Severe Myasthenia Gravis: Key Aspects of Etiology, Diagnosis and Treatment

Dr. Agnė Petrėnaitė

Introduction

Myasthenia gravis is an autoimmune disease in which autoantibodies bind to acetylcholine receptors or functionally related molecules on the postsynaptic membrane of the neuromuscular junction. These antibodies cause skeletal muscle weakness, which is the hallmark of the disease (1–3). Muscle weakness may be generalized or localized, with proximal muscles more severely affected than distal muscles, and almost always involves the ocular muscles, leading to diplopia and ptosis (2). Skeletal muscles are typically affected symmetrically, except for the ocular muscles, which are usually affected asymmetrically, resulting in weakness of several different eye muscles. Muscle weakness increases with exercise and sustained physical effort, leading to muscle fatigue. The severity of this symptom varies throughout the day, with normal muscle strength usually experienced in the morning. The degree of muscle weakness may also vary from day to day.

Myasthenia gravis is one of the most common disorders affecting the neuromuscular junction. The incidence of the disease is 8–10 cases per 1 million population per year, with a prevalence of 150–250 cases per 1 million population (4). Lambert-Eaton myasthenic syndrome and neuromyotonia are also rare disorders affecting the skeletal muscle system and developing as a result of autoantibodies acting on receptors at the neuromuscular junction (5). Congenital myasthenic syndromes and toxin-induced conditions, such as botulism, can also affect the neuromuscular junction and cause muscle weakness.

This article reviews the latest diagnostic tests for myasthenia gravis, updated treatment algorithms, and personalized treatment based on biomarkers. The diagnosis of myasthenia gravis is confirmed by a combination of characteristic symptoms and signs together with positive specific autoantibody tests (6). Antibodies against acetylcholine receptors, muscle-specific kinase, and lipoprotein receptor-related protein 4 (LRP4) are specific and sensitive markers of myasthenia gravis. Based on the evaluation of these markers and pathogenic variations, myasthenic syndromes are classified into subgroups. In this disease, the pathogenic potential of induced antibodies depends on the receptor epitope, binding configuration, IgG subclass, antibody concentration, and antibody accessibility to the motor endplate of the muscle fiber (7).

When antibody testing is negative, the diagnosis of myasthenia gravis is confirmed by neurophysiological studies and evaluated based on the response to treatment (8). The diagnosis is supported by a positive ice test, defined as the disappearance of ptosis after ice is applied to the drooping eyelid for 2 minutes. Thymus imaging studies should be evaluated during the preoperative period (9). The main value of these studies is the detection of thymoma. Imaging studies are neither specific nor sensitive for detecting thymic hyperplasia. Antibody testing allows more accurate assessment of thymus gland pathology (10).

Symptomatic and immune system-targeted supportive therapy has a very good effect; therefore, the prognosis of the disease in terms of muscle strength, functional ability, quality of life, and survival is good (11, 12). The goal of treatment should be complete or nearly complete remission—for example, as long as the patient is receiving medication, there should be no symptoms or signs of myasthenia.

Clinical and Pathogenic Manifestations of the Disease

Variants of myasthenia gravis are evaluated by taking into account autoimmune mechanisms, mechanisms of antibody action, target molecules in skeletal muscle, thymus gland status, genetic characteristics, response to treatment, and disease phenotype. Patients with myasthenia gravis must be classified into subgroups based on distinct disease characteristics. Each patient must be assigned to only one group (Table 1). Classifying individual patients on the basis of completely discordant clinical and non-clinical features is a real challenge for neurologists. Subgroup classification determines the choice of treatment and the prognosis of the disease.

Fifteen percent of all patients with myasthenia gravis have symptoms related to ocular muscle dysfunction. Only half of patients with ocular myasthenia have detectable ocular muscle antibodies (13). The most common initial symptoms of this form of the disease are ptosis and diplopia, but ocular muscle dysfunction persists in only a minority of patients. Ninety percent of patients with ocular myasthenia that persists for 2 years after symptom onset continue to have localized weakness of the ocular muscles and never develop generalized myasthenia. Myasthenia gravis characterized by muscle-specific kinase antibodies never presents as ocular myasthenia, whereas acetylcholine receptor and LRP4 antibodies can be detected in ocular myasthenia (2). Detection of muscle antibodies increases the risk of developing generalized myasthenia.

Titin antibodies, which are primarily found in patients with thymoma and are characteristic of late-onset myasthenia gravis, together with acetylcholine receptor antibodies, are markers of a severe disease course (10, 20). Ryanodine receptor antibodies, detected in 70% of patients with thymoma and severe myasthenia gravis and in 14% of those with late-onset myasthenia gravis (10), are markers of a more severe disease course but do not have disease-modifying effects. Kv1.4 antibodies are detected in 10–20% of patients with acetylcholine receptor antibodies (21, 22). The phenotype of early- and late-onset severe myasthenia gravis does not differ.

Myasthenia gravis with muscle-specific kinase antibodies occurs in 1 to 10 cases of the disease (23). This form of myasthenia is more common in the Mediterranean region of Europe than in Northern Europe. It is also more prevalent in northern regions of East Asia than in southern regions (24). Genetic predisposition rather than environmental factors is believed to be the main reason for regional differences in the prevalence of this form of the disease. Patients with muscle-specific kinase antibody-positive myasthenia gravis experience more pronounced muscle weakness, sometimes accompanied by muscle atrophy, as well as more prominent facial muscle weakness and bulbar symptoms. Weakness of the limbs and ocular muscles occurs less frequently, and fluctuations in muscle strength throughout the day and from day to day are less pronounced than in myasthenia gravis with acetylcholine receptor antibodies.

LRP4 antibodies are very rare and are found in 1–3% of patients with myasthenia gravis (25, 26). These patients experience only mild to moderate disease symptoms. Neither LRP4 antibody-positive myasthenia gravis nor muscle-specific kinase antibody-positive myasthenia gravis is associated with thymus pathology. Only isolated cases of patients with muscle-specific kinase antibodies or LRP4 antibodies in combination with acetylcholine receptor antibodies have been described (1, 6). Such patients should be classified according to muscle-specific kinase and LRP4 antibodies.

Some patients with myasthenia gravis do not have detectable antibodies against neuromuscular junction proteins. It has been found that 10–15% of patients are seronegative (27). In patients with seronegative myasthenia gravis, the diagnosis should be reassessed and antibody testing repeated after 6–12 months.

A small percentage of patients are diagnosed with agrin antibodies in the absence of other antibodies typical of the disease (28). These antibodies are specific to myasthenia gravis. Agrin acts on the postsynaptic membrane of the neuromuscular junction and is involved in neuromuscular transmission, but the pathogenic effect of agrin antibodies has not been established. Collagen Q and cortactin antibodies have also been detected in some patients (1, 29). The specificity of these antibodies for myasthenia gravis has not been proven.

Myasthenia Gravis Is Often Associated With Comorbidities

Comorbidities are common in patients with myasthenia gravis. About 15% of patients are diagnosed with another autoimmune disease (19, 30), most commonly those with early-onset myasthenia gravis and thymic hyperplasia. Thyroiditis is the most common comorbidity, followed by systemic lupus erythematosus and rheumatoid arthritis. Thyroid dysfunction is particularly common in patients with ocular myasthenia.

One-third of patients with thymoma develop myasthenia gravis. Although a strong and unique association between thymoma and myasthenia gravis has been established, thymoma is also associated with an increased risk of certain other autoimmune diseases. Blood cytopenias, hypogammaglobulinemia, polymyositis, POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M component, Skin changes), neuromyotonia, and autoimmune encephalitis are more common in patients with thymoma, although these disorders are rare in patients with myasthenia gravis.

The prevalence of optic neuromyelitis with aquaporin-4 antibodies is 40 cases per 1 million inhabitants. This disease has a specific association with myasthenia gravis. Optic neuromyelitis can develop either before the onset of myasthenia or after the diagnosis of myasthenia gravis. Amyotrophic lateral sclerosis is more common in patients with myasthenia gravis than in the general population. Overall, autoimmune disease is a risk factor for the development of amyotrophic lateral sclerosis, but the association with myasthenia gravis is particularly strong.

Myocarditis is rare, but the risk of developing this condition is increased in patients with myasthenia gravis. However, heart disease and heart failure associated with myasthenia gravis are very rare. Clinical studies have not found an association between myasthenia gravis and increased mortality due to heart disease. Functional imaging studies have shown mild subclinical dysfunction. Myocarditis is associated with myasthenia gravis through Kv1.4 muscle receptors. Antibodies against acetylcholine receptors, muscle-specific kinase, and LRP4 do not cross-react with cardiac muscle. In contrast, antibodies against Kv1.4, titin, and ryanodine receptors can affect cardiac muscle.

Most patients with myasthenia gravis do not have an increased risk of developing cancer. An exception is the group of patients with thymoma. An increased risk of cancer has been identified in patients with thymoma, regardless of whether they have myasthenia gravis. Lymphomas have been reported more frequently in patients with myasthenia gravis. In a clinical trial conducted in Denmark, the use of azathioprine for immunosuppressive treatment of myasthenia gravis did not affect the risk of developing cancer. However, in a similar clinical trial conducted in the Netherlands, the use of azathioprine to treat inflammatory bowel disease slightly increased the risk of cancer. An increased risk of lip cancer was also found with high doses of azathioprine.

Treatment of myasthenia gravis can increase the risk of developing comorbidities. When prednisolone is used, osteoporosis prophylaxis is required, and patients must be monitored for weight gain, increased blood glucose levels, and hypertension. Anticholinergic drugs used for symptomatic treatment have transient effects, and their effects on the autonomic nervous system may limit the dose that can be administered. The risk of comorbidities is a significant challenge in the treatment of patients with myasthenia gravis.

Pharmacological Treatment of Severe Myasthenia Gravis

Symptomatic Treatment Drugs

All subgroups of severe myasthenia gravis respond to acetylcholinesterase inhibition. Pyridostigmine is the first-line drug for the treatment of all forms of severe myasthenia gravis. Neostigmine and ambenonium chloride are also acetylcholinesterase inhibitors, but they are less effective than pyridostigmine in many patients. By increasing acetylcholine release from the presynaptic membrane, 3,4-diaminopyridine or ephedrine usually produces a mild beneficial effect, although this is often insufficient in clinical practice.

Severe myasthenia gravis associated with muscle-specific kinase antibodies responds less well to symptomatic treatment than other myasthenia gravis subgroups. Juvenile myasthenia gravis shows an excellent response to pyridostigmine treatment. The pyridostigmine dose is selected by assessing its effect on muscle strength and dose-dependent adverse effects, which usually involve gastrointestinal function. Typical adverse drug effects include diarrhea, abdominal pain, spasms, bloating, nausea, increased salivation, urinary retention, and increased sweating. The dose must be individualized for each patient and may vary from day to day. The effect of pyridostigmine remains unchanged for many years. In patients with mild disease who achieve complete remission with symptomatic treatment, no additional drugs are recommended.

Immunosuppressive Treatment

For most patients with myasthenia gravis, immunosuppressive treatment is necessary to fully or partially restore physical function and quality of life. Immunosuppressive drugs are prescribed to all patients in whom symptomatic treatment alone does not provide a sufficient effect. First-line immunosuppressive therapy consists of prednisolone combined with azathioprine (11, 12, 46).

Varying the prednisolone dose on different days often reduces the adverse effects of glucocorticoids, although evidence from clinical trials is limited (2). To avoid exacerbation of the disease, the usual dose is increased gradually, from 60 mg to 80 mg on different days. Once control of disease symptoms has been achieved, together with additional symptomatic treatment, the glucocorticoid dose should be slowly reduced to the lowest effective maintenance dose, which usually ranges from 10 mg to 40 mg on different days.

The main goal of myasthenia gravis treatment is to prevent generalization of the disease. Retrospective and observational clinical studies have shown that prednisolone monotherapy reduces this risk. Treatment with low doses of glucocorticoids is recommended by many experts for patients with ocular myasthenia gravis who have persistent symptoms and risk factors, such as detectable acetylcholine receptor antibodies, an enlarged thymus gland (47), or neurophysiological findings indicating involvement of muscles other than the ocular muscles (13, 48, 49).

For most patients treated with prednisolone, azathioprine is added because this combination results in better functional outcomes and fewer adverse effects than prednisolone monotherapy (50). If glucocorticoids are contraindicated or the patient refuses to take them, azathioprine monotherapy may be prescribed. The recommended dose is 2–3 mg per kilogram of body weight.

Azathioprine inhibits purine synthesis, thereby suppressing cell proliferation, particularly that of B and T cells. Whenever possible, thiopurine methyltransferase activity should be assessed before azathioprine treatment is initiated, because low activity of this enzyme increases the risk of adverse effects associated with azathioprine (51, 52). This enzyme is inactive in only 0.3% of the total population, while low activity is detected in 10% of the population. Azathioprine is not recommended for patients with no thiopurine methyltransferase activity, while patients with low enzyme activity should receive a lower dose of azathioprine.

The effect of azathioprine on muscle weakness often becomes apparent only several months after treatment is initiated; therefore, during this period, patients may require another immunosuppressive medication. Long-term treatment with azathioprine is safe for patients of all age groups (43).

Many guidelines recommend mycophenolate mofetil for the treatment of mild or moderate myasthenia gravis, although the benefit of prescribing this medication was not demonstrated in two short-term prospective studies (53–55). This drug blocks purine synthesis and inhibits the proliferation of B and T cells. Methotrexate, cyclosporine, and tacrolimus are second-line immunosuppressive drugs (56–58). The effects of these drugs are similar to those of azathioprine.

Rituximab is a potentially promising drug for the treatment of myasthenia gravis (59). This monoclonal antibody specifically binds to the CD20 surface antigen on B lymphocytes, making it effective in the treatment of antibody-mediated diseases such as severe myasthenia gravis. Rituximab also affects T cells. An expert group that approved the latest myasthenia gravis guidelines was unable to reach a consensus regarding the role of rituximab in the treatment of this disease (11).

Small clinical studies have shown that two-thirds of patients with severe myasthenia gravis in whom prednisolone and azathioprine were insufficient experienced significant improvement with rituximab treatment (60). The recommended induction dose has not been established. Treatment should be repeated after several months if symptoms recur.

Monoclonal antibodies have also been found to have a beneficial effect in the treatment of other autoimmune diseases. They affect the functions of B and T cells, complement, and other immune-active components (61, 62).

Patients who develop myasthenia gravis at an older age or whose disease is associated with thymoma or muscle-specific kinase antibodies are more likely to develop the most severe form of the disease. They usually require long-term immunosuppressive treatment, although some patients with late-onset myasthenia gravis have a milder disease course similar to that of early-onset myasthenia gravis.

The detection of antibodies against muscle-specific kinase, titin, ryanodine receptors, or Kv1.4 is an indication for immunosuppressive treatment. Myasthenia gravis characterized by antibodies against muscle-specific kinase responds better to rituximab treatment.

Thymectomy – Another Way to Treat Myasthenia Gravis

For patients with myasthenia gravis who are diagnosed with thymoma, thymectomy—the surgical removal of the thymus gland—should be performed. Positive outcomes have been observed in this subgroup following thymectomy. The benefits of total thymectomy have also been demonstrated in patients with early-onset myasthenia gravis in whom thymoma was not detected. The main pathogenic mechanism involving the thymus gland in myasthenia gravis is the production of acetylcholine receptor antibodies.

Many clinical studies have compared outcomes in patients who underwent thymectomy with those who did not undergo surgery. Almost all studies demonstrated better outcomes in patients who underwent thymectomy. An international randomized controlled trial involving 126 participants with early- or late-onset myasthenia gravis confirmed the benefits of early thymectomy in patients with generalized myasthenia, a disease duration of no more than 3–5 years, an age not exceeding 60–65 years, and symptoms that were not adequately controlled with cholinesterase inhibitors. Patients who underwent thymectomy experienced reductions in disease symptoms, the need for immunosuppressive treatment, and disease relapses during 3 years of follow-up. The differences were clinically significant. It is recommended that all thymic tissue be removed, including the portion of the gland located within the mediastinal fat.

Guidelines recommend early thymectomy for patients with early-onset myasthenia gravis. These patients often have thymic hyperplasia. Thymectomy should also be considered in children with myasthenia. Most patients with late-onset myasthenia have an atrophic thymus. However, thymic hyperplasia may develop in younger patients within the late-onset myasthenia group.

Thymectomy should be considered in patients with generalized myasthenia gravis who have acetylcholine receptor antibodies and develop symptoms between the ages of 50 and 65 years, particularly when disease markers resemble those of early-onset myasthenia. Current scientific evidence does not support thymectomy in patients with myasthenia gravis associated with muscle-specific kinase or LRP4 antibodies.

Thymectomy is not recommended for the treatment of ocular myasthenia because there is no evidence that surgical intervention influences the prevention of disease generalization or remission. However, thymectomy in ocular myasthenia should be considered when medical treatment is ineffective, the patient has acetylcholine receptor antibodies, and neurophysiological studies indicate a risk of developing generalized disease.

Thymectomy is also not recommended for patients with negative results on all muscle antibody tests. However, some of these seronegative patients have acetylcholine receptor antibodies that are not detected by routine testing. Therefore, in patients with negative muscle antibody tests but signs of generalized disease resembling early-onset disease markers, thymectomy should be considered if the disease is resistant to immunosuppressive therapy.

Severe Myasthenic Crisis: Treatment Specifics

Patients with progressive muscle weakness requiring intubation or non-invasive ventilation should be treated with rapidly acting immunosuppressive therapies. Severe myasthenic crisis, characterized by rapid deterioration of the patient's condition and progressive muscle weakness, requires similar treatment.

Increasing generalized weakness, respiratory and cardiac insufficiency, severe infection, and concomitant pathologies require decisions regarding the treatment of myasthenic crisis in the Intensive Care Unit. Monitoring vital functions and blood gas parameters has limited value because the patient's condition may deteriorate rapidly and unexpectedly, resulting in myasthenic exhaustion.

Intravenous immunoglobulins and plasmapheresis are effective treatments for severe myasthenia. The choice between these treatment methods depends on individual patient factors, clinical experience, availability, and established practice. Intravenous immunoglobulins are generally more favorable for patients because of milder adverse effects. In some patients, only one of these treatment methods may be effective.

Treatment with these methods should be combined with long-term immunosuppressive therapy. In some patients, the treatment effect may be delayed. Immunosuppressive therapy should be combined with intensive therapy until disease remission is achieved. Myasthenic crisis with respiratory failure is currently a rare condition, and mortality from myasthenic crisis is low.

Maintenance Treatment of Myasthenia and Patient Monitoring

Low- or moderate-intensity physical activity and systematic training programs tailored to the patient's condition are recommended for patients with myasthenia gravis. Overweight should be avoided. Visual aids may be used for ocular symptoms.

Muscle relaxants, penicillamine, and certain antibiotics, including fluoroquinolones, macrolides, and aminoglycosides, should not be prescribed to patients with myasthenia gravis whenever possible. Statins may exacerbate myasthenia, but myasthenia gravis is not a contraindication to statin treatment when statins are necessary. The indications for prescribing statins to patients with myasthenia are the same as those for patients without the disease. If statins are indicated, they may be prescribed, although caution is required because of the possibility of worsening muscle weakness.

Respiratory failure caused by weakness of the diaphragm and intercostal muscles represents the greatest danger. Particular attention should therefore be paid to respiratory function in patients with myasthenia gravis during any surgical intervention, including thymectomy. Optimal treatment of all comorbidities is an important component of myasthenia gravis management. This represents a significant challenge in elderly patients with comorbidities.

Oral administration of pyridostigmine and prednisolone is safe during pregnancy. Recent literature indicates that treatment with azathioprine and cyclosporine is also safe for pregnant women. However, mycophenolate mofetil and methotrexate are contraindicated because of the risk of teratogenic effects. Women are advised to avoid pregnancy for 1 year after discontinuing rituximab treatment.

Intravenous immunoglobulins and plasmapheresis may be administered if the patient's condition worsens during pregnancy. Breastfeeding should be encouraged. Transient neonatal myasthenia occurs in 15% of newborns because of the transfer of IgG antibodies against acetylcholine, muscle-specific kinase, and LRP4 receptors through the placenta.

Summary

Myasthenia gravis is an autoimmune disease characterized by the binding of autoantibodies to acetylcholine receptors on the postsynaptic membrane of the neuromuscular junction, leading to skeletal muscle weakness. All patients with myasthenia gravis should be classified into subgroups according to different disease manifestations, as these determine the choice of treatment strategy.

Pyridostigmine is the first-choice drug for symptomatic treatment, while prednisolone combined with azathioprine is used for immunosuppressive therapy. Patients with myasthenia gravis who are diagnosed with thymoma should undergo thymectomy. Symptomatic, immunosuppressive, surgical, and supportive treatments have a very good effect; therefore, the prognosis of the disease in terms of muscle strength, functional ability, quality of life, and survival is good.

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References in the editorial office