Which preexisting condition would contraindicate the use of pyridostigmine?

Even though no rigorously tested treatment trials have been reported and no clear consensus exists on treatment strategies, myasthenia gravis (MG) is one of the most treatable neurologic disorders. Several factors (eg, severity, distribution, rapidity of disease progression) should be considered before therapy is initiated or changed. Treatment regimens are individualized depending on the severity of the myasthenia (MGFA class), patient age, serology status, thymic pathology, concurrent medical issues, patient and physician preference and physician experience.

In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG. Definitions were developed for goals of treatment, minimal manifestation status (MMS), remission, ocular MG, impending crisis, crisis, and refractory MG. Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. [53]

MGFA Task Force defined goals of treatment of MG to achieve Minimal Manifestation Status (MMS) or better, with no more than grade 1 Common Terminology Criteria for Adverse Events (CTCAE) medication side effects. Operational definitions were set as follows:

Definition of remission: The patient has no symptoms or signs of MG. Weakness of eyelid closure is accepted, but there is no weakness of any other muscle on careful examination. Patients taking cholinesterase inhibitors (ChEIs) every day with reasonable evidence to support symptomatic benefit are therefore excluded from this category.

MMS: The patient has no symptoms or functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of remission have mild weakness.

CTCAE grade 1 medication side effects: asymptomatic or only mild symptoms; intervention not indicated.

Definition of ocular MG (based on dysfunction due to MG at a specified point in time, and not dependent upon the duration of disease): MGFA Class I: Any ocular muscle weakness. May have weakness of eye closure. Strength in all other facial, bulbar, and limb muscles is normal. (It is recognized that some patients report fatigue when strength testing is normal. The physician should use clinical judgment in attributing fatigue to generalized MG in the absence of objective nonocular weakness).

Definition of impending myasthenic crisis: Rapid clinical worsening of MG that, in the opinion of the treating physician, could lead to crisis in the short term (days to weeks).

Definition of manifest myasthenic crisis (the concept of crisis focuses on the clinical implications—it represents a serious, life-threatening, rapid worsening of MG and potential airway compromise from ventilatory or bulbar dysfunction): MGFA Class V: Worsening of myasthenic weakness requiring intubation or noninvasive ventilation to avoid intubation, except when these measures are employed during routine postoperative management (the use of a feeding tube without intubation places the patient in MGFA Class IVB).

Definition of refractory MG: Unchanged or worse after corticosteroids and at least 2 other immunosuppressant agents, used in adequate doses for an adequate duration, with persistent symptoms or side effects that limit functioning, as defined by patient and physician

Pharmacologic therapy includes anticholinesterase medication and immunosuppressive agents, such as corticosteroids and nonsteroid immunosuppressants like azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, sirolimus, rituximab, cyclophosphamide, and other immunomodulatory therapies that include plasmapheresis, and intravenous immune globulin (IVIg).

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

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

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

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Pharmacologic Therapy

Medications are used in myasthenia gravis (MG) to manage symptoms and control immune system activity.

Acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) inhibitors and immunomodulating therapies are the mainstays of myasthia gravis (MG) treatment.

Pyridostigmine is used for symptomatic treatment only. It does not treat the underlying disease.

In the mild form of the disease, AChE inhibitors are used initially. These agents include pyridostigmine and neostigmine. Pyridostigmine is used for maintenance therapy. [6, 7] Neostigmine is generally used only when pyridostigmine is unavailable. Edrophonium is primarily but rarely used as a diagnostic tool to predict the response to longer-acting cholinesterase inhibitors (see Workup). [43]

AChE inhibitors have a wide variability in the effective dose, depending on the severity and current activity of the disease and the presence of other factors that influence cholinergic transmission (eg, certain antibiotics, antidysrhythmic medications, and impaired renal function). [7, 18] Most patients are able to titrate the dosage of their medication to control disease symptoms, but severe exacerbations can occur in patients with previously well-controlled disease. [7]

Pyridostigmine dose should be adjusted as needed based on symptoms. The ability to discontinue pyridostigmine can be an indicator that the patient has met treatment goals and may guide the tapering of other therapies. Corticosteroids or IS therapy should be used in all patients with MG who have not met treatment goals after an adequate trial of pyridostigmine.

Corticosteroids

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

The corticosteroid regimen should be tailored according to the patient’s overall improvement. The lowest effective dose should be used on a long-term basis. Because of the delayed onset of effects (3–4 months), steroids are not recommended for routine use in the emergency department (ED). Patients who are taking long-term moderate or high doses of steroids may have suppressed adrenal function and may require stress doses (eg, hydrocortisone 100 mg IV in an adult) during acute exacerbations. [7]

Once patients achieve treatment goals (MMS or remission), the corticosteroid dose should be gradually tapered. In many patients, continuing a low dose of corticosteroids long-term can help to maintain the treatment goal.

Limited evidence from randomized, controlled trials (RCTs) suggests that corticosteroid therapy provides a short-term benefit in MG; this supports the conclusions of previous observational studies, as well as expert opinion. A systematic review found no clear difference between steroids and IVIg or azathioprine; however, further trials are indicated because of the flaws in the trials reviewed. [19]

Other immunosuppressive agents

Nonsteroidal immunosuppressant agents (AZA, MMF, MTX, CyA, etc.) should be used alone when corticosteroids are contraindicated or refused. A nonsteroidal IS agent should be used initially in conjunction with corticosteroids when the risk of steroid side effects is high based on medical comorbidities. A nonsteroidal immunosuppressant agent should be added to corticosteroids when the steroid side effects, deemed significant by the patient or the treating physician; when a response to an adequate trial of corticosteroids is failed; or the corticosteroid dose cannot be reduced due to symptom relapse.

Other medications that are used to treat more difficult cases include azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these medications is far from proved, and caution should be advised against using any of them lightly. [20, 21, 44]

The mainstay of therapy is still azathioprine, usually after an initial dose of corticosteroids. Cyclosporine and occasionally methotrexate and cyclophosphamide are used for severe cases, while tacrolimus is under investigation. [45] No evidence-based studies fully prove the usefulness of AChE inhibitors, corticosteroids, and other immunosuppressive agents in improving ocular symptoms. In addition, the effect of corticosteroids and azathioprine on the progression to generalized MG is still uncertain. [48]

To date, most of the studies on immunomodulatory therapy have had few participants and have found it difficult to assess the efficacy of the addition of immunosuppressive therapy to the previous regimens of corticosteroids and AChE inhibitors. Furthermore, most of the RCTs were short-term and did not evaluate long-term usage of these drugs. As a result, good RCT data on the use of immunosuppressive agents as monotherapy or dual therapy with steroids are absent. [49]

However, limited evidence indicates that cyclosporine and cyclophosphamide improve symptoms in MG and decrease the amount of corticosteroid usage. The more common drugs used in MG, such as azathioprine and tacrolimus, show no clear benefit in use. [49]

For nonsteroidal immunosuppressant agents, once treatment goals have been achieved and maintained for 6 months to 2 years, the IS dose should be tapered slowly to the minimal effective amount. Dosage adjustments should be made no more frequently than every 3–6 months.

The danger of tapering too soon. Tapering of immunosuppressant drugs is associated with risk of relapse, which may necessitate upward adjustments in dose. The risk of relapse is higher in patients who are symptomatic, or after rapid taper. It is usually necessary to maintain some immunosuppression for many years, sometimes for life.

Eculizumab 

Eculizumab is a monoclonal antibody directed toward complement 5 (C5). It is indicated for generalized myasthenia gravis in patients who are anti-acetylcholine receptor (AchR) antibody positive. The precise mechanism by which eculizumab exerts its therapeutic effect in generalized MG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. 

Approval of eculizumab was based on data from the REGAIN clinical trials. In the phase 3, multicenter, randomized, double-blind, placebo-controlled part of the REGAIN study, 62 patients were randomized to eculizumab and 63 to placebo. Patients were randomly assigned (1:1) to either IV eculizumab or IV matched placebo for 26 weeks. The primary efficacy endpoint for gMG was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at week 26. Treatment with eculizumab showed a statistically significant difference in the mean change from baseline to week 26 in MG-ADL total scores (–4.2 points vs. –2.3 points). [54]  

In the open-label extension phase, MG exacerbation rate was reduced by 75% compared with the previous year in patients taking eculizumab (p < 0.0001). Improvements were sustained over 3 years. During the open-label extension trial, patients previously on placebo showed rapid and sustained improvements (p < 0.0001). [55]

Efgartigimod alfa

Efgartigimod alfa is a human IgG1 antibody Fc fragment that binds to neonatal Fc receptor (FcRn), which reduces the circulating IgG. The FDA approved efgartigimod alfa for the treatment of generalized MG in adults who test positive for AchR antibody.

Approval was based on a phase 3 trial, where 167 patients with generalized MG were randomized to receive efgartigimod alfa or placebo. In cycle 1, more patients in the efgartigimod-treated group were MG-ADL responders (68%) compared to placebo (30%) (p < 0.0001). The most frequent adverse reactions were headache and nasopharyngitis. [56]

Life-threatening treatment with plasma exchange and IV immune globulin

Plasma exchange (PLEX) and intravenous immune globulin (IVIg) are appropriately used as short-term treatments in patients with MG with life-threatening signs such as respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction; when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations. The choice between PLEX and IVIg depends on individual patient factors (e.g., PLEX cannot be used in patients with sepsis and IVIg cannot be used in renal failure) and on the availability of each. Both are equally effective in the treatment of severe generalized MG, but the efficacy of IVIg is less certain in milder MG or in ocular MG. Also expert consensus suggests that PLEX is more effective and works more quickly than IVIg.

Impending MG crisis requires hospital admission and close observation of respiratory and bulbar function in an intensive care unit for management. When the FVC declines to < 15 mL/kg or negative inspiratory pressure (NIF) is < 30 cm H2O, intubation is recommended for airway protection. Mechanical ventilation is initiated to reduce the work of breathing, and improve ventilation. PLEX and IVIg are used as short-term treatment for impending and manifest myasthenic crisis. It is good practice to start corticosteroids or other immunosuppressant agents at the same time when starting PLEX or IVIg to achieve a sustained clinical response. PLEX is discontinued if 2 weeks pass without a meaningful response. While the patient is intubated, pyridostigmine is avoided to minimize secretions.

A treatment strategy using the following regimen for refractory MG, or MG presenting in crisis is as follows:

• Do 5 PLEX sessions.

• Start azathioprine (AZA)

• IV methylprednisolone at dose of 500-1000 mg daily for 5 days may be used, followed by 0.8 mg/kg IV daily until patient is capable of taking medications by mouth. Start prednisone at 60 mg PO daily for 2 weeks, then 50 mg PO daily for 2 weeks, then 40 mg PO daily for a month. This is followed by a slow taper by 5 mg per month to reach 20 mg/day. Around this time (6 months), the imuran (AZA) reaches therapeutic efficacy ("kicks in"). From then on, taper prednsione 2.5 mg per month while monitoring for worsening of myasthenia symptoms. Goal is to achieve prednisone 5–7.5 mg PO daily or 10 mg every other day (no significant side effects if continued on this dose). 

Although the steroids may initially worsen the patient’s myasthenia symptoms, it is not an issue as the patient is in the ICU setting and intubated. It is hypothesized that corticosteroids have a mild neuromuscular blocking properties that precede their immunomodulatory beneficial effects.

The use of IVIg as maintenance therapy can be considered for patients with refractory MG or for those in whom immunosuppressant agents are relatively contraindicated.

Although cholinergic crises are now rare, excessive ChEI cannot be completely excluded as a cause of clinical worsening. ChEIs like pyridostigmine can cause an increase of airway secretions, which may exacerbate breathing difficulties during a crisis.

Rituximab

Rituximab has emerged as a potentially effective therapeutic option for treatment of MG when first- and second-line immunotherapy fails. Patients with MuSK-MG appear to respond well to corticosteroids and to many steroid-sparing immunosuppressant agents, particularly rituximab. It is a chimeric monoclonal antibody that targets the CD20 angtigen found on subsets of the B-cell lineage. CD20 is expressed by all mature B cells but not on the pre-B or differentiated plasmablasts and plasma cells. Apart from showing significant clinical improvement, rituximab also allowed for tapering and even discontinuation of other immunsuppressants in both AChR and MuSK MG patients. However, relapses are known to occur on stopping rituximab.

Rituximab regimens

Dosage regimen 1:

• Rituximab 1 gm IV on day 1 and day 14

• Further rituximab doses depend on whether CD19 count has returned to normal (usually at 6 months)

• Rituximab 1 gm IV once at 6 months, if indicated

Dosage regimen 2:

• Rituximab 375/m2 IV every 12 weeks for 48 weeks

• Prednisone 60 mg daily until minimal manifestation state, then taper to 10 mg every 4 weeks

Often patients are started on prednisone in the outpatient setting when their MG is mild. The strategy here is to increase the dose gradually until symptoms resolve or minimal manifestation status is achieved. Initially, patients are started on prednisone 20 mg daily and the dose is increased by 5 mg every 3–5 days until symptoms resolve. Patients are usually kept on the dosage that achieved minimal manifestation state for a month, then the dose is gradually tapered (no faster than 5 mg every 2 weeks down to a dose of 20 mg daily, and then by 2.5 mg every two weeks). [5, 57]

MG induction as a side effect of cancer immunotherapy with checkpoint inhibitors (PD-1, PD-L1, and CTLA-4) is described to rapidly progress to myasthenic crisis and must be aggressively treated by discontinuation of immunotherapy with the checkpoint inhibitors and initiation of high-dose steroids along with IVIg or plasmapheresis. 

Aminoglycoside antibiotics inhibit ACh release from nerve terminals by competing with Ca++. Administration of calcium salts overcomes this effect.

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Management of neonatal myasthenia gravis

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

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

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

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Complications

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

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

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

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

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Plasmapheresis

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

Plasmapheresis is an effective therapy for myasthenia gravis (MG) and is often the initial treatment of choice in myasthenic crisis. Also, it is used to optimize control in preparation for surgery. Improvement in strength may help to achieve rapid postoperative recovery and to shorten the period of assisted ventilation. Long-term regular plasmapheresis on a weekly or monthly basis can be used if other treatments cannot control the disease.

Complications are primarily limited to complications of intravenous (IV) access (eg, central line placement) but also may include hypotension and coagulation disorders (though less commonly). Patients will need careful monitoring of fibrinogen and may need FFB if fibrinogen levels drop to less than 150 mg/dL prior to the next pheresis. There is a risk of hypocalcemia, central-line-associated bloodstream infection (CLABSI), thrombocytopenia, thromboembolism, and heparin-induced thrombocytopenia.

ACE inhibitors must be stopped 24 hrs before treatment and until treatment is completed.

Plasmapheresis is given as 250 mL/Kg total divided every other day over 5-6 exchanges. The onset of action is 1-7 days with maximal effect in 1-3 weeks.

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Thymectomy

Thymic abnormalities are common in patients with myasthenia gravis (MG). Of patients with generalized MG, 85% have thymic hyperplasia, and 10-15% have thymoma. Thymic pathology in early-onset generalized MG is invariably thymic hyperplasia. These patients invariably are anti-AChR-ab positive. 

There is evidence that resident cells in the thymus, including myoid cells and epithelial cells, express various subunits of AChR, including the α subunit. Additional factors found uniquely in hyperplastic MG thymus include increased expression of chemokines that attract immigrant CD4+ T and B cells; the presence of nAChR-reactive B and CD4+ T cells and anti-AChR antibody-secreting plasma cells; cytokines that can facilitate B cell activation, differentiation, and survival; and possibly decreased CD4+ CD25+ regulatory T cell function. [58]

An extended trans-sternal thymectomy is standard of care and is indicated for all patients with thymoma and for patients aged 10-55 years without thymoma but who have generalized MG. Patients with thymomas almost always have anti-AChR-ab and so one must look carefully for thymoma in late-onset patients with anti-AChR-ab positive status. Removal of thymoma is essential to prevent local dissemination and systemic metastases. In late onset patient with MG and thymoma, thymectomy probably does not change the course of MG. Thymectomy has been proposed as a first-line therapy in most patients with generalized myasthenia. [52]  In patients who have myasthenia gravis like symptoms but who are seronegative order a CT of chest regardless, to check for thymic pathology, since a small percentage of these patients may subsequently seroconvert to anti-AChR-ab positive status.

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

Thymectomy is not recommended in patients with antibodies to muscle-specific kinase (MuSK), because of the typical thymus pathology, which is very different from the more common type of MG characterized by seropositivity for AChR antibodies. [53] Current evidence also does not support an indication for thymectomy in patients with LRP4, or agrin antibodies.

Thymectomy may be considered in patients with generalized MG without detectable AChR antibodies if they fail to respond adequately to immunosuppressant therapy, or to avoid/minimize intolerable adverse effects from immunosuppressant therapy. [59]

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

Thymectomy may induce remission. This occurs more frequently in young patients with a short duration of disease, hyperplastic thymus, more severe symptoms, and a high antibody titer, although a high titer of antibody is not consistently linked to better outcome. [60]

Remission rate increases with time: at 7-10 years after surgery, it reaches 40-60% in all categories of patients except those with thymoma. In the absence of a thymoma, 85% of patients experience improvement, and 35% of these patients achieve drug-free remission. In a study by Nieto et al, the rate of remission in the presence of thymic hyperplasia was 42% compared to 18% in patients with thymoma. [58]

As there is a long delay in onset of beneficial effect of thymectomy for MG, an elective procedure should be performed when the patient is stable and deemed safe to undergo a procedure where postoperative pain and mechanical factors can limit respiratory function.

Robotic thymectomy

A robotic minimally invasive approach to thymectomy has been used. [61] In a review of 100 consecutive patients who underwent left-sided robotic thymectomy for MG, Marulli et al demonstrated the safety and efficacy of this procedure. No deaths or intraoperative complications occurred. On 5-year clinical follow-up, 28.5% of patients had complete stable remission, and 87.5% showed overall improvement. Remission was significantly more likely in patients with preoperative Myasthenia Gravis Foundation of America class I to II MG. [62]

Myasthenia Gravis Foundation of America (MGFA) classification of thymectomy

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

The Myasthenia Gravis Foundation of America (MGFA) has proposed a classification scheme for thymectomy, which is primarily based on techniques described in various published reports. [3]

The MGFA thymectomy classification is as follows:

• T-1 transcervical thymectomy – Basic; extended

• T-2 videoscopic thymectomy - Classic or VATS (video-assisted thoracic surgery) thymectomy; VATET (video-assisted thoracoscopic extended thymectomy)

• T-3 transsternal thymectomy – Standard; extended

• T-4 transcervical and transsternal thymectomy

Randomized trial of thymectomy in myasthenia gravis

Trans-sternal thymectomy has been known to improve MG in many anecdotal case reports and has been adopted as an effective way to manage the disease and even induce remission or lessen the requirements or perhaps remove the need of prednisone and other immunosuppressants.

Randomized Trial of Thymectomy in Myasthenia Gravis is a landmark study. This is the first randomized trial of thymectomy in MG. The cohort of patients who were involved in the trial had generalized MG and were acetylcholine receptor antibody positive. Patients who entered the study were between the ages of 18 and 65 years, and none could have a duration of MG based on their historical presentations that exceeded 5 years. Patients were randomized one to one to thymectomy plus prednisone or to prednisone alone. They could go on prednisone as long as they did not exceed a dosage of 50 mg a day. Other immunosuppressants were excluded. The intervention was an extended trans-sternal thymectomy in order to get as much thymic tissue as possible. The primary outcome was tiered and included both outcomes of the disease based on QMG score and prednisone dose. The outcome was that not only was the prednisone requirement less in the thymectomy group, but there was a better outcome in patients who underwent thymectomy. Also, the requirement of azathioprine was reduced in the thymectomy patients. Therefore, over a period of 3 years, thymectomy was associated with more favorable clinical outcomes with respect to requirements for prednisone and azathioprine therapy, the number of symptoms and the distress level related to immunosuppressive agents, and the need for hospitalization to manage disease exacerbations. [61]

An upper age limit for extended transternal thymectomy is not determined. Patients with an upper age limit of 65 years without significant medical comorbid conditions can be considered for thymectomy.

Phrenic nerve injury resulting in diaphragmatic paralysis and paresis of recurrent laryngeal nerve were some known complications.

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Diet and Activity

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

Educate patients about the fluctuating nature of weakness and exercise-induced fatigability. Patients should be as active as possible but should rest frequently and avoid sustained physical activity. Patients are instructed to begin an aerobic exercise program.

Patients are instructed to start a low-sodium, low-carbohydrate, high-protein diet to prevent excessive weight gain.

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Pregnancy and Myasthenia Gravis

In an review of literature involving 322 pregnancies in 225 myasthenic mothers, 31% had no change in their myasthenic symptoms, 28% improved, and 41% deteriorated during pregnancy. [63] . Of the pregnant myasthenic mothers, 30% had exacerbation of the disease in the post-partum period. In general, pyridostigmine and, if needed, prednisone are used, whereas other immunomodulating agents are avoided if possible beause of teratogenic concerns.

Current information indicates that azathioprine and cyclosporine are relatively safe in expectant mothers who are not satisfactorily controlled with or cannot tolerate corticosteroids. Current evidence indicates that mycophenolate mofetil and methotrexate increase the risk of teratogenicity and are contraindicated during pregnancy. (These agents previously carried Food and Drug Administration [FDA] Category C (cyclosporine), D (azathioprine and mycophenolate mofetil), and X (methotrexate) ratings.) The FDA has recently discontinued this rating system, and replaced it with a summary of the risks of using a drug during pregnancy and breastfeeding, along with supporting data and relevant information to help health care providers make prescribing and counseling decisions. Although this statement achieved consensus, there was a strong minority opinion against the use of azathioprine in pregnancy. Azathioprine is the nonsteroidal immunosuppressant of choice for MG in pregnancy in Europe but is considered high risk in the United States. This difference is based on a small number of animal studies and case reports.

PLEX or IVIg are useful when a prompt, although temporary, response is required during pregnancy.

Pregnant women with myasthenia gravis should be considered high-risk pregnancies and followed closely by an obstetrician, neonatologist, and a neuromuscular clinician. Planning for pregnancy should be instituted well in advance to allow time for optimization of myasthenic clinical status and to minimize risks to the fetus. Magnesium sulfate is avoided if possible if preeclampsia develops due to its neuromuscular blocking properties. It is preferable to give regional anesthesia for delivery and cesarean section.

All babies born to myasthenic mothers should be examined for evidence of transient myasthenic weakness, even if the mother’s myasthenia is well controlled, and should have rapid access to neonatal critical care support.

Chest CT without contrast can be performed safely during pregnancy, although the risks of radiation to the fetus need to be carefully considered. Unless there is a compelling indication, postponement of diagnostic CT until after delivery is preferable.

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Juvenile Myasthenic Gravis

It is estimated that approximately 10% of non-neonatal autoimmune myasthenia gravis (MG) cases that are acquired will occur before the age of 18 years, and the majority occur subsequent to puberty. The mean age of onset ranges from 7 to 14 years. All features are identical with adult myasthenia gravis, except age. [60]  Children with acquired autoimmune ocular MG are more likely than adults to go into spontaneous remission. Thus, young children with only ocular symptoms of MG can be treated initially with pyridostigmine. Immunotherapy can be initiated if goals of therapy are not met. Children are at particular risk of steroid side effects, including growth failure, poor bone mineralization, and susceptibility to infection, due in part to a delay in live vaccinations. It is recommended that for long-term treatment with corticosteroids use of the lowest effective dose to minimize side effects is acceptable. Maintenance PLEX or IVIg as alternatives to immunosuppressant agents in JMG is also recommended.

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IVIg

IVIg is given as 400 mg/kg daily for 5 days (2 g/kg total).

Onset of action: 1-2 weeks with maximal effect: 1-3 weeks. 

Benefit can last for 3-5 weeks.

The effect of IVIg variable and slower in onset when compared to PLEX.

The dose is spreading over more days in patients with renal disease (Cr >1.4), diabetes mellitus, congestive heart failure, and in elderly.

Advantages: Noninvasive.  Pretreatment with NS 250 mL; Tylenol and Benadryl can mitigate complications.

Disadvantages:  Risk of hypersensitivity with IgA deficiency (should check IgA levels before starting), aseptic meningitis, headache, chills, myalgias, transient hypertension, fluid overload, acute tubular necrosis, hyperviscosity syndrome (stroke, MI, cryoglobulinemia, monoclonal gammopathy, high lipoproteins, or preexisting vascular disease).  Benefits last only a few weeks.

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Medication

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Media Gallery

• Normal neuromuscular junction showing a presynaptic terminal with a motor nerve ending in an enlargement (bouton terminale): Synaptic cleft and postsynaptic membrane with multiple folds and embedded with several acetylcholine receptors.

• Acetylcholine receptor. Note 5 subunits, each with 4 membrane-spanning domains forming a rosette with a central opening. The central opening acts as an ion channel.

• CT scan of chest showing an anterior mediastinal mass (thymoma) in a patient with myasthenia gravis.

• Increasing left ptosis developing upon sustained upward gaze in patient with myasthenia gravis (A through F). Note limited elevation of left eye, denoting superior rectus palsy (A). A initially, C after around 20 seconds, F after 1 minute.

• Cogan sign. Patient changes gaze from downward position (A) to primary position (B). Both lids are seen to overshoot in twitch (B) before gaining their initial ptotic position (D). In this case, Cogan sign is seen more obviously on right, whereas left lid is more ptotic.

• CT scan of chest and mediastinum showing thymoma in patient with myasthenia gravis.

• Repetitive nerve stimulation at frequency of 2 Hz showing increasing decrement in amplitude of compound muscle action potential up to fourth response (42% amplitude loss), after which it stabilizes.

• Single-fiber electromyography showing so-called jitter phenomenon (second action potential wave group).

• What is myasthenia gravis? Myasthenia gravis is an autoimmune disease that's categorized as a type II hypersensitivity that involves autoantibodies binding acetylcholine receptors on skeletal muscle cells. Courtesy of Osmosis.org (https://www.osmosis.org/).

• Motor end plate and innervation. Courtesy of Wikimedia Commons.

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Tables

• Distribution of weakness in a large cohort of patients with myasthenia gravis (n=609)

Distribution of weakness in a large cohort of patients with myasthenia gravis (n=609)

Distribution of WeaknessPercentage of PatientsLocalized ocular17%Ocular and generalized50%Ocular and bulbar13%Ocular and limb20%

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Author

Abbas A Jowkar, MBBS Clinical Assistant Professor, Department of Medicine, Western Michigan University, Home Stryker, MD, School of Medicine; Neurologist, Bronson Neuroscience Center--Kalamazoo

Abbas A Jowkar, MBBS is a member of the following medical societies: American Academy of Neurology, American Academy of Physician Assistants, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

William D Goldenberg, MD Assistant Professor, Department of Emergency Medicine, Uniformed Services University of the Health Sciences; Staff Emergency Physician, Naval Medical Center San Diego

William D Goldenberg, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Emergency Medicine Residents' Association, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Aashit K Shah, MD, FAAN, FANA Professor and Associate Chair of Neurology, Director, Comprehensive Epilepsy Program, Program Director, Clinical Neurophysiology Fellowship, Detroit Medical Center, Wayne State University School of Medicine

Aashit K Shah, MD, FAAN, FANA is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Neurological Association

Disclosure: Received research grant from: Lundebck pharma.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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