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Overview: Myasthenia Gravis

Myasthenia Gravis (MG) is an autoimmune disorder that affects the neuromuscular junction, meaning the method by which the nerves tell the muscle to contract. It specifically affects a receptor for the neurotransmitter nicotinic acetylcholine (ACh). In MG, there are autoantibodies that are produced that interfere with these receptors. These antibodies can be detected on blood testing in up to 90% of people who have MG. MG occurs about twice as often in women than men and has a prevalence of about 1 in 10,000 to 20,000 people. The symptoms often peak in the second and third decades of life in women and the fifth and sixth decade of life in men, but it can occur at any point in life. MG tends to co-occur with other autoimmune disorders, such as rheumatoid arthritis, autoimmune thyroid disease, or lupus.

Features of Myasthenia Gravis symptoms

MG can have muscle weakness in various portions of body, but the typical finding is that the degree of weakness will be “fatigable” or increase with increased use of the muscle group. About half of MG patients may first present with weakness of the muscles around the eye, such as having a droopy eyelid (“ptosis”) or with double vision that results from the eyes not aligning properly due to muscle weakness. Bulbar symptoms may include a change in speech or difficulty swallowing, extremity weakness can cause difficulty walking or holding the arms about the head, or respiratory weakness can cause difficulty in breathing. The weakness typically worsens with exercise and improves with rest. Often, the symptoms are more prominent as the day goes on (“diurnal” weakness) and are improved in the morning. In addition to physical stress, emotional stress, infection, or exposure to certain medications can worsen weakness.

Diagnosis

Taking that captures a fatigable weakness is often the most important component to coming to the correct diagnosis of MG, there are several other tests that are often used to confirm the diagnosis

Electromyogram (EMG)

EMG is nerve-muscle testing using small electrical signals. A particular type of EMG called repetitive stimulation can be seen to select muscles and evaluate for abnormalities that suggest MG. Single fiber EMG can also occasionally be used.

Serum antibody testing

Blood tests can be obtained to evaluate for various ACh antibodies, including ACh binding antibody, ACh bloding antibody, or ACh modulating antibody. Some patients instead have antibodies to muscle specific kinase (MuSK). These patients may have more bulbar and neck/shoulder weakness and often have less of a fatigable nature to the weakness Voltage Gated Calcium Channel (VGCC) antibodies can be seen in a related condition called Lambert Eaton Myasthenic Syndrome (LEMS)

Tensilon test

Occasional a medication called Tensilon (edrophonium) can be given to see if there is a change in weakness to suggest MG. This has largely been replaced by the above studies, as this medication can have significant side effects.

Treatment

There are a variety of treatment options for MG. Often, the Neurologist can utilize multiple of these approaches to address the condition from various angles and optimize disease control.

Thymectomy

The thymus is a gland in the upper chest that typically has less function after childhood. Abnormalities in the thymus gland have been known to be associated with MG for decades. 50-70% of people with MG have excessive thymus tissue and 10-15% of people with MG have a more severe thymoma, or collection of abnormal cancerous thymus cells. With the diagnosis of MG, a Neurologist may order a CT scan of the chest to evaluate the thymus. Thymectomy – a surgery to remove the thymus – may be considered in people with MG who have moderate or severe symptoms or especially those who are inadequately controlled with cholinesterase inhibitors alone. About 75% of patients who have MG and undergo thymectomy then have significant improvement in MG symptoms.

Cholinesterase Inhibitors

Cholinesterase inhibitors work by reducing the breakdown of ACh, therefore allowing an increased concentration of the neurotransmitter to be available This is first-line therapy for symptom control in MG. Pyridostigmine bromide (Mestinon) is the most common option. This is taken in a tablet form several times a day. Side effects can include stomach cramping, diarrhea, muscle twitching, or excessive salivation. These side effects are usually dose-dependent, so the dose can be reduced if side effects are troublesome.

Steroid sparing immunosuppressants

A variety of immunosuppressant medications have been used in MG, with the goal of suppressing the antibodies that cause MG symptoms and also allowing for less dependence of steroids. The medications themselves are from various classes and have their own side effect profiles. A neurologist will take a detailed history and counsel a person on making an individualized choice with regards to the medication. Options include mycophenalate mofetil (CellCept), azathioprine (Imuran), cyclosporine, rituximab (Rituxan), or others. Subcutaneous IVIG or intermittent IVIG/PLEX can be considered. Please see below for details regarding these options.

Corticosteroids

Corticosteroids, such as Prednisone, can help control the autoimmune process of MG. Curiously, in the short term steroids can actually worsen MG if started at too high of a dose, so typically steroids are started at a relatively low dose and may slowly be adjusted. If there is a good response to steroids, the Neurologist may try to slowly decrease the steroid dose to find the lowest dose that still has good control of symptoms. Long-term use of steroids can have risks including immunosuppression, high blood pressure, osteoporosis, diabetes or other problems – so many times the Neurologist will start a steroid-sparing immunosuppressive to limit the amount of steroids needed.

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Treatment of acute MG crisis / flares

MG symptoms can occasionally “flare” or cause a critical worsening of symptoms, which can cause more serious problems such as difficulty breathing or difficulty walking. At times, a specific event can cause this, such as physical stressors (such as surgery), emotional stressors, or exposure to certain medications. MG crises usually require hospitalization where the person’s respiratory status can be supported and treatments can be started.

Plasma Exchange / Plasmapheresis

Plasma Exchange (PLEX) is a process by which a large volume of a person’s plasma is removed. This typically would be done every other day for 5 to 7 exchanges. The goal is to remote ACh receptor antibodies that are causing disease in the plasma. This can result in improvement in just days with peak effect in 2 to 3 weeks. The benefit wears off between 4 and 8 weeks after the procedure. Complications can include low blood pressure, abnormal electrolytes, bleeding, or complications related to a central line placement.

High dose IV Immunoglobulins (IVIG)

IVIG is a product that contains pooled plasma from many donors. This is infused daily, typically over a 5 day period. The goal is that antibodies in the IVIG will bind to the problematic ACh receptor antibodies so they are neutralized. IVIG is about as effective at PLEX in treating MG crises. Symptoms usually improve within 1 week of IVIG and have relief for 4 to 8 weeks. Common side effects of IVIG can include chills, headache, or fever. Benadryl or Tylenol can help prevent these side effects. Other serious side effects such as stroke, renal failure, or aseptic meningitis are very rare.

Supportive care

A myasthenic crisis is a serious medical emergency, as it can lead to inability to breath due to diaphragm weakness or inability to swallow without aspiration due to weakness in the mouth and throat. At times, a person may need to be intubated and put on a ventilator until the crisis is resolved. Tube feeding may also need to replace eating by mouth. The medical team will also make sure to support blood pressure and evaluate for and correct any other underlying medical problem, such as an infection.

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Medications that can worsen MG

Certain medications can affect the neuromuscular junction cause worsening of myasthenia gravis. These include D-penicillamine, chloroquine, quinine, quinidine, procainamide, or botulinum toxin. Less severe but notable effects can also be seen by fluoroquinolone antibiotics (such as Cipro), aminoglycoside antibiotics, beta blockers, certain muscle relaxants, or others. All providers should be aware when a person has MG to take care to ensure that the person is not given any inappropriate medications. The Myasthenia Gravis Foundation keeps a list of medications which may be avoided in MG, which is referenced below.

Cholinergic Crisis

Ironically, the use of too much cholinergic medications (including with the use of mestinon) can cause a cholinergic muscle weakness that may at first seem like MG weakness but is in fact due to excessive ACh effect rather than a block of ACh effect. The Neurologist will take a detailed history and physical to differentiate this, as the treatment is very different. Features that may suggest a cholinergic crisis instead of a myasthenic crisis include abdominal cramps, diarrhea, excessive secretions, small pupils, sweating, or twitching of the muscles

Congenital Myasthenia Gravis

Myasthenia Gravis is distinctly different from Myasthenia Gravis. Instead of being an autoimmune disease, Congenital Myasthenia Gravis refers to a collection of rare hereditary conditions that affect the neuromuscular junction. There are no abnormal ACh receptor antibodies, the weakness and symptoms are more stable, and they do not respond to immune therapy. Many of these patients do respond to mestinon. There are various subtypes with unique genetic mutations.

Lambert Eaton Myasthenic Syndrome (LEMS)

LEMS is a pre-synaptic neuromuscular junction disorder, meaning that it affects where the nerves would usually send a signal to the muscles. This tends to cause extremity weakness that is more proximal – closer to the trunk – and may cause difficulty climbing chairs or getting out of a chair. It is less common to have eyelid drooping, double vision, difficulty swallowing, or difficulty breathing. In contrast to MG, at times people with LEMS note that symptoms actually improve in strength with repeated exercise. This is more rare than MG. About half of people with LEMS may have an underlying malignancy, so the Neurologist who diagnosis LEMS will do a thorough evaluation to find any underlying cancer. The most commonly associated malignancy is small-cell lung cancer. The blood test associated with LEMS is a voltage-gated calcium channel antibody. Treatment includes treating any associated malignancy, use of mestinon, use of immunosuppressants, and sometimes 3,4-Diaminopyridine – which is unique to LEMS.

Further resources

ninds.nih.gov