| Highlights: |
• Diagnosis often begins with antibody testing, while electrodiagnostic testing is useful in selected patients. • Pyridostigmine is given to patients with mild symptoms or as adjuvant therapy for those with more severe disease. • Corticosteroids and corticosteroid-sparing agents are indicated based on a variety of patient characteristics. • Thymectomy is primarily reserved for younger patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. |
| Introduction: |
Myasthenia gravis is a chronic autoimmune neuromuscular disorder that causes skeletal muscle weakness. Its pathophysiology involves a loss of acetylcholine receptor (AChR) function at the neuromuscular junction.
Certain skeletal muscle groups are more likely to be involved than others, but the pattern varies widely among patients and depends on the individual clinical course. Consequently, myasthenia gravis is generally classified as ocular (in which the weakness is limited to the extrinsic ocular muscles and the levator palpebrae superioris) or generalized (in which muscles beyond those of the ocular shape are involved, including those of the extremities, the bulbar muscle and the oropharyngeal region, and the respiratory muscles).
The following 12 frequently asked questions and answers are intended to provide up-to-date, high-yield, clinically relevant information about myasthenia gravis.
1- What populations are at risk?
First-degree relatives of people with myasthenia gravis are at increased risk not only for myasthenia gravis, but also for other autoimmune diseases. Thyroid disease (Hashimoto’s thyroiditis, Graves’ disease) is the most common, followed by rheumatoid arthritis.
The disease can appear at any age, but onset has a bimodal distribution, with the first peak in patients in their teens and 20s, and the second peak in patients in their 50s and 60s. The age of onset has progressively increased, along with the proportion of men, so the preponderance of women is increasingly less.
2- When should a clinician think about this diagnosis?
Think of myasthenia gravis when a patient has weakness and fatigue, especially of the eye muscles resulting in variable diplopia, ptosis, and weak eye closure. These are the central clinical features.
Muscle weakness fluctuates, classically worsening with sustained or repetitive physical activity, in the evening or during the night, and improving with rest. In arms and legs, weakness usually affects the proximal muscles more than the distal ones. In the mouth and neck, prominent bulbar weakness may be seen, including dysarthria, nasal speech, dysphagia, poor saliva control, difficulty chewing, and neck weakness.
It is important to note that patients generally do not have sensory or pain symptoms, bowel or bladder dysfunction, or changes in mental status or cognition. Additionally, deep tendon reflexes are usually intact. Table 1 lists common disorders in the differential diagnosis of myasthenia gravis and their distinguishing features.
| Disorder | Similarities with myasthenia gravis | Differences with myasthenia gravis |
| Lambert-Eaton syndrome | Weakness and fatigue | Less prominent ocular or oculobulbar characteristics . Areflexia or hyporeflexia. Autonomic characteristics (dry mouth, erectile dysfunction). Positive antibody against the P/Q voltage-gated calcium channel. High-frequency repetitive nerve stimulation testing shows an incremental response. |
| Botulism | Ocular findings (diplopia and ptosis), bulbar dysfunction, generalized weakness | Acute attack, possible history of food poisoning. Descending paralysis. Dilation of the pupil (mydriasis). Prominent autonomic dysfunction. Single-phase course. High-frequency repetitive nerve stimulation testing shows an incremental response. |
| Amyotrophic Lateral Sclerosis | Bulbar dysfunction and weakness | Slow progressive course. No ocular findings. Symptoms do not fluctuate. Findings of upper motor neuron dysfunction (eg, hyperreflexia, spasticity). Electromyography showing prominent active and chronic denervation or reinnervation, or both. |
| myopathy | Proximal extremity weakness | Relative absence of ocular findings. Symptoms do not fluctuate. Elevation of creatine kinase and presence of myositis-specific antibodies in cases of autoimmune or inflammatory myositis. The repetitive nerve stimulation test is normal, while the electromyography needle shows polyphasic motor unit potentials of short duration and low amplitude, with or without abnormal spontaneous activity. |
| Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy | Generalized weakness | Sensory symptoms such as pain and paresthesia. Symptoms do not fluctuate. Hyporeflexia or areflexia The cerebrospinal fluid has elevated proteins, non-significant pleocytosis. Nerve conduction studies reveal findings consistent with demyelination. |
| Thyroid eye disease | Diplopia | Ptosis is rare. Symptoms do not fluctuate. Other ocular findings such as edema, redness, conjunctival injection and exophthalmos. MRI showing enlargement of extraocular tissue. |
| Oculopharyngeal muscular dystrophy | Ptosis, diplopia, dysphagia | Slowly progressive course. Absence of symptomatic fluctuation. Relative absence of prominent weakness in the extremities. Elevation of creatine kinase. Mutations in the PABPN1 gene; mostly autosomal dominant inheritance pattern. |
TABLE 1. Key features that distinguish myasthenia gravis from other common diagnoses.
3- What tests should be requested?
Antibody tests are ordered first, followed in some patients by electrodiagnosis and other tests.
| Antibody tests |
First-line diagnostic tests are usually serological.
Anti-AChR antibody is highly specific (>90%) and very sensitive (up to about 85%) in those with generalized myasthenia gravis.
Anti-MuSK antibodies. In patients with myasthenia gravis who are seronegative for anti-AChR antibodies, up to 37% possess anti-MuSK antibodies. However, the sensitivity of the anti-AChR antibody is lower, around 50%, in those who have purely ocular myasthenia gravis.
Antilipoprotein-related protein 4 (LRP4) antibody is found in the remaining 3% to 50% of patients with generalized myasthenia gravis who are seronegative for anti-AChR and anti-MuSK antibodies.
Anti-striated muscle antibodies. They are much less specific for myasthenia gravis and are seen in about 30% of patients. They are most useful as a marker of thymoma, especially in people who are not elderly. Therefore, myasthenia gravis cannot be reliably diagnosed on the basis of positive antistriated muscle antibody alone.
| Electrodiagnostic tests |
Two electrodiagnostic tests (repetitive nerve stimulation and single-fiber electromyography) provide objective evidence of impaired neuromuscular junction transmission and are useful in diagnosing myasthenia gravis. They do not need to be performed in all patients, but they provide supportive diagnostic evidence, especially in those who are seronegative and when rapid confirmation is needed.
Repetitive nerve stimulation uses repeated "trains" of nerve stimulation to generate electrical muscle responses. The sensitivity and specificity of repetitive nerve stimulation depend on the nerve and muscle combinations examined, the severity of myasthenia gravis, and the cutoff values used for a decremental response. Its overall diagnostic sensitivity ranges from 30% to 80% for generalized disease, with lower sensitivity in milder disease or when examining distal muscles. In ocular myasthenia gravis, its sensitivity is only 10% to 30%.
Single-fiber electromyography uses small needle electrodes to measure the variability of potentials of a single muscle fiber, a reflection of neuromuscular junction transmission. It is more sensitive than repetitive nerve stimulation (62% to 99% for ocular myasthenia gravis and 75% to 98% for generalized myasthenia gravis). Therefore, a normal result in a clinically weak muscle basically rules out myasthenia gravis. Its reported specificity ranges from 66% to 98% for ocular myasthenia gravis and up to 98% for generalized myasthenia gravis.
| Other tests |
Testing for common comorbid conditions, for example, chest CT or MRI for thymic abnormalities, is also useful in patients with suspected myasthenia gravis. One should be alert to clinical features that may suggest comorbid autoimmune conditions that would require additional serologic testing, such as thyroid-stimulating immunoglobulin, antithyroid peroxidase, antithyroglobulin, or rheumatoid factor.
4 - How does the natural course affect treatment?
Myasthenia gravis tends to progress, especially in the early years, so we recommend treating it aggressively with immunosuppressants at first and then gradually tapering off.
Approximately half of patients can achieve remission or minimal symptoms with low-dose immunotherapy. However, doctors should be careful about stopping immunotherapy altogether, as only about 10% of patients can achieve complete stable remission without this intervention.
5- What instructions should patients receive?
After the disease is diagnosed, patients should be informed of its typical course and largely benign prognosis. Points to discuss include:
• Specific symptoms of the disease, including warning signs.
• The importance of the progressive trend in the severity and frequency of symptoms, rather than their transient worsening.
• Common exacerbation triggers, such as heat, infection, surgery, pregnancy, emotional disorders, and certain medications.
• The intended medication regimen, particularly immunotherapy and potential side effects, to ensure compliance.
Many myasthenia gravis patients are cautious about physical exertion, fearing that exercise will worsen their symptoms. However, most can tolerate and benefit from some form of activity. Patients with mild disease can participate in resistance and aerobic training. For those with severe symptoms, stretching exercises such as tai chi, yoga, and balance training are often most appropriate. Simply being more active and reducing sedentary time overall is important.
6- What medications are best to avoid?
Because some medications can trigger or worsen myasthenic symptoms, all patients, especially those with significant weakness, should be observed for increased weakness each time a new medication is started. In principle, if a patient’s condition deteriorates when given a new medication, the drug should be withdrawn.
Drugs that are clearly contraindicated in myasthenia gravis include telithromycin, intravenous magnesium, botulinum toxin, and penicillamine.
7- How should pyridostigmine be used?
Pyridostigmine, the most commonly used acetylcholinesterase inhibitor for the symptomatic treatment of myasthenia gravis, is usually used alone in mild cases or in combination with immunosuppressants in more severe cases. However, its effectiveness may be minimal in patients with severe or long-term disease.
The dose of pyridostigmine can be titrated up to 240 to 360 mg daily, but side effects are more common at higher doses and overdose can cause increased weakness. In practice, if a patient needs more than 240 mg per day, it is time to move to immunotherapy. Once myasthenia gravis is controlled with immunotherapy, most patients do not need pyridostigmine.
The most common side effects are gastrointestinal, for example abdominal cramps, loose stools and flatulence. Bradycardia, bronchospasm, increased sweating, excessive tearing, muscle spasms and cramps are other effects to consider. To control these manifestations, oral glycopyrrolate or hyoscyamine can be taken at the same time as pyridostigmine doses.
8- When should corticosteroids be used?
According to consensus guidelines, corticosteroids or nonsteroidal immunosuppressive medications should be used in all patients with myasthenia gravis who have not met their treatment goals after an adequate trial of pyridostigmine.
Outpatients with mild to moderate symptoms may be started on prednisone 20 mg daily and gradually increase the daily dose by 10 mg every 1 to 2 weeks to approximately 60 mg daily, titrating the dose based on clinical response. Once significant improvement is seen after starting corticosteroid therapy, there is no need to wait for maximum improvement to occur before beginning to taper these medications.
9- When should other immunosuppressants be used?
Non-steroidal immunosuppressive therapies should be considered in the following situations:
• Significant lack of response to prednisone.
• More than 1 relapse after prednisone taper.
• Inability to reduce prednisone to a minimum acceptable dose.
• Contraindications to prednisone, such as morbid obesity, brittle diabetes mellitus, peptic ulcer, high risk of osteoporosis, or significant side effects of prednisone.
Non-steroidal immunosuppressive drugs such as azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus and rituximab have been widely used in myasthenia gravis to avoid the use of corticosteroids. Newer agents recently approved, such as eculizumab, ravulizumab, and efgartigimod, could also serve this purpose.
Sometimes nonsteroidal immunosuppressive therapy may also be given as an initial immunosuppressant for patients with mild disease who are satisfied with a slow course of improvement. In patients with significant weakness who have contraindications to corticosteroids, intravenous immunoglobulin, efgartigimod, or plasma exchange may be used initially to accelerate clinical improvement while allowing time for an alternative nonsteroidal immunosuppressive therapy to produce its therapeutic effect.
10- What is the role of the thymus? Who should have a thymectomy?
The thymus gland is essential in the development of central tolerance and T cell differentiation and therefore is likely to play an important role in the immunopathogenesis of myasthenia gravis.
In approximately 10% of patients, myasthenia gravis is a paraneoplastic manifestation of an underlying thymic neoplasm (usually thymoma, rarely thymic carcinoma). However, thymic lymphoid hyperplasia is seen in up to 65% of patients with myasthenia gravis. Lymphoid hyperplasia consists of numerous lymphocytes, macrophages, and plasma cells, reflecting autoimmunity underlying the severe disease that often begins in the thymus gland.
Thymectomy is indicated in all patients with thymic neoplasms. Otherwise, candidacy for thymectomy depends on several factors, including AChR antibody status, severity, duration of disease, and age of the patient.
Thymectomy in similar adult patients aged 50 years or younger is likely to improve clinical outcomes and allow for minimal pharmacotherapy, including the use and dosing of immunosuppressants.
The benefit of thymectomy in patients aged 51 to 65 years is more equivocal, and thymectomy is generally avoided in patients older than 65 years as the risk-benefit ratio is less favorable.
11- How can myasthenic crisis be prevented, recognized and treated?
A myasthenic crisis is a life-threatening worsening of respiratory or bulbar muscle weakness related to myasthenia gravis that is severe enough to require intubation, mechanical ventilation, or both.
The key measures to prevent myasthenic crisis are constant monitoring of the disease (including adherence to the medication regimen and careful withdrawal of immunosuppressants) and avoidance of triggering or precipitating factors.
| Recognize myasthenic crisis |
Most patients with myasthenic crisis do not present solely with respiratory failure. Rather, neuromuscular respiratory weakness usually occurs in the setting of worsening generalized or bulbar weakness. Therefore, clinical features indicating significant worsening of deficits in these areas may provide warning signs.
Of note, classic features of respiratory distress, such as the use of accessory respiratory muscles, may be attenuated during a crisis and should not be overly relied upon. Orthopnea is a more specific feature than dyspnea, indicating significant neuromuscular respiratory weakness (especially of the diaphragm). Significant weakness in the neck flexors and shoulder external rotators also typically correlates with respiratory muscle weakness.
A screening test that can be performed at the bedside or over the phone is the single breath count test. The patient is asked to take a deep breath and, on the subsequent exhalation, count from 1 onwards at a routine speaking rate (about 2 counts per second) until they need to take another breath. The inability to count to 20 on a single breath indicates significant respiratory weakness.
However, more formal spirometric measurements are ideal and the “20-30-40 rule” should be taken into account. This means that patients must be admitted or transferred to the intensive care unit for respiratory and airway management.
respiratory capacity if the vital capacity falls below 20 ml/kg, if the maximum inspiratory pressure (also known as negative inspiratory force) becomes less negative than -30 cm H2O, or if the maximum expiratory pressure falls below 40 cm H2O.
| Management of myasthenic crisis |
Management of myasthenic crisis involves optimizing medical management of intercurrent medical illnesses (including infections), eliminating any culprit medications, and administering aggressive immunotherapies aimed at rapidly improving neuromuscular junction transmission.
The main therapies are plasmapheresis (also known as plasma exchange) and intravenous immunoglobulin, but usually not both. Both plasmapheresis and intravenous immunoglobulin can begin to produce clinical improvements within several days. However, since its effectiveness may begin to wane within a few weeks, a concomitant increase in background immunotherapy (e.g., corticosteroids) is needed. Anticholinesterase medications are usually discontinued during a myasthenic crisis, especially if the patient must be intubated, as discontinuation will reduce oropharyngeal secretions and the risk of aspiration.
12- What new treatments are on the horizon?
The complement inhibitors eculizumab and ravulizumab and the neonatal Fc-receptor blocker efgartigimod have recently been approved by the US Food and Drug Administration for the treatment of AChR antibody-positive myasthenia gravis, and many are being studied. newer treatments with diverse mechanisms of action.
Newer immunotherapies are generally more selective in their immunological targets than older ones. Consequently, they have the advantage of causing fewer adverse effects, including life-threatening infections. However, they are very expensive and a major drawback is their "financial toxicity." For many patients, older broad-spectrum immunotherapies will remain a key component of treatment due to lower cost, ease of use, and potential to induce remission. However, the pace of major therapeutic innovations in the field is unprecedented and the future of myasthenia gravis treatment is promising.
