Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Myasthenia gravis (MG), once a uniformly disabling and even fatal disorder, can be managed effectively with current therapeutic strategies. Many patients can even achieve sustained remission. The therapeutic approach has certain general principles, but it is highly individualized for each patient. It depends upon the age of the patient, the severity of the disease, particularly dictated by respiratory or bulbar involvement, and the pace of progression [1-4].
This topic will discuss the general treatment of MG. Detailed reviews of chronic immunomodulating therapies for MG and thymectomy for MG are found separately. Myasthenic crisis and the treatment of ocular MG and MG in pregnancy are also discussed in greater detail separately. (See "Chronic immunomodulating therapies for myasthenia gravis" and "Thymectomy for myasthenia gravis" and "Management of myasthenia gravis in pregnancy" and "Ocular myasthenia gravis" and "Myasthenic crisis".)
OVERVIEW — There are four basic therapies used to treat myasthenia gravis (MG):
●Symptomatic treatments (anticholinesterase agents)
●Chronic immunomodulating treatments (glucocorticoids and other immunosuppressive drugs)
●Rapid immunomodulating treatments (plasmapheresis and intravenous immune globulin)
●Surgical treatment (thymectomy)
Symptoms can be treated with acetylcholinesterase inhibitors (also called anticholinesterase medications) . These medications are all that is ever needed for some patients. Pyridostigmine bromide (Mestinon) is the main cholinesterase inhibitor currently in use. (See 'Symptomatic treatment' below.)
However, most patients with MG require some form of immunotherapy at some point in their illness, if not indefinitely. Even when immunotherapeutic drugs are used, it is common to continue the use of anticholinesterase medications in order to reduce the dosage of immunosuppressive drugs and therefore minimize their adverse effects. Balancing the improvement of MG symptoms with the side effects of the immunotherapeutic agents is always a challenge for the clinician and patient.
Commonly used immunotherapeutic drugs in MG are prednisone, azathioprine, cyclosporine, and mycophenolate mofetil. In some circumstances, particularly in those with refractory MG, other agents such as rituximab, periodic intravenous immune globulin (IVIG), monthly pulse cyclophosphamide, and tacrolimus may be considered. (See "Chronic immunomodulating therapies for myasthenia gravis".)
Plasmapheresis and IVIG are rapid immunotherapies that work quickly but have a short duration of action. These are usually reserved for certain situations, such as myasthenic crisis, preoperatively before thymectomy, as a "bridge" while initiating slower acting immunotherapies, or as an adjuvant to other immunotherapeutic medications in patients with refractory MG. (See 'Rapid immunotherapies' below.)
Many experts believe that thymectomy is beneficial in those patients less than age 60 who have generalized MG without thymoma, although there are no prospective randomized, blinded, controlled trials . However, it generally takes years for the benefits of thymectomy to accrue. (See "Thymectomy for myasthenia gravis".)
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.
SYMPTOMATIC TREATMENT — The initial therapy for most patients with myasthenia gravis (MG) is an oral anticholinesterase (ie, acetylcholinesterase inhibitor) medication, usually pyridostigmine bromide. Acetylcholinesterase inhibitors retard the degradation of acetylcholine (ACh) that occurs by enzymatic hydrolysis in the neuromuscular junction . As a result, the effect of ACh is prolonged, leading to a variable improvement in strength.
Acetylcholinesterase inhibitors provide marked improvement in some patients and little or none in others. 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 .
Acetylcholinesterase inhibitors are the first line of treatment due to their safety and ease of use. Pyridostigmine (Mestinon) is the usual choice. Neostigmine is available but not commonly used. 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.
Pyridostigmine dosing — Pyridostigmine has a rapid onset of action (15 to 30 minutes) with peak action at about 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 time 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. The dose is then titrated by its effect. The maximal dose and frequency is usually 120 mg every four hours while awake. An occasional patient will need to take a dose every three hours, 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 [9,10], up to a total daily dose of 7 mg/kg.
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".)
It should be kept in mind that no fixed 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 (see 'Side effects' below). 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.
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 'Alleviating side effects' below).
A long-acting formulation of pyridostigmine (Mestinon TS, 180 mg) is also available. It is 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.
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.
Alleviating side effects — 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 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
●Propantheline 15 mg
●Hyoscyamine sulfate 0.125 mg
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.
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.
Some have advocated the use of the edrophonium (Tensilon) test to determine if there is too much or too little anticholinesterase effect in this setting, but this has not proved to be reliable and is not recommended. (See "Diagnosis of myasthenia gravis", section on 'Edrophonium test'.)
CHRONIC IMMUNOTHERAPIES — The second therapeutic modality in myasthenia gravis (MG) is the administration of immunomodulating agents. Glucocorticoids are widely used as well as other agents, most commonly, azathioprine, mycophenolate mofetil, and cyclosporine. The onset of action varies considerably, and this plays a role in the choice of therapy (table 1).
The administration of moderate or high doses of glucocorticoids leads to remission in about 30 percent of patients and marked improvement in another 50 percent. The onset of benefit generally begins within two to three weeks. However, a transient deterioration occurs in up to 50 percent of patients with MG when high-dose glucocorticoids are started, usually occurring 5 to 10 days after the initiation and lasting around five or six days. For this reason, glucocorticoids are started in high doses only in hospitalized patients who are receiving concurrent plasmapheresis or intravenous immune globulin (IVIG) for myasthenic crisis. (See "Myasthenic crisis".)
To avoid the transient worsening, an outpatient glucocorticoid dose escalation regimen works quite effectively.
A detailed discussion of glucocorticoids and other immunomodulating agents for MG as well as the data supporting their use is found separately. (See "Chronic immunomodulating therapies for myasthenia gravis".)
RAPID IMMUNOTHERAPIES — The rapid therapies used in myasthenia gravis (MG) are also immunomodulating but are distinct because of their quick onset, transient benefit, and their use in select situations. Both plasmapheresis and intravenous immune globulin (IVIG) start to work quickly (over days), but the benefits are only short term (weeks). These therapeutic modalities are used most often in the following situations:
●Myasthenic crisis (see "Myasthenic crisis")
●Preoperatively before thymectomy or other surgery (see "Thymectomy for myasthenia gravis")
●As a "bridge" to slower acting immunotherapies (see 'Bridge therapy' below)
●Periodically to maintain remission in patients with MG that is not well controlled despite the use of chronic immunomodulating drugs
Plasmapheresis — Plasmapheresis (plasma exchange) directly removes acetylcholine receptor (AChR) antibodies from the circulation. Clinical improvement with plasmapheresis roughly correlates with the reduction in antibody levels, as illustrated by the following reports [11-13].
●In five patients with refractory MG (moderate to severe disability despite treatment with thymectomy, high-dose prednisone, and cholinesterase inhibitors), plasmapheresis combined with prednisone and azathioprine therapy produced clinical improvement . Serial determinations of serum AChR antibody titers showed a decline to a mean of 21 percent of the baseline levels concurrently with improved strength. Clinically improved patients maintained lowered AChR titers, whereas clinical relapses were associated with a rebound in AChR titers.
●In seven patients with acquired MG who had elevated serum AChR antibody titers there was an inverse association between improvement of muscle strength and fall of anti-AChR titers . There was a minimum time lag of two days for the clinical response to plasmapheresis.
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'.)
Plasmapheresis is not a useful long-term treatment, since the need for repeated exchanges often leads to problems with venous access (see 'Complications' below).
A potential innovation, not widely adapted, is the use of plasmapheresis with an immunosorbent column consisting of staphylococcal protein A . This technique more efficiently removes IgG, the immunoglobulin that includes those against acetylcholine receptors in MG.
In a further refinement, a Japanese group has designed an acetylcholine receptor antibody-specific immunosorbent column using a peptide isolated from the acetylcholine receptor of Torpedo Californica, called Medisorba MG. This column is targeted to remove the blocking acetylcholine receptor antibody . This technique is approved for use in Japan where it has produced clinical improvement in 78 percent of cases . Its potential advantages include selective removal of anti-AChR antibodies without removing other useful immunoglobulins from the plasma and no requirement for albumin replacement. However, it has limited clinical use and has not yet been shown to be superior to plasmapheresis with regard to efficacy, cost, and safety.
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 . (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 . 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 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 an exacerbation of myasthenia. The limited evidence supporting its use in this situation is discussed separately. (See "Myasthenic crisis", section on 'Intravenous immune globulin'.)
IVIG also offers an alternative to plasmapheresis or multiple immunosuppressive agents in select patients with refractory MG, as a preoperative treatment before thymectomy [19,20], or as a "bridge" to slower acting immunotherapies.
As with myasthenic crisis, there are limited data regarding the effectiveness of IVIG for MG without crisis [21,22].
●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) . 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 . 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.
●In earlier observational reports, IVIG was effective in nearly 70 to 75 percent of patients with MG [25,26].
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, congestive heart failure, or are older adults.
The side effects of IVIG [27,28] 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 IgA deficiency; however, it is rarely seen in patients treated for autoimmune neuromuscular diseases . 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 primary immunodeficiency".)
THERAPEUTIC APPROACH — The above discussion details the various options in the treatment of the patient with myasthenia gravis (MG) along with certain general principles that can act as a framework for treating patients (see 'Overview' above). However, it should always be kept in mind that the treatment of MG is highly individualized for each patient. Treatment choices depend on the age of the patient, the severity of the disease, particularly the presence of bulbar or respiratory symptoms, and the pace of progression.
In addition, special circumstances can dictate different approaches to treat MG. This section will review the approach in adults with generalized MG and ocular MG, adults over 60 years of age, and children. The treatment of MG in pregnancy and approach to severe MG exacerbations including myasthenic crisis is mentioned below but is discussed in greater detail separately. (See "Management of myasthenia gravis in pregnancy" and "Myasthenic crisis".)
Generalized myasthenia — The initial step in most adult patients with mild or moderate disease is symptomatic therapy in the form of pyridostigmine bromide (see 'Symptomatic treatment' above). Those with severe disease, or rapidly worsening disease, should be treated much like those in myasthenic crisis (see "Myasthenic crisis") using rapid therapies (ie, intravenous immunoglobulin or plasmapheresis) followed by longer-acting immunotherapies (see "Chronic immunomodulating therapies for myasthenia gravis") such as glucocorticoids, azathioprine, mycophenolate mofetil, or cyclosporine.
When starting pyridostigmine for an older adolescent or adult, we begin at 30 mg (1/2 tab) with meals three times a day for two to three days to assess the cholinergic side effects (see 'Pyridostigmine dosing' above). For those with excessive cholinergic side effects we add an agent (eg, glycopyrrolate 1 mg with each pyridostigmine dose) to block those bothersome symptoms. For those who tolerate the pyridostigmine well, with or without anticholinergics, we increase the dose by 30 mg increments 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. For those with bothersome symptoms upon awakening in the morning, we use a long-acting form of pyridostigmine (Mestinon TS 180 mg) at bedtime.
For children and younger adolescents, the initial dose is 0.5 to 1 mg/kg every four to six hours (see 'Pyridostigmine dosing' above). 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.
For those patients on pyridostigmine alone whose symptoms are under good control or in remission, we simply follow their clinical course. Thymectomy should be considered in all adult patients under age 60 as well (see "Thymectomy for myasthenia gravis"). Although there are some patients who do well long-term on pyridostigmine alone, most patients with generalized MG ultimately require some form of immunotherapy (see "Chronic immunomodulating therapies for myasthenia gravis").
Addition of immunomodulating agent — An immunotherapeutic agent is usually required for patients who remain significantly symptomatic on pyridostigmine, or who become symptomatic again after a temporary response to pyridostigmine. The choice of agent (most often prednisone, azathioprine, mycophenolate, or cyclosporine) depends on many factors. These include the relative contraindications to glucocorticoids (such as diabetes or advanced age), liver disease (precluding azathioprine use), renal disease (precludes cyclosporine use), or leukopenia (problematic for both azathioprine and mycophenolate). The desired time for response onset also is a factor (table 1), varying from two to three weeks with prednisone to approximately 12 months with azathioprine. Cost is another important consideration. (See "Chronic immunomodulating therapies for myasthenia gravis".)
In young adult patients, particularly those of child-bearing potential, we favor the use of glucocorticoids. We often can get a good response with high doses initially and then maintain that response after a slow taper down to low doses (on the order of 10 mg daily of prednisone). We also use glucocorticoids in older individuals who need a relatively quick response to immunotherapy and then try to add another agent (most often azathioprine or mycophenolate mofetil) to replace the glucocorticoids for the long term.
There are a number of reasonable approaches to starting prednisone, including daily and alternate day dosing. Dosing of glucocorticoids, including dose escalation and tapering, is discussed separately. (See "Chronic immunomodulating therapies for myasthenia gravis", section on 'Glucocorticoids'.)
For patients who cannot be tapered to low doses without clinical relapse or in those patients where long-term prednisone is not desirable, even at low doses, another immunomodulating agent is substituted.
We add a glucocorticoid-sparing agent, or glucocorticoid replacement, when we are down to the lowest dose of prednisone that will maintain a reasonable clinical response. Effective glucocorticoid-sparing agents include azathioprine, mycophenolate mofetil, and cyclosporine. (See "Chronic immunomodulating therapies for myasthenia gravis", section on 'Glucocorticoid-sparing agents'.)
After the minimum time to onset of clinical response for the added immunotherapy (eg, often 12 months or more for azathioprine) has passed, we then slowly taper prednisone to as low a dose as can be achieved, preferably none at all. After the glucocorticoids have been tapered, we then try to taper pyridostigmine. Many, but certainly not all, patients can be minimally symptomatic or in remission on one immunotherapy agent alone.
Monitoring response to immunotherapy — The response to immunotherapy should be judged, as it is for symptomatic treatment with pyridostigmine, by improvement in the clinical symptoms and neurologic deficits on examination. In general, following the acetylcholine receptor (AChR) 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 . 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.
Bridge therapy — For those patients with MG in whom it is especially desirable to avoid glucocorticoids (such as those with poorly controlled diabetes) or for those who are not successfully weaned to lower doses of prednisone, we often use monthly courses of intravenous immune globulin (IVIG) until the more slowly acting immunotherapy takes effect. Monthly plasmapheresis is an alternative to IVIG. However, venous access problems develop with frequent use of plasmapheresis, making it less practical than IVIG for use as a bridge therapy.
Refractory disease — There is a small cohort of patients with generalized MG who are refractory to, or are limited by the specific toxicities of, the first-line immunotherapies (eg, azathioprine, mycophenolate, or cyclosporine). Some require unacceptably high doses of glucocorticoids despite concurrent use of these agents. In these refractory patients, monthly IVIG or the use of rituximab is often beneficial. (See "Chronic immunomodulating therapies for myasthenia gravis", section on 'Choice of agent'.)
Need for thymectomy — In parallel with symptomatic treatment and immunotherapeutic agents for MG, we consider thymectomy because of its potential longer-term benefit. (See "Thymectomy for myasthenia gravis".)
Patients with thymoma clearly need surgical treatment. However, the need for thymectomy is less certain in those with nonthymomatous tissue. We advise such patients that the likelihood of medication-free remission is about twice as high with thymectomy than without, and that the likelihood of becoming asymptomatic is about one and a half times as high with thymectomy . We also emphasize that the benefit of thymectomy is delayed and accrues over several years postoperatively. (See "Thymectomy for myasthenia gravis", section on 'Efficacy'.)
We advocate thymectomy as soon as the patient's degree of weakness is sufficiently controlled to permit surgery, if the patient is amenable to that surgery. We also prefer to have patients on relatively low doses of glucocorticoids, if possible, to avoid postoperative problems with wound healing.
For patients with preoperative bulbar or respiratory symptoms, we try to defer surgery until they are reasonably well controlled. We administer IVIG or perform a series of plasma exchanges one or two weeks before surgery, if these respiratory or bulbar symptoms persist. The exact timing of surgery and what techniques are appropriate are issues not settled.
Ocular myasthenia — The elements of treatment for ocular myasthenia gravis (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'.)
Age 60 and over — We do not routinely suggest thymectomy in patients over 60 years of age, unless a thymoma is present. (See "Thymectomy for myasthenia gravis", section on 'Patient age and severity of disease' and "Clinical presentation and management of thymoma and thymic carcinoma".)
Although there are no firm data to support a strict age limit for this surgical therapy, many feel that thymectomy is less likely to be beneficial in this age group due to the high incidence of thymic involution and an increased operative risk due to comorbidities. We use age 60 as a rough rule of thumb, but this is moderated by the patient's overall health, functional age, and the patient's wishes after reviewing the issues with him or her. Despite the reluctance at many centers to perform this surgery on older patients with MG, there is some evidence that patients over age 60 may benefit from the procedure .
Other than a tendency to use glucocorticoids more sparingly in this group, the use of pyridostigmine, azathioprine, and mycophenolate mofetil does not differ from that detailed above. Due to the potential renal side effects, we do not commonly use cyclosporine in these patients. There are few studies that look at the treatments in this particular age group. However, the usefulness of immunotherapy is supported by a study of outcome at one year or longer in 149 patients with disease onset after age 60 who were treated with azathioprine with or without prednisone . Better outcomes and fewer side effects were observed when prednisone was avoided or was combined with azathioprine.
Children — As with adults, the treatment of children with MG should be individualized based on the severity and pace of the disease [9,10,32]. Pyridostigmine is the first line of therapy (see 'Pyridostigmine dosing' above). If anticholinesterase medications are not sufficient, plasmapheresis or intravenous immune globulin 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. Azathioprine, mycophenolate mofetil, and cyclosporine have been used successfully in juvenile MG [10,32], 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 . Thymectomy is a widely accepted option for peripubertal and postpubertal children with generalized MG who have positive acetylcholine receptor antibodies or who are seronegative [9,10,32-34]. The rates of improvement and remission seen in uncontrolled series appear to be similar to that reported in adults after thymectomy . Thorascopic thymectomy, potentially a more acceptable treatment in this age group, has been used successfully in a small case series . 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 .
Similar to adults with MuSK antibody-positive MG (see "Thymectomy for myasthenia gravis", section on 'MuSK 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 [9,32].
The clinical outcome in childhood MG varies with age of onset, race, and sex . 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 antiacetylcholine receptor antibodies. Neonatal myasthenia is discussed separately. (See "Neuromuscular junction disorders in newborns and infants".)
Myasthenic crisis — Myasthenic crisis is a life-threatening condition, and it is characterized by neuromuscular respiratory failure. 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".)
Drugs that may exacerbate myasthenia — Certain drugs, such as aminoglycosides and neuromuscular blocking agents, have established pharmacologic adverse effects on neuromuscular transmission (table 2). 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 (table 3). 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.
The list of medications that may exacerbate MG (table 2 and table 3) is not comprehensive. The clinician should consider the potential for increasing weakness in any patient with MG receiving a new medication, even if it is not on the list of drugs that may cause an exacerbation. In general, all drugs that are respiratory depressants (eg, benzodiazepines, narcotics, sedatives) should be used with caution in patients with known myasthenia gravis.
Medications that can cause a significant increase in weakness in patients with MG (table 2) include fluoroquinolone, ketolides (particularly telithromycin) and aminoglycoside antibiotics, beta blockers, procainamide, quinidine, quinine, and magnesium . A number of other drugs may unmask or exacerbate MG, particularly the neuromuscular blocking agents used during anesthesia, which can lead to prolonged postoperative weakness and ventilator dependence. In a literature review of drug-induced myasthenia, aminoglycoside-related postoperative respiratory depression caused the greatest frequency of drug-induced neuromuscular blockade .
Penicillamine, used in other autoimmune diseases, induces an autoimmune myasthenic syndrome in approximately 1 percent of cases. It simulates primary MG in that it can induce ocular or generalized weakness with the production of acetylcholine receptor antibodies [39,40]. The myasthenic symptoms eventually resolve after penicillamine is discontinued. (See "Differential diagnosis of myasthenia gravis", section on 'Penicillamine-induced myasthenia'.)
●Fluoroquinolone (such as ciprofloxacin and levofloxacin) antibiotics may exacerbate muscle weakness in some patients with MG . Fluoroquinolones should be used with caution in patients with known MG, if at all.
●Aminoglycosides should be avoided and only used if absolutely necessary with close monitoring.
●Telithromycin has been associated with severe exacerbations or unmasking of MG in several case reports, often within two hours of the first dose . Therefore, telithromycin should not be used in patients with MG. (See "Azithromycin, clarithromycin, and telithromycin", section on 'Warnings about telithromycin'.)
●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 . These drugs should be judiciously titrated if used.
●Lidocaine and procaine may cause worsening if injected intravenously.
●Magnesium sulfate is relatively contraindicated because magnesium has a significant inhibitory effect on acetylcholine release.
●Penicillamine should be avoided in patients with MG because it can induce MG.
●Certain cardiac drugs, such as all beta blockers and procainamide, should be used with caution.
●Although glucocorticoids are a common treatment for MG, at high doses they may cause a significant exacerbation of MG symptoms during early stages of treatment. For this reason, glucocorticoids should be started in high doses only in hospitalized patients who are receiving concurrent plasmapheresis or IVIG for myasthenic crisis.
●Among anticonvulsants, phenytoin and gabapentin rarely have been associated with exacerbation of MG, but these drugs may be used if needed. Experimental evidence suggests that ethosuximide and carbamazepine may cause increased weakness, but there are no clinical reports.
●Central nervous system depressants, opioids, and muscle relaxants may increase MG symptoms when these agents are used concurrently or given in high doses.
●Statin treatment may be associated with MG, as suggested by a few case reports and case series [44-48] that describe a total of 12 patients with new or worsening MG in the context of extensive use of these drugs. Exacerbation of pre-existing MG within a few months of starting statin therapy was reported in eight patients [46-48], including six from a single-center retrospective study of 170 patients with MG who were surveyed about statin treatment . Symptoms of de novo MG developed within weeks of starting statins in four patients [46,47]. Unmasking of subclinical MG due to statin-related myotoxicity was one possible explanation for some of the new cases, and the coincidental occurrence of autoimmune MG with statin therapy was another. However, statins are thought to rarely produce other autoimmune disorders, such as statin-induced, immune-mediated necrotizing myopathy . Thus, in de novo MG cases, the statin may play an immunomodulatory role and induce antibody-mediated 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 casual may require withdrawal from the medication and a rechallenge.
Immunizations — Patients with generalized MG who develop respiratory infections are at increased risk of myasthenic exacerbations and respiratory compromise . 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. In 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, that 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 . Furthermore, inactivated vaccines (eg, pneumococcal and intramuscular influenza vaccines) generally are considered safe in adults or children with immunocompromising conditions or on immunosuppressive drugs.
However, 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 :
●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)".)
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 (Streptococcus pneumoniae) conjugate vaccines in children".)
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
●The four basic therapies for myasthenia gravis (MG) include symptomatic treatments (anticholinesterase agents), chronic immunotherapies (glucocorticoids and other immunosuppressive drugs), rapid immunotherapies (plasma exchange and intravenous immune globulin [IVIG]), and thymectomy. The time of onset of clinical effect of each of these therapies for MG varies considerably (table 1). (See 'Overview' above.)
●We recommend treatment with acetylcholinesterase inhibitors as the first line of treatment for symptomatic MG (Grade 1B). Pyridostigmine is the most widely used choice. For adults and older adolescents, a typical starting dose 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 'Symptomatic treatment' above.)
●Most patients with MG will need some form of immunotherapy in addition to pyridostigmine. We recommend adding immunotherapy for patients who remain significantly symptomatic on pyridostigmine, or who become symptomatic after a temporary response to pyridostigmine (Grade 1B). Glucocorticoids, azathioprine, mycophenolate mofetil, and cyclosporine are the most widely used (see 'Chronic immunotherapies' above). This approach is discussed in greater detail separately. (See "Chronic immunomodulating therapies for myasthenia gravis".)
●Plasmapheresis (with plasma exchange) and IVIG work quickly but have a short duration of action. In addition to treatment of myasthenic crisis, these rapid therapies are useful in presurgical treatment of moderate to severe MG. They are also used as a "bridge" when initiating slower acting immunotherapies, and as periodic adjuvants to other immunotherapeutic medications in refractory MG. (See 'Rapid immunotherapies' above.)
●We suggest thymectomy for patients without thymoma below age 60 years who have generalized MG and either have AChR antibodies, or have no detectable AChR or MuSK antibodies (ie, seronegative MG) (Grade 2C). We suggest not performing thymectomy in patients with MuSK antibody-associated MG without thymoma (Grade 2C). (See 'Generalized myasthenia' above and 'Age 60 and over' above and "Thymectomy for myasthenia gravis".)
●Attempted surgical excision is the treatment of choice for nonmetastatic thymoma and thymic carcinoma. (See "Clinical presentation and management of thymoma and thymic carcinoma", section on 'Management'.)
●A number of drugs may unmask or exacerbate MG (table 2). Avoidance of fluoroquinolone, aminoglycoside and ketolide antibiotics, magnesium sulfate, chloroquine and hydroxychloroquine, penicillamine, and botulinum toxin in patients with MG is prudent. Likewise, beta blockers, procainamide, quinidine, and quinine should be avoided when possible. Other drugs are usually well-tolerated in patients with MG but occasionally have been associated with an MG exacerbation (table 3). Cautious use of these drugs is advised whenever there is a clear requirement for any of these agents. (See 'Drugs that may exacerbate myasthenia' above.)
●The treatment of MG is highly individualized and depends upon the age of the patient, the severity of the disease, and the pace of progression. Treatment options and suggestions for generalized MG, ocular MG, patients over 60, and children are discussed in detail above. (See 'Generalized myasthenia' above and 'Ocular myasthenia' above and 'Age 60 and over' above and 'Children' above.)
●For all individuals with generalized MG, and those with ocular MG who are within three years of onset, we suggest pneumococcal vaccination and annual intramuscular (inactivated) seasonal influenza vaccination (Grade 2C). Patients being treated with immunotherapy for MG should not receive the live-attenuated (intranasal) influenza vaccine, or the live-attenuated varicella or zoster (shingle) vaccines. (See 'Immunizations' above.)
●The management of MG in pregnancy is discussed separately. (See "Management of myasthenia gravis in pregnancy".)
●The management of rapidly worsening MG and myasthenic crisis is discussed separately. (See "Myasthenic crisis".)
- Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010; 17:893.
- Farrugia ME, Vincent A. Autoimmune mediated neuromuscular junction defects. Curr Opin Neurol 2010; 23:489.
- Silvestri NJ, Wolfe GI. Myasthenia gravis. Semin Neurol 2012; 32:215.
- Díaz-Manera J, Rojas García R, Illa I. Treatment strategies for myasthenia gravis: an update. Expert Opin Pharmacother 2012; 13:1873.
- Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev 2014; :CD006986.
- Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55:7.
- Punga AR, Stålberg E. Acetylcholinesterase inhibitors in MG: to be or not to be? Muscle Nerve 2009; 39:724.
- Liu GT, Volpe NJ, Galetta SL. Eyelid and facial nerve disorders. In: Neuro-Ophthalmology, Liu GT, Volpe NJ, Galetta SL (Eds), WB Saunders, Philadelphia 2001. p.496.
- Ionita CM, Acsadi G. Management of juvenile myasthenia gravis. Pediatr Neurol 2013; 48:95.
- Chiang LM, Darras BT, Kang PB. Juvenile myasthenia gravis. Muscle Nerve 2009; 39:423.
- Dau PC, Lindstrom JM, Cassel CK, et al. Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 1977; 297:1134.
- Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG. Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange. Neurology 1978; 28:266.
- Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev 2002; :CD002275.
- Benny WB, Sutton DM, Oger J, et al. Clinical evaluation of a staphylococcal protein A immunoadsorption system in the treatment of myasthenia gravis patients. Transfusion 1999; 39:682.
- Miyahara T, Oka K, Nakaji S. Specific immunoadsorbent for myasthenia gravis treatment: development of synthetic peptide designed to remove antiacetylcholine receptor antibody. Ther Apher 1998; 2:246.
- Nakaji S, Hayashi N. Adsorption column for myasthenia gravis treatment: Medisorba MG-50. Ther Apher Dial 2003; 7:78.
- Rodnitzky RL, Goeken JA. Complications of plasma exchange in neurological patients. Arch Neurol 1982; 39:350.
- Ebadi H, Barth D, Bril V. Safety of plasma exchange therapy in patients with myasthenia gravis. Muscle Nerve 2013; 47:510.
- Pérez Nellar J, Domínguez AM, Llorens-Figueroa JA, et al. [A comparative study of intravenous immunoglobulin and plasmapheresis preoperatively in myasthenia]. Rev Neurol 2001; 33:413.
- Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol 2005; 252 Suppl 1:I14.
- Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 2012; 12:CD002277.
- Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012; 78:1009.
- Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology 2007; 68:837.
- Barth D, Nabavi Nouri M, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 2011; 76:2017.
- Arsura E. Experience with intravenous immunoglobulin in myasthenia gravis. Clin Immunol Immunopathol 1989; 53:S170.
- Cosi V, Lombardi M, Piccolo G, Erbetta A. Treatment of myasthenia gravis with high-dose intravenous immunoglobulin. Acta Neurol Scand 1991; 84:81.
- Dalakas MC. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999; 22:1479.
- Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile. Pharmacol Ther 2004; 102:177.
- Sanders DB, Burns TM, Cutter GR, et al. Does change in acetylcholine receptor antibody level correlate with clinical change in myasthenia gravis? Muscle Nerve 2014; 49:483.
- Tsuchida M, Yamato Y, Souma T, et al. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999; 67:1563.
- Evoli A, Batocchi AP, Minisci C, et al. Clinical characteristics and prognosis of myasthenia gravis in older people. J Am Geriatr Soc 2000; 48:1442.
- Andrews PI. Autoimmune myasthenia gravis in childhood. Semin Neurol 2004; 24:101.
- Tracy MM, McRae W, Millichap JG. Graded response to thymectomy in children with myasthenia gravis. J Child Neurol 2009; 24:454.
- Evoli A. Acquired myasthenia gravis in childhood. Curr Opin Neurol 2010; 23:536.
- Kolski H, Vajsar J, Kim PC. Thoracoscopic thymectomy in juvenile myasthenia gravis. J Pediatr Surg 2000; 35:768.
- Andrews PI, Massey JM, Howard JF Jr, Sanders DB. Race, sex, and puberty influence onset, severity, and outcome in juvenile myasthenia gravis. Neurology 1994; 44:1208.
- Mehrizi M, Fontem RF, Gearhart TR, Pascuzzi RM. Medications and Myasthenia Gravis (A Reference for Health Care Professionals), Indiana University School of Medicine (Department of Neurology), 2012.
- Barrons RW. Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy 1997; 17:1220.
- Komal Kumar RN, Patil SA, Taly AB, et al. Effect of D-penicillamine on neuromuscular junction in patients with Wilson disease. Neurology 2004; 63:935.
- Kuncl RW, Pestronk A, Drachman DB, Rechthand E. The pathophysiology of penicillamine-induced myasthenia gravis. Ann Neurol 1986; 20:740.
- Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf 2011; 34:839.
- Perrot X, Bernard N, Vial C, et al. Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment. Neurology 2006; 67:2256.
- Dillon FX. Anesthesia issues in the perioperative management of myasthenia gravis. Semin Neurol 2004; 24:83.
- Parmar B, Francis PJ, Ragge NK. Statins, fibrates, and ocular myasthenia. Lancet 2002; 360:717.
- Engel WK. Reversible ocular myasthenia gravis or mitochondrial myopathy from statins? Lancet 2003; 361:85.
- Cartwright MS, Jeffery DR, Nuss GR, Donofrio PD. Statin-associated exacerbation of myasthenia gravis. Neurology 2004; 63:2188.
- Purvin V, Kawasaki A, Smith KH, Kesler A. Statin-associated myasthenia gravis: report of 4 cases and review of the literature. Medicine (Baltimore) 2006; 85:82.
- Oh SJ, Dhall R, Young A, et al. Statins may aggravate myasthenia gravis. Muscle Nerve 2008; 38:1101.
- Gale J, Danesh-Meyer HV. Statins can induce myasthenia gravis. J Clin Neurosci 2014; 21:195.
- Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 1997; 48:1253.
- Zinman L, Thoma J, Kwong JC, et al. Safety of influenza vaccination in patients with myasthenia gravis: a population-based study. Muscle Nerve 2009; 40:947.
- Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58:e44.