Myasthenia gravis can be difficult to diagnose and you may need several tests. First a GP will ask about your medical history and symptoms. Alternatively, an optician may have noticed problems such as double vision or eyelid droop. If they think you could have a problem with your brain or nerves, they may refer you to a specialist for tests in hospital to help diagnose myasthenia gravis and rule out other conditions with similar symptoms. The main test for myasthenia gravis is a blood test to look for a type of antibody (produced by the immune system) that stops signals being sent between the nerves and muscles. A high level of these antibodies usually means you have myasthenia gravis. But not everyone with the condition will have a high level of antibodies, particularly if it's only affecting the eye muscles (ocular myasthenia). The blood test may be repeated at a later date if the result is normal but your symptoms continue or get worse. If your blood test result is normal but the doctor still thinks you could have myasthenia gravis, they may suggest an electrical test of your nerves and muscles. These tests, known as electromyography, involve inserting very small needles into your muscles to measure the electrical activity in them. The needles are typically inserted around the eyes, in the forehead or possibly in the arms. The electrical recordings can show whether the signals sent from the nerves to the muscles are being disrupted, which may be a sign of myasthenia gravis. You may also have a CT scan or MRI scan of your chest to check if your thymus gland is bigger than usual or has grown abnormally (a thymoma). The thymus gland is a small gland in the chest that forms part of the immune system. Problems with the gland are closely associated with myasthenia gravis. Sometimes an MRI brain scan may also be carried out to check that your symptoms are not being caused by a problem in your brain. If it's still not clear what's causing your symptoms, the doctor may recommend a test called an edrophonium test. It involves having an injection of a medicine called edrophonium chloride. If you have a sudden but temporary improvement in muscle strength after the injection, it's likely you have myasthenia gravis. But this test is rarely done these days because there's a risk it could cause potentially serious side effects, such as a slow heartbeat and breathing problems. It's only done if absolutely necessary and in a hospital setting where treatment for any side effects is readily available.
Page last reviewed: 17 January 2020
Medications are used in myasthenia gravis (MG) to manage symptoms and control immune system activity. 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. 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] 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] 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:
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 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:
Dosage regimen 2:
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. |
A health care provider prescribed a diagnostic workup for a client who may have myasthenia gravis
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