancy planning should take place well in advance, to optimize the woman's clinical status. If indicated, thymectomy should be carried out before pregnancy. Most women with well-controlled MG remain stable during pregnancy. Every pregnant woman with MG should be under the care of a multidisciplinary team before, during, and after the birth. Spontaneous vaginal birth is safe in most cases, although there is a slightly increased risk of birth complications.[1][90][133]

Oral pyridostigmine is the first-line treatment for MG during pregnancy; intravenous cholinesterase inhibitors should not be used. Prednisone is the preferred immunosuppressant. Azathioprine, cyclosporine, and tacrolimus are thought to be relatively safe, and may be considered if benefits outweigh risks, but mycophenolate and methotrexate are contraindicated due to teratogenicity. All drugs should be used at the lowest possible dose.[1][90][133]

Both IVIG and plasma exchange can be used for rapid treatment, after careful consideration of the risks versus benefits of treatment for both the mother and child.[1][120][133] IVIG has been trialed as monotherapy in a small series of pregnant women with MG, with promising results. However, studies with larger populations are required before any recommendations can be made.[134]

All babies born to mothers with MG should be checked for evidence of transient myasthenic weakness (neonatal MG).[1][133]