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Overview of the treatment of myasthenia gravis

Overview of the treatment of myasthenia gravis
Literature review current through: Jan 2024.
This topic last updated: Aug 17, 2023.

INTRODUCTION — Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by fluctuating motor weakness involving ocular, bulbar, limb, and/or respiratory muscles. The weakness is due to an antibody-mediated, immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction (acetylcholine receptors or receptor-associated proteins). MG is the most common disorder of neuromuscular transmission.

This topic will discuss the overall treatment of generalized MG. Detailed reviews of chronic immunotherapies for MG and thymectomy for MG are found separately. (See "Chronic immunotherapy for myasthenia gravis" and "Role of thymectomy in patients with myasthenia gravis".)

Other aspects of myasthenia gravis are discussed separately.

(See "Pathogenesis of myasthenia gravis".)

(See "Clinical manifestations of myasthenia gravis".)

(See "Diagnosis of myasthenia gravis".)

(See "Differential diagnosis of myasthenia gravis".)

(See "Myasthenic crisis".)

(See "Management of myasthenia gravis in pregnancy".)

THERAPEUTIC APPROACH

Overview of therapies — There are four primary therapies used to treat MG:

Symptomatic treatment (acetylcholinesterase inhibition) to increase the amount of acetylcholine (ACh) available at the neuromuscular junction

Chronic immunotherapies (glucocorticoids and nonsteroidal immunosuppressive and immunomodulatory agents) to target the underlying immune dysregulation

Rapid but short-acting immunomodulating treatments (therapeutic plasma exchange and intravenous immune globulin [IVIG])

Surgical treatment (thymectomy)

The time of onset of clinical effect of each of these therapies for MG varies considerably (table 1). This plays a large role, in addition to the pace and severity of the disease, in choosing the appropriate therapy for a given patient.

Treatment goals and response assessment — The goals of therapy in MG are to render patients minimally symptomatic or better while minimizing side effects from medications. MG is a chronic but treatable disease, and many patients can achieve sustained remission of symptoms and full functional capacity.

The response to pyridostigmine and other therapies is judged by improvement in the clinical symptoms and neurologic deficits on examination. Baseline neurologic function and deficits should be documented at the start of therapy and monitored for change over time as therapies are added or tapered.

In general, following acetylcholine receptor (AChR) or other antibody levels as a marker for treatment response in MG is not recommended. Data are limited in the modern era of commercially available AChR antibody levels, but one study of 66 patients with MG found that AChR antibody levels correlated only weakly with clinical changes [1]. Antibody levels fell in 92 percent of patients who improved, but also in 63 percent of those who did not improve. Thus, AChR antibody levels were not a good biomarker for improvement in MG.

Avoidance of drugs that may exacerbate myasthenia — Certain drugs, such as aminoglycosides and neuromuscular blocking agents, have established pharmacologic adverse effects on neuromuscular transmission. Use of these drugs can further reduce the effectiveness of neuromuscular transmission in a patient with MG and cause increased clinical weakness. Many other drugs have been associated with myasthenic exacerbation in case reports. Although the cause and effect has not been established for most of these medications, they should be used cautiously, if at all, in patients with MG.

A good rule of thumb in generalized MG is to assume that any medication may exacerbate MG and to watch for worsening following the introduction of a new medication. Whether the association with clinical worsening of MG is coincidental or causal may require withdrawal from the medication and a rechallenge.

The list of medications that may exacerbate MG (table 2) is not comprehensive [2,3]. In addition to the list below, all drugs that are respiratory depressants (eg, benzodiazepines, opioids, sedatives) should be used with caution in patients with known MG. The following drugs are some of the more common prescription drugs associated with worsening MG:

Fluoroquinolones (such as ciprofloxacin and levofloxacin) and macrolides (such as azithromycin and erythromycin) may exacerbate muscle weakness in some patients with MG [2,4]. Fluoroquinolones and macrolides should be used with caution in patients with known MG, if at all. Telithromycin was a ketolide type macrolide that was associated with severe exacerbations or unmasking of MG in several case reports, often within two hours of the first dose [5]. It was discontinued in the United States in 2016 and has since been discontinued worldwide [6].

Aminoglycosides should be avoided and only used if absolutely necessary with close monitoring.

Neuromuscular blocking agents may be necessary for anesthesia or intubation, but their use delays emergence from anesthesia, recovery of muscle strength, and weaning from mechanical ventilation [7]. These drugs should be judiciously titrated if used.

Magnesium sulfate is relatively contraindicated because magnesium has a significant inhibitory effect on ACh release.

Penicillamine should be avoided in patients with MG because it can induce MG [8,9]. (See "Differential diagnosis of myasthenia gravis", section on 'Other conditions'.)

Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, are used as immunotherapy in certain cancers (eg, metastatic melanoma and nonsmall cell lung cancer). These drugs enhance immune responses and have been reported to trigger autoimmune MG [10-12]. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Neurologic'.)

Certain cardiac drugs, such as all beta blockers, procainamide, and quinidine, may worsen MG. They should be used with caution [2].

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) have occasionally been reported to unmask or exacerbate MG [13-20]. However, statins are not contraindicated in patients with MG and should be used in those with appropriate cardiovascular indications. Patients with MG should be more carefully monitored for the development of weakness.

Other medications that may exacerbate weakness in MG based on experimental data or case reports include lithium and phenothiazines (eg, chlorpromazine, prochlorperazine), certain antiepileptics (eg, gabapentin, phenytoin), and calcium channel blockers [2,21-25].

Immunizations — Patients with generalized MG who develop respiratory infections are at increased risk of myasthenic exacerbations and respiratory compromise [26]. This increased risk may be shared by patients with ocular MG of more recent onset (less than three years) because they are still at risk of progressing to generalized disease. By contrast, patients with stable ocular MG of three or more years duration are much less likely to develop generalized disease and therefore are not considered to be at increased risk of myasthenic exacerbations or respiratory compromise.

Current guidelines recommend annual seasonal influenza vaccination for all individuals receiving immunosuppressive therapy, and for those with neurologic conditions, including neuromuscular disorders such as generalized MG, or ocular MG within three years of onset, which can potentially compromise the handling of respiratory secretions. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups'.)

A population-based study suggests that the inactivated (intramuscular) influenza vaccine is safe in adults with MG [27]. Furthermore, inactivated vaccines (eg, pneumococcal and intramuscular influenza vaccines) generally are considered safe in adults or children with immunocompromising conditions or on immunosuppressive drugs.

The pneumococcal vaccine is recommended for all individuals with chronic pulmonary conditions and for those receiving immunosuppressive therapy. While MG does not usually result in chronic pulmonary disease, we suggest pneumococcal vaccination for all individuals with generalized MG, and for those with ocular MG who are within three years of onset, because of the risk that infection may trigger an MG exacerbation or crisis. (See "Pneumococcal vaccination in adults" and "Pneumococcal vaccination in children".)

Most live-attenuated vaccines should be avoided in patients with MG taking immunosuppressive medications such as prednisone, azathioprine, or mycophenolate mofetil. These patients should not receive the live-attenuated (intranasal) influenza vaccine. However, guidelines support the administration of the live-attenuated zoster vaccine for varicella-positive patients aged 50 to 59 years and all patients aged ≥60 years who are receiving therapies that induce low levels of immunosuppression, including the following [28]:

Low-dose prednisone (<2 mg/kg; maximum ≤20 mg/day) or equivalent

Azathioprine (≤3 mg/kg/day)

Zoster vaccine is not recommended in patients who are highly immunocompromised. The use of zoster vaccine is discussed in greater detail elsewhere. (See "Vaccination for the prevention of shingles (herpes zoster)".)

Guidance during COVID-19 pandemic — Infections may trigger a myasthenic crisis but the prevalence in patients with MG who develop coronavirus disease 2019 (COVID-19) infection is unknown. A physician-reported registry has been established to collect outcome data to assess this burden [29]. However, because many patients with MG are on immunosuppressive or immunomodulatory therapies may be at increased risk for contracting COVID-19 and experiencing more severe infection. In a retrospective cohort study, the incidence of hospitalization due to severe COVID-19 infection was higher for patients with MG than matched controls (31 versus 15 percent) [30]. (See "COVID-19: Clinical features", section on 'Spectrum of severity and fatality rates'.)

Guidance on care of patients with MG during the COVID-19 pandemic has been issued by a variety of expert groups, including an international panel of MG experts and the European Academy of Neurology [31,32]. In general, patients are advised to continue existing therapies unless there are clinical reasons to change, since reduction or discontinuation poses risk of worsening MG. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Management of patients with neurologic conditions'.)

COVID-19 vaccination is recommended for patients with autoimmune conditions like MG, unless they have a specific contraindication, such as an allergy to a component of the vaccine. It is uncertain if the vaccine is as effective for patients with MG on immunosuppressive medications as for other patients because none of the vaccine trials to date included people who were on immunosuppressant therapy. However, one cohort found that vaccinated patients were substantially less likely to contract COVID-19 infection than unvaccinated controls (hazard ratio 0.43, 95% CI 0.3-0.6) [30]. In addition, patients with some neurologic conditions, including those taking immunosuppressive medications, may be at high risk for severe illness from COVID-19. Vaccines to COVID-19 are felt to be safe in patients with MG and have generally not associated with worsening of MG symptoms in retrospective studies [33-36]. Vaccination has been associated with a reduced risk of hospitalization and mortality in a retrospective series of patients with MG who developed COVID-19 infection [37]. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

INITIAL SYMPTOMATIC THERAPY

Pyridostigmine — The initial therapy for most patients with mild to moderate MG is an oral acetylcholinesterase inhibitor (ie, anticholinesterase), usually pyridostigmine [38]. Neostigmine is available in an oral form but not commonly used.

Patients with severe disease, or rapidly worsening disease, should be treated much like those in myasthenic crisis using rapid therapies (ie, plasma exchange or intravenous immune globulin [IVIG]) followed by glucocorticoids and other immunotherapies. (See "Myasthenic crisis".)

Mechanism and response — Acetylcholinesterase inhibitors retard the degradation of acetylcholine (ACh) that occurs by enzymatic hydrolysis in the neuromuscular junction [39]. As a result, the effect of ACh is prolonged, leading to a variable improvement in strength in patients with MG.

Although there have not been randomized trials of pyridostigmine or other acetylcholinesterase inhibitors to characterize efficacy for patients with MG, robust observational data and clinical experience support the ability of pyridostigmine to objectively improve symptoms in patients with MG [38,40,41].

The response to pyridostigmine is not uniform, however. Pyridostigmine provides marked improvement in some patients and little or none in others. In particular, most patients with muscle-specific tyrosine kinase (MuSK)-positive disease have a poor response to anticholinesterase agents. (See 'MuSK-positive or LRP4-positive MG' below.)

Often the symptom improvement may be mixed; as an example, there may be resolution of neck weakness and ptosis with persistence of diplopia. In general, limb and bulbar symptoms (dysphagia, fatigable chewing, and dysarthria) respond better to anticholinesterase drugs than the ocular manifestations (ptosis and diplopia). Diplopia is particularly resistant to these medications in many patients [42]. (See "Ocular myasthenia gravis", section on 'Symptomatic management of ptosis and diplopia'.)

Acetylcholinesterase inhibitors provide only symptomatic therapy and are usually not sufficient in generalized MG. Nonetheless, in some patients this is the only therapy ever needed for good control. (See 'Addition of immunotherapy' below.)

Dose and titration — Pyridostigmine has a rapid onset of action (15 to 30 minutes) with peak action at approximately two hours, and its effects last for three to four hours, sometimes longer. Despite its short duration of action, some patients can use it quite effectively with doses every six hours or three times a day. Others need a dose every three hours to maintain symptomatic benefit.

For adults and older adolescents, a common starting dose is pyridostigmine 30 mg three times a day with meals for two to three days to assess the cholinergic side effects. For those with excessive cholinergic side effects we add an agent (eg, oral glycopyrrolate 1 mg with each pyridostigmine dose) to block those bothersome symptoms. (See 'Side effect management' below.)

For those who tolerate the pyridostigmine well, with or without anticholinergics, we increase each dose by 30 mg increments every two to three days until we get to a good therapeutic effect or are limited by side effects. The maximum dose is usually 120 mg every four hours while awake. An occasional patient may need to take it every three hours while awake, but never at shorter intervals. Almost all adult patients require a total daily dose of ≤960 mg, divided into four to eight doses.

For children and younger adolescents, the initial dose is 0.5 to 1 mg/kg every four to six hours with meals [43,44]. This can be titrated up slowly based on the therapeutic response and side effects. The maximal daily dose is 7 mg/kg per 24 hours divided in five to six doses.

Pyridostigmine is available as scored 60 mg tablets and as a liquid formulation. Pyridostigmine is also available in an intravenous preparation and can be given in patients who cannot take oral drugs. This is usually in the setting of myasthenic crisis. (See "Myasthenic crisis".)

Importantly, no single pyridostigmine dosing schedule fits all patients. Most adult patients who respond do so in the range of 60 to 90 mg every four to six hours while awake. Some adults require as much as 120 mg every three to four hours while awake. Doses above this are rarely beneficial and are usually limited by the bothersome cholinergic side effects. When a patient has significant persistent weakness despite the use of pyridostigmine in sufficient doses, or the side effects preclude effective dosing, then immunotherapy is generally warranted. (See 'Addition of immunotherapy' below.)

The dose regimen used must be thoughtfully individualized to get symptomatic benefits and to limit unnecessary cholinergic side effects. As an example, many patients only have significant symptoms in the evening. An adult patient might do well with no pyridostigmine until a lunchtime dose of 60 mg followed four hours and eight hours later by 90 mg. Those who have trouble chewing or mild dysphagia might benefit by taking a dose 30 minutes before a meal. There are numerous combinations that work best for an individual patient, based upon the severity of symptoms, the response to pyridostigmine, and toleration of side effects. Medications that alleviate some of the cholinergic side effects of pyridostigmine may also be helpful. (See 'Side effect management' below.)

A long-acting formulation of pyridostigmine is also available, but we advise only selective use. It can be used as a bedtime dose in patients with persistent, severe weakness upon awakening. Most patients, however, do better after a night's sleep, and those with mild weakness upon awakening may do as well by taking a standard pyridostigmine dose at that time. Long-acting pyridostigmine is not a good choice for daytime use because its variable release and delayed absorption make it difficult to provide a consistent effect and to regulate the overall pyridostigmine dose.

Cholinergic side effects — Adverse effects of pyridostigmine are mostly due to the cholinergic properties of the drug. These cholinergic effects can be dose-limiting in many patients. The most bothersome muscarinic side effects include abdominal cramping and diarrhea. Others are increased salivation and bronchial secretions, nausea, sweating, and bradycardia. Nicotinic side effects are also frequent and include fasciculations and muscle cramping. However, these are usually less bothersome than the gastrointestinal effects.

Cholinergic crisis — A potential major side effect of excessive anticholinesterase medication is weakness, which can be difficult to distinguish from worsening MG. This paradoxical weakening with anticholinesterase medications is called "cholinergic crisis." However, cholinergic crisis is rarely if ever seen with dose limitation of pyridostigmine to ≤120 mg every three hours, or a total daily dose of ≤960 mg.

Cholinergic crisis is so rare that it should not be the presumed cause of increasing weakness unless the doses taken are known to significantly exceed this range. Otherwise, even in the presence of cholinergic side effects, it should be assumed that the patient's underlying MG is worsening, and appropriate treatment should be initiated.

Side effect management — Taking pyridostigmine with food can help to reduce bothersome gastrointestinal side effects. Muscarinic side effects can be controlled in many patients with the use of oral anticholinergic drugs that have little or no effect at the nicotinic receptors (ie, do not produce increased weakness). These include the following agents:

Glycopyrrolate 1 mg by mouth

Propantheline 15 mg by mouth

Hyoscyamine sulfate 0.125 mg by mouth

These anticholinergic drugs can be taken prophylactically three times a day or, alternatively, with each pyridostigmine dose.

Prominent diarrhea can be reduced by the addition of loperamide (Imodium) or diphenoxylate hydrochloride-atropine sulfate (Lomotil) with or without other anticholinergic drugs.

Use of intravenous atropine or glycopyrrolate in the setting of cholinergic crisis is reviewed separately. (See "Anesthesia for the patient with myasthenia gravis", section on 'Cholinergic crisis'.)

ADDITION OF IMMUNOTHERAPY — For those patients on pyridostigmine alone whose symptoms are under good control or in remission, we simply follow their clinical course. Although some patients do well on long-term pyridostigmine alone, most patients with generalized MG require additional therapy directed at the underlying immune dysregulation at some point in their illness, if not indefinitely.

Immunotherapy is indicated for patients who remain significantly symptomatic on pyridostigmine, or who become symptomatic again after a temporary response to pyridostigmine. Glucocorticoids are typically used initially, and many patients with generalized MG require addition of a nonsteroidal immunotherapeutic agent such as azathioprine or mycophenolate for maintenance and to spare long-term glucocorticoid toxicities.

Initiation of glucocorticoids and chronic immunotherapies is reviewed separately. (See "Chronic immunotherapy for myasthenia gravis", section on 'Glucocorticoids' and "Chronic immunotherapy for myasthenia gravis", section on 'Glucocorticoid-sparing therapy'.)

ROLE AND TIMING OF THYMECTOMY — In parallel with symptomatic pyridostigmine treatment and immunotherapeutic agents for MG, thymectomy has therapeutic role in selected patients. Each of these indications is reviewed in more detail separately:

Patients with thymoma – In the approximately 10 to 15 percent of patients with MG associated with a thymoma, surgery is indicated for patients in whom a complete resection is considered feasible. Management includes complete resection of the thymus and sometimes involves chemotherapy and radiation therapy in cases of potentially resectable or unresectable disease. (See "Role of thymectomy in patients with myasthenia gravis", section on 'Patients with a thymic mass'.)

Patients without thymoma – Thymectomy in the absence of thymoma is recommended in patients with generalized MG and acetylcholine receptor (AChR) antibodies who are ≤50 years of age (algorithm 1). The benefit of thymectomy is delayed and accrues over several years postoperatively. The role of thymectomy in other patient groups, such as those without AChR antibodies, older patients, and those with ocular MG, is more controversial, and treatment decisions are individualized. (See "Role of thymectomy in patients with myasthenia gravis", section on 'Patients with nonthymomatous myasthenia gravis'.)

The indications, timing, and pre- and postoperative care of a patient with MG undergoing thymectomy should be managed by the surgeon in close collaboration with anesthesiology and a neurologist or other clinician with expertise in MG to minimize the risk of perioperative worsening and respiratory failure due to MG. (See "Anesthesia for the patient with myasthenia gravis", section on 'Preoperative evaluation'.)

ACUTE EXACERBATIONS

Myasthenic crisis — Transient worsening of myasthenic symptoms can be precipitated by concurrent infection, surgery, pregnancy, childbirth, certain medications (table 2), tapering of immunotherapeutic medications, or spontaneously as part of the natural history of the disease.

When severe, patients are at risk for life-threatening neuromuscular respiratory failure referred to as myasthenic crisis. Severe bulbar weakness that produces dysphagia and aspiration often complicates the respiratory failure. Patients in myasthenic crisis typically experience increasing generalized weakness as a warning, although occasionally a patient will present with respiratory insufficiency out of proportion to their limb or bulbar weakness.

The evaluation and treatment of myasthenic crisis is discussed separately. (See "Myasthenic crisis".)

Less severe exacerbations — Patients with MG frequently have worsening symptoms that are not severe enough to be considered a myasthenic crisis. As with a myasthenic crisis, the initial focus of treatment is to address any external causes of an exacerbation, such as treating a concomitant infection or stopping a medication that may worsen myasthenia.

Beyond external factors, treatment approach should be individualized based on the rate of neurologic decline; the presence or absence of dysphagia, dyspnea, and any other major functional limitations; and the rate of onset of the various therapies (table 1). Some potentially work within hours (pyridostigmine), within days (intravenous immune globulin [IVIG] or plasma exchange), or within weeks (glucocorticoids). Depending on the severity of symptoms and rate of change, treatment settings range from outpatient to inpatient to intensive care unit (ICU).

In the mildest flares (eg, recurrent ptosis or diplopia, mild facial or limb weakness, or mild dysarthria), the choice may be to simply increase the dose of pyridostigmine, initiate or increase the dose of glucocorticoids, or monitor closely without medication changes while treating a secondary cause of the exacerbation. On the other end of the spectrum, if there are increasing dysphagia or dyspnea and concerns for the ultimate development of a myasthenic crisis, the patient may be admitted to an ICU setting for close respiratory monitoring. Treatment in this circumstance is the same as with a myasthenic crisis. (See "Myasthenic crisis".)

Plasma exchange and IVIG as rescue or bridge therapies — Therapeutic plasma exchange (plasmapheresis) and IVIG are immunomodulating "rapid" therapies for MG in that they start to work quickly (over days), but the benefits are only short term (weeks). Based on limited direct comparisons, they have similar efficacy in MG, and the choice among them is primarily based on factors related to clinician preference and convenience.

These rapid therapeutic modalities are used most often in the following situations:

Acute exacerbations, including myasthenic crisis (see "Myasthenic crisis")

Preoperatively, before thymectomy or other surgery (see "Role of thymectomy in patients with myasthenia gravis")

As a "bridge" to slower-acting immunotherapies (eg, azathioprine or mycophenolate) for patients in whom it is especially desirable to avoid or minimize glucocorticoid use

Therapeutic plasma exchange

Mechanism and efficacy — Therapeutic plasma exchange (plasmapheresis) directly removes acetylcholine receptor (AChR) antibodies from the circulation. Clinical improvement with plasmapheresis roughly correlates with the reduction in antibody levels [45-47]. The beneficial clinical effect of plasmapheresis is usually seen within days, but the benefit typically lasts only three to six weeks. In addition, the AChR antibody levels rebound within weeks if no concurrent immunotherapy (eg, glucocorticoids) is used.

Plasmapheresis is an established treatment for seriously ill patients in the midst of myasthenic crisis. The evidence supporting its use in this situation is discussed separately. (See "Myasthenic crisis", section on 'Plasma exchange'.)

In patients with less severe exacerbations, supportive data include observational studies [45-48] as well as the randomized trial discussed below, in which IVIG and plasma exchange had similar efficacy in 81 adults with MG and worsening weakness requiring change in therapy [49]. (See 'Mechanism and efficacy' below.)

Plasmapheresis is not a useful long-term treatment, since the need for repeated exchanges often leads to problems with venous access. (See 'Complications' below.)

Course of treatment — A typical course of treatment consists of five exchanges (3 to 5 L of plasma each) over 7 to 14 days. The replacement fluid is albumin when used in the treatment of MG. Although done daily in some circumstances, exchanges done every other day are probably more effective in reducing the antibody levels due to the time it takes for the extravascular immunoglobulin to re-equilibrate after each plasma exchange. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Complications — Repeated plasmapheresis invariably leads to inadequate peripheral venous access and then requires placement of a large bore, double lumen central catheter (subclavian or internal jugular). Significant chronic catheter complications can result, such as infection and thrombosis. In addition to the catheter complications, plasmapheresis can also produce other adverse effects including bleeding, hypotension, cardiac arrhythmias, muscle cramps, and a toxic reaction to the citrate used in the procedure [50,51]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

Despite these concerns, plasmapheresis can be used safely for patients with MG. In an analysis of 42 patients with moderate to severe MG who were treated with plasmapheresis in a prospective trial, there were no complications in 55 percent and mild to moderate complications that did not require stopping treatment in 45 percent [48]. The adverse events in this study were mainly citrate reactions and peripheral vascular access problems that were easily managed. In most cases, plasmapheresis was performed in the outpatient setting (90 percent) using peripheral venous access (83 percent).

Intravenous immune globulin (IVIG)

Mechanism and efficacy — IVIG is pooled immunoglobulin from thousands of donors. The mechanism of action for IVIG in MG is uncertain. As with plasmapheresis, the effect of IVIG is seen typically in less than a week, and the benefit can last for three to six weeks. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Mechanisms of action'.)

IVIG is used in the same setting as plasmapheresis to quickly reverse a severe and life-threatening exacerbation of myasthenia. The limited evidence supporting its use in myasthenic crisis is discussed separately. (See "Myasthenic crisis", section on 'Intravenous immune globulin'.)

IVIG also offers an alternative to plasmapheresis or multiple immunotherapeutic agents in select patients with refractory MG, as a preoperative treatment before thymectomy [52,53], or as a "bridge" to slower-acting immunotherapies. Based on observational studies and the randomized trials described below, a positive short-term response to IVIG is seen in approximately two-thirds of patients with nonsevere exacerbations [49,54-58].

In a double-blind trial, 51 patients with mild to moderate MG and worsening weakness were randomly assigned to IVIG (2 g/kg given over two days) or placebo (an equivalent volume of dextrose 5 percent in water) [56]. Exclusion criteria included respiratory distress, vital capacity <1 liter, and severe swallowing difficulty. Patients treated with IVIG showed a modest but statistically significant improvement compared with placebo in the Quantitative Myasthenia Gravis (QMG) score for disease severity at day 14. The improvement persisted but failed to achieve statistical significance at day 28. In subgroup analysis, IVIG treatment was associated with clinically and statistically significant improvement in patients with more severe disease at study onset (QMG >10.5), but no improvement was observed in patients with milder disease (QMG <10.5).

A double-blind randomized trial compared treatment with IVIG versus plasmapheresis for 81 adults with MG and worsening weakness requiring change in therapy [49]. At baseline, 59 percent of patients had mild disease, 40 percent had moderate disease, while only 1 percent had severe disease. Patients who had a flare producing moderate to severe disease (a QMG score >10.5) were treated. At day 14, a similar proportion of patients assigned to IVIG and plasmapheresis had improved (69 versus 65 percent), and the duration of improvement was also similar with longer follow-up.

Dose and side effects — The total dose of IVIG is 2 g/kg, usually over two to five days. Spreading the dose over more days is preferable in those who have renal disease, have congestive heart failure, or are older adults.

The side effects of IVIG [59,60] are most commonly mild and are related to the infusion rate. These include headache, chills, dizziness, and fluid retention. Other uncommon complications include aseptic meningitis, acute renal failure, thrombotic events, and anaphylaxis.

The acute nephrotoxicity that occurs in some patients appears to be related to the high sucrose content of some preparations of IVIG; the risk is increased with underlying renal insufficiency. Anaphylaxis has been associated with immunoglobulin A (IgA) deficiency; however, it is rarely seen in patients treated for autoimmune neuromuscular diseases [60]. Thrombotic events associated with IVIG use include myocardial infarction, stroke, and pulmonary embolism. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Immune globulin therapy in inborn errors of immunity".)

Biologic therapies — Efgartigimod alfa, rozanolixizumab, ravulizumab, and zilucoplan are biologic agents used as chronic immunotherapy for patients with AChR antibody-positive generalized MG. The time to onset of effect for some of these agents is as early as two weeks, so they may also be used as bridge therapy to slower-acting immunotherapies for patients in whom it is especially desirable to avoid or minimize glucocorticoid use. (See "Chronic immunotherapy for myasthenia gravis", section on 'Rozanolixizumab' and "Chronic immunotherapy for myasthenia gravis", section on 'Zilucoplan' and "Chronic immunotherapy for myasthenia gravis", section on 'Efgartigimod' and "Chronic immunotherapy for myasthenia gravis", section on 'Ravulizumab'.)

Pulsed glucocorticoids — Some have used pulsed intravenous methylprednisolone (eg, 2 g daily for 1 to 2 days) for moderate exacerbations of MG, followed by 30 mg of oral prednisone, and a case series suggested that there is a faster onset of action and less in the way of transient worsening than with oral prednisone alone [61]. One randomized trial showed that there was a marked improvement in patients with MG after only one pulse compared with placebo-treated patients, and that the mean duration of improvement was eight weeks [62].

Intravenous methylprednisolone is generally avoided in patients with myasthenic crisis, who are receiving IVIG or plasmapheresis to achieve short-term stabilization, because of a potential to increase the risk of critical illness myopathy [63].

REFRACTORY DISEASE — Approximately 10 percent of patients with generalized MG are refractory to, or are limited by the specific toxicities of, conventional immunosuppressive and immunomodulatory therapies. Some require unacceptably high doses of glucocorticoids despite concurrent use of first-line steroid-sparing agents. In these refractory patients, treatment is individualized and may include strategies such as maintenance intravenous immune globulin (IVIG), rituximab, eculizumab, and pulsed cyclophosphamide. (See "Chronic immunotherapy for myasthenia gravis", section on 'Refractory disease'.)

SPECIAL POPULATIONS

Ocular myasthenia — The elements of treatment for ocular MG (OMG) are the same as with generalized MG. However, differences in the symptomatology, disability, and prognosis lead to some differences in the treatment approach for these patients. This is discussed in more detail separately. (See "Ocular myasthenia gravis", section on 'Treatment'.)

MuSK-positive or LRP4-positive MG — Growing clinical evidence suggests that muscle-specific tyrosine kinase (MuSK)-positive MG has important differences with regard to treatment compared with acetylcholine receptor (AChR) antibody-positive and seronegative MG [38]. Most patients with MuSK-positive disease are poorly responsive to anticholinesterase agents as well as thymectomy [3]. Patients with low-density lipoprotein 4 (LRP4)-positive MG may be responsive to immunotherapy, but the role of thymectomy has not been established [3,64].

The approach to chronic immunotherapy in patients with MuSK or LRP4-positive MG is discussed separately. (See "Chronic immunotherapy for myasthenia gravis", section on 'MuSK-positive MG'.)

Children — As with adults, the treatment of children with MG should be individualized based on the severity and pace of the disease [43,44,65]. Pyridostigmine is the first line of therapy (see 'Dose and titration' above). If anticholinesterase medications are not sufficient, plasmapheresis or intravenous immune globulin (IVIG) may be used, but the benefits are transient.

Glucocorticoids are generally limited to severe disease that is unresponsive to these interventions. Glucocorticoids retard bone growth, increase the risk of adult osteoporosis, and are especially problematic for chronic use in children [38]. Azathioprine, mycophenolate mofetil, and cyclosporine have been used successfully in juvenile MG [44,65], but concerns about serious adverse effects, including impaired fertility and the late development of malignancy, are of even greater concern than in adults.

As a long-term treatment for MG, thymectomy has been performed successfully and with low morbidity in children [66]. Thymectomy is a widely accepted option for peripubertal and postpubertal children with generalized MG who have positive AChR antibodies or who are seronegative [38,43,44,66,67]. The rates of improvement and remission seen in uncontrolled series appear to be similar to those reported in adults after thymectomy [66]. Thorascopic thymectomy, potentially a more acceptable treatment in this age group, has been used successfully in a small case series [68]. The likelihood of improvement or remission after a single procedure (thymectomy) compared with long-term immunotherapy makes this option a reasonable consideration in all children who have more than mild disease. No significant deleterious consequences of removing the thymus in childhood have been reported [65].

Similar to adults with MuSK antibody-positive MG (see "Role of thymectomy in patients with myasthenia gravis", section on 'MuSK and LRP4 antibody-positive myasthenia'), children with MuSK-positive MG have not been shown to benefit from thymectomy. Therefore, thymectomy is not recommended for this group. The role of thymectomy in prepubertal children remains controversial. This group has a higher incidence of spontaneous remission and is also more likely to be seronegative, making confirmation of the diagnosis more difficult [43,65].

The clinical outcome in childhood MG varies with age of onset, race, and sex [69]. White children with prepubertal onset have the best prognosis. The spontaneous remission rate is 44 percent in these children, and they respond well to early thymectomy.

Pregnancy and the neonate — Pregnancy has a variable effect on the course of MG. It does not worsen the long-term outcome, but the MG may worsen during the course of pregnancy. The first trimester and the month postpartum are the periods of highest risk of exacerbation.

The management of myasthenia in pregnancy is discussed separately. (See "Management of myasthenia gravis in pregnancy".)

Transient neonatal MG develops in 10 to 20 percent of infants born to myasthenic mothers due to transplacental passage of anti-AChR antibodies. Neonatal myasthenia is discussed separately. (See "Neuromuscular junction disorders in newborns and infants".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myasthenia gravis" and "Society guideline links: Thymomas and thymic carcinomas" and "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Myasthenia gravis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Goals and classes of therapies – The goals of therapy in MG are to render patients minimally symptomatic or better while minimizing side effects from medications. The four basic therapies for myasthenia gravis (MG) include:

Symptomatic therapy with an acetylcholinesterase inhibitor (pyridostigmine)

Chronic immunotherapies

Rapid but transient immunomodulatory therapies (plasma exchange and intravenous immune globulin [IVIG])

Thymectomy

The time of onset of clinical effect of each of these therapies for MG varies considerably (table 1). (See 'Overview of therapies' above.)

General care for all patients

Avoid drugs that may exacerbate MG – Some medications should be avoided in patients with MG because they can reduce the effectiveness of neuromuscular transmission in a patient with MG and cause increased clinical weakness (table 2). (See 'Avoidance of drugs that may exacerbate myasthenia' above.)

Routine vaccination – Administration of seasonal influenza vaccination and pneumococcal vaccine is indicated to mitigate risk of respiratory compromise and myasthenic crisis that can occur with respiratory infections. Patients being treated with immunosuppressive therapy for MG should not receive the live-attenuated (intranasal) influenza vaccine or the live-attenuated varicella or zoster (shingle) vaccines. (See 'Immunizations' above.)

Initial symptomatic therapy – Symptomatic therapy in patients with MG consists of an acetylcholinesterase inhibitor such as oral pyridostigmine. Pyridostigmine alone provides marked improvement in some patients and little or none in others. (See 'Mechanism and response' above.)

A typical starting dose of pyridostigmine for adults and older adolescents is 30 mg three times a day. For children and younger adolescents, the initial dose is 0.5 to 1 mg/kg every four to six hours. The dose of pyridostigmine is then titrated by its effect. (See 'Dose and titration' above.)

Immunotherapy – Most patients with generalized MG require additional therapy directed at the underlying immune dysregulation. Glucocorticoids and/or other immunotherapies are indicated for patients who remain significantly symptomatic on pyridostigmine. (See "Chronic immunotherapy for myasthenia gravis".)

The role of thymectomy – In parallel with symptomatic pyridostigmine treatment and immunotherapeutic agents for MG, thymectomy has a therapeutic role for patients with thymoma as well as selected patients with nonthymomatous generalized MG. Thymectomy for patients with MG is reviewed in detail separately. (See "Role of thymectomy in patients with myasthenia gravis".)

Acute exacerbations – Transient worsening of myasthenic symptoms can be precipitated by concurrent infection, surgery, pregnancy, childbirth, medications (table 2), tapering of immunotherapeutic medications, or spontaneously as part of the natural history of the disease. (See 'Acute exacerbations' above.)

When severe, patients are at risk for life-threatening neuromuscular respiratory failure referred to as myasthenic crisis. The management of rapidly worsening MG and myasthenic crisis is discussed separately. (See "Myasthenic crisis".)

Therapeutic options for exacerbations vary by symptom severity and patient risk factors. Options for rescue and/or bridge therapy include (see 'Acute exacerbations' above):

-Plasmapheresis (see 'Therapeutic plasma exchange' above)

-IVIG (see 'Intravenous immune globulin (IVIG)' above)

-Biologic therapies (eg, efgartigimod alfa, ravulizumab, rozanolixizumab, or zilucoplan) (see 'Biologic therapies' above)

-Pulsed glucocorticoids (see 'Pulsed glucocorticoids' above)

Patients with refractory disease – Approximately 10 percent of patients with generalized MG have symptoms that are refractory to or limited by specific toxicities of conventional immunomodulatory therapies (eg, high-dose glucocorticoids). Therapeutic options for refractory MG are reviewed in detail separately. (See "Chronic immunotherapy for myasthenia gravis", section on 'Refractory disease'.)

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