Myasthenia gravis (MG)
Myasthenia gravis (MG; from Greek: myos = muscle, asthenos = weakness, and Latin: gravis = severe) is an autoimmune disease of the neuromuscular junction (NMJ), and is considered a classic example of an antibody-mediated autoimmune disease. MG is a rare disorder, with an estimated prevalence of 70–163 per million for acetylcholine receptor (AChR) MG, and around 1.9–2.9 per million for muscle specific kinase (MuSK) MG. Women are more often affected than men, with a female to male ratio of 3:1 for AChR MG and a ratio of 9:1 for MuSK MG.
The role of the thymus in MG
The thymus is essential for T-cell differentiation and for the establishment of central tolerance. Interactions between thymicstromal cells expressing self-antigens and developing thymocytes lead to the elimination of auto reactive T cells. The self-tolerant Tcells continue their differentiation before being exported to theperiphery. Thymic stromal cells include epithelial cells, mesenchymal cells, and a few myoid cells.
Under physiological conditions, most thymic cells are thymocytes and stromal cells. The number of B cells is very small. In the majority of MG patients (i.e., in AChR-MG patients), the thymus exhibits structural and functional changes that are characterized by the presence of a tumor (i.e., thymoma) or by the development of germinal centers (GCs) containing a large number of B cells (i.e. Follicular hyperplasia). In EOMG, follicular hyperplasia is very common, while in the LOMG, thymomas are frequently observed. These morphological changes of the thymus are primarily associated with the AChR-MG.
The condition is caused by an abnormality of the body’s immune system whereby the body develops antibodies which impair the communication between nerves and muscles. Normally, the chemical messenger or neurotransmitter, called acetylcholine, is released from nerves and binds to specific receptors on muscle cells in order to produce a muscle movement.
In myasthenia gravis, antibodies target and block these receptors, resulting in muscle weakness and fatigue. It is not known what causes these antibodies to be produced but genetic factors and family history are thought to be important. Myasthenia gravis is known as an autoimmune disease and is associated with other autoimmune diseases where genetic factors are important, such as rheumatoid arthritis and type 1 diabetes.
Signs and symptoms
Individuals with myasthenia gravis suffer from muscle weakness and fatigue, which typically worsens with repeated muscle use and improves with rest. These symptoms usually progress over a number of years. Most people experience eye symptoms such as drooping eyelids or double vision due to weakness of the muscles surrounding the eyes.
Other signs and symptoms may include difficulties with walking, arm movements, coordination and balance due to leg and arm muscle weakness. When muscles of the face and throat are affected, individuals may have difficulties speaking, chewing and swallowing as well as limited facial expressions.
Factors which may trigger or worsen exacerbations of the disease include bright sunlight, extreme heat, emotional stress, surgery, other illnesses and some medications, such as beta blockers. In rare cases, severe shortness of breath may occur due to weakness of the muscles of breathing, which is an emergency situation requiring mechanical assistance with breathing.
Acetylcholine receptor MG is an autoimmune disorder caused by the production of antibodies directed against the nicotinic acetylcholine receptor (AChR). Roughly 80% to 90% of patients with MG will have measurable antibodies to the AChR in their serum. Overall antibody testing for AChR is fairly specific, with false-positive antibodies being extremely rare from a reliable laboratory. Thymoma is present in about 10% of patients with AChR-positive MG (and most of them have thymic hyperplasia). Therefore, patients positive for AChR antibodies must be screened with a computed tomography (CT) or MRI of the chest for thymoma.
In patients without AChR antibodies, muscle-specific receptor tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4) antibodies maybe found.
Muscle-specific receptor tyrosine kinase
The second most common antibody found is MuSK antibody. Series vary in the percentage found to be positive for MuSK but in general about one-fourth of all patients negative for AChR will be found positive for MuSK (roughly 25% of all patients negative for the AChR Ab or 5% of all patients with autoimmune MG). MuSK patients often have distinctive clinical characteristics. Such patients tend to be younger women (younger than 40 years) with disproportionate bulbar, neck extensor, shoulder, and respiratory symptoms with increased likelihood of “fixed weakness” and have a lower likelihood of abnormal repetitive stimulation and edrophonium test results. MuSK patients have no associated thymus abnormalities (and are not candidates for thymectomy) and are more likely to be refractory to a variety of therapies (such as cholinesterase inhibitors and many immune therapies). Conversely the MuSK patients tend to respond very favorably to rituximab and plasma pheresis.
Low-density lipoprotein receptor-related protein 4
A less common MG antibody seen in patients without AChR and MuSK (often referredto as the “double-negative” patients) is the LRP4. The LRP4 antibody is found in about1% to 2% of all patients with autoimmune MG. The LRP4-positive patients do not have association with thymic pathology, and thymectomy is not indicated in their management. Patients with LRP4 MG were noted to have a younger age of onset and was more common in women compared with other “double-negative” patients who do not have LRP4. LRP4 patients tend to have relatively mild severity and often have pure ocular manifestations, and LRP4 patients are observed to generally respond favorable to pyridostigmine or prednisone. Studies looking at patterns of clinical characteristics and distinctive responses to the various MG treatment options are ongoing. Regarding specificity, LRP4 antibodies have also been found in occasional patients with amyotrophic lateral sclerosis and thus positive results should be interpreted in the proper clinical context.
Occasional patients without AChR, MuSK, and LRP4 (“triple-negative” patients) are found to have anti-agrin antibodies. However, most cases of anti-agrin antibodies are also found along with MuSK, LRP4, or AChR antibodies. Agrin is a protein of the basal lamina with 2 isoforms. Neural agrin seems to bind to LRP4, which activates MuSK, leading to clustering of AChR.
When antibody testing is negative (10%–15% of patients with MG), Electromyography (EMG) can aid in the diagnosis. An EMG can confirm a disorder of the NMJ as well as evaluate for other possible causes of weakness including myopathy or motor neuron disease. Repetitive stimulation of a motor nerve at a slow frequency (2–3 Hz) can demonstrate decrement greater than 10% in patients with dysfunction of the NMJ. Decrement is more prominent in patients with postsynaptic disorders than presynaptic. Overall sensitivity is about 50% but higher in clinically weak muscles and lower with ocular MG. Single-fiber EMG is more sensitive (about 90%) than repetitive stimulation.
First part of management is patient education. The Muscular Dystrophy Association and Myasthenia Gravis Foundation are the 2 organizations that offer educational material and pamphlets for patients. Another crucial part of management is recognizing when to hospitalize a patient with MG. Patients with rapidly worsening symptoms, moderate-to-severe dysphagia, or dyspnea should be evaluated and admitted urgently. Signs of respiratory failure should be monitored closely. Evaluation of MG crisis triggers, such as surgery, medication, infection, hyper- or hypothyroidism, or medication change, should be performed and addressed promptly.
Pharmacologic treatment should be individualized and based on patient’s symptoms and comorbid diagnosis. First-line treatment in MG is reversible cholinesterase inhibitors (CEI) such as pyridostigmine or neostigmine. CEI are generally safe without significant long-term complications. However, too much of CEI can lead to skeletal muscle weakness (cholinergic weakness), uncommon in patients on oral CEI.
Corticosteroids are commonly used for moderate to severe MG, although prospective controlled trials documenting benefits are lacking. Expert opinion and patient compliance despite complications support its use in patients with moderate to severe symptoms. There is no consensus on dosing of corticosteroids but typically aim for a higher dose (60–80 mg/d of prednisone) initially. Most of the patients (approximately 80%) will show marked improvement or remission, and only 5% have no response. A lack of response should raise the question of the diagnosis. Typical improvement begins around the 1 to 2 weeks and gradually continues over the next 3 to 9 months. Approximately half of the patients will experience temporary worsening of weakness starting1 to 2 days after initiating steroids and lasting 3 to 4 days. The weakness can be severe enough in 10% of patients to require ventilation or a feeding tube. Therefore, many patients with moderate to severe disease should be hospitalized for initiation of steroids.
Rituximab is a monoclonal antibody directed against the CD20 antigen on B cells, which has over the last decade become widely used in the treatment of patients with AChR-positive MG and MuSK MG. Major benefit is well established for most of the MuSK-positive patients. Hehir and colleagues reported results of a prospective controlled double-blind trial in MuSK-positive patients with MG. The primary clinical endpoint was the “Myasthenia Gravis Status and Treatment Intensity” (MGSTI), a measure reflecting Myasthenia Gravis Foundation of America (MGFA) post intervention status as well as requirements for additional immunotherapy. With median follow-up of3.5 years 58% (14/24) of the rituximab-treated patients achieved the primary outcome target compared with 16% (5/31) of controls. In addition, at the time of last visit, 29%of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/d) compared with 74% of controls (mean dose 13 mg/d). This study provides class IV evidence for benefit of rituximab in MuSK patients with MG.
Plasma exchange (plasmapheresis or PLEX) removes antibodies (including AChR antibodies) from the plasma. Improvement is typically seen within 1 to 2 weeks but only lasting 1 to 2 months. Because of the rapid improvement with PLEX, it is commonly used in MG crises. A typical exchange removes 5 L of plasma every other day for about 5 exchanges. Complications included bradycardia, hypotension, electrolyte imbalance, hemolysis, infection, and access problems. Maintenance PLEX (one ex-change every 1–8 weeks) has been used in patients with refractory myasthenia, especially MuSK patients.
Historically patients with MG have often been advised to be cautious about prolonged physical exertion. To learn if progressive resistance training or aerobic training are possible and effective in patients with MG 15 patients with generalized MG were randomly assigned to 20 sessions over an 8-week period. Overall only 1 patient dropped out of the training session, and adverse events were seen in both groups, including 2 with increased bulbar symptoms and 3 with increased fatigue. The progressive resistance-training group showed increases in maximal strength and functional capacity. This study would suggest that most of the patients with MG can tolerate exercise therapy and some demonstrate improved strength and function