Myasthenia Gravis

History

Myasthenia Gravis (MG) is a chronic autoimmune disorder of neuromuscular transmission resulting in muscle weakness. The term "myasthenia" is Latin for muscle weakness, and "gravis" for grave or serious. Thomas Willis first described a patient with MG in 1672. There were other sporadic case descriptions over the years and in 1900, Campbell and Bramwell collected 60 cases of MG from the literature. Still the cause of the disease remained a mystery, until 1960 when Simpson proposed that myasthenia gravis was caused by antibodies against the acetylcholine receptor. In 1973 Patrick and Lindstrom demonstrated that MG is autoimmune in origin by showing that rabbits immunized with Torpedo acetylcholine receptor became myasthenic. Today, MG is one of the most thoroughly understood neurological disorders, which has lead to treatments which vastly improve the length and quality of life of myasthenics.

Clinical Presentation

Epidemiology

The incidence of MG is 5 -10 cases per million population per year, which results in a prevalence in the US of 25,000 cases. MG is considered a sporadic disease, meaning that it seems to strike at random and it does not run in families. There is no racial predominance, but in people who present with MG at < 40 years old, 75% are women. Those > 40 years old are 60% men. This pattern is often summarized by stating that MG is a disease of young women and old men. In those patients who have MG as a consequence of having a thymoma (see below), there is no age or sex predominance.

Clinical Features

The primary clinical feature of MG is muscle weakness. Because MG is a disorder of the neuromuscular junction, it cannot cause any sensory or autonomic symptoms. It also does not cause any bowel or bladder symptoms. It should be considered in the presentation of any isolated and otherwise unexplained weakness. The key feature of weakness due to MG is its variability. Patients will experience a waxing and waning of strength throughout the day, with a tendency to fatigue later in the day, or even towards the end of a particular task. Progressive difficulty chewing during a meal, for instance, is a common complaint. Another characteristic is a proximal > distal distribution.

The first, or presenting, symptom of MG is ocular weakness, causing ptosis (drooping eye lids) and/or diplopia (double vision), in 63% of cases. Frequencies of other presenting symptoms are: leg weakness, 10%; fatigue, 9%; dysphagia, 6%; slurred or nasal speech, 5%; difficulty chewing, 4%; other weakness, 3%. Symptoms of weakness tend to worsen with various stressors, such as exertion, heat, infection, and in the post partum period. Patients with MG also are more sensitive to some agents used in general anesthesia, such as benzodiazepines, which can acutely worsen their MG. Extubation after general anesthesia, therefore, may be prolonged. Other drugs which may worsen MG include aminoglycosides, quinine, antiarrhymthmics, and muscle relaxants.

On examination the key feature is fatigable weakness, with normal sensation, reflexes, and coordination. Ptosis and diplopia can be elicited with sustained upward gaze for 30-60 seconds. Repeated testing of proximal muscle strength also may bring out weakness.

The clinical course of MG is highly variable between patients. Out of all MG patients, 14% remain with Ocular symptoms only, which is referred to as Ocular MG. Ocular MG rarely becomes systemic after 2 years. The maximum severity of MG is reached within 1 year in 55% of cases, and within 5 years in 85%. Modern treatment has vastly improved the clinical course of MG. In 1940 - 57 there was 31% fatality from MG. By 1985 this figure dropped to 7%. The most dangerous aspect of MG is so-called Myasthenic Crisis, which refers to any respiratory compromise due to muscle weakness from MG. Respiratory failure requiring ventilation can occur in severe cases.

Pathophysiology

Myasthenia gravis is a disorder of neuromuscular transmission. In order to understand what causes MG, we must first describe what constitutes normal neuromuscular transmission.

Normal Neuromuscular Transmission

Acetylcholine (ACh) is synthesized in the nerve terminal by action of the enzyme choline acetyltransferase. ACh is then stored in vesicles, forming a quantum, containing about 10,000 molecules of ACh. Quanta of ACh are released into the nerve terminal by calcium dependent exocytosis - the fusing of the vesicles with the outer membrane wall. ACh then binds to the post-synaptic ACh receptor, resulting in a transient increase in membrane permeability to Na, K, Ca, and Mg, leading to an Endplate potential (EPP). Spacial and temporal summation of the EPPís are usually sufficient to reach threshold and cause a muscle membrane action potential. Acetycholinesterase and diffusion deactivates the ACh and terminates neuromuscular transmission.

Acetylcholine Receptor Antibody

The culprit in MG is an abnormally created antibody which has activity against the acetylcholine receptor, which is why MG is classified as an autoimmune disease. The AChR antibody is polyclonal and is present in 85-95% of MG cases. The antibody blocks neuromuscular transmission by several mechanisms - blockade of receptor sites by steric hindrance, destruction of AChR (complement mediated), and crosslinking of AChR which causes increased turnover by endocytosis (from 5-6 days to 2.5 days).

These effects collectively decrease the number of acetylcholine molecules binding to receptors, therefore decreasing the number of EPP's, and decreasing the likelihood of the muscle fiber reaching threshold depolarization and contracting. The resulting decrease in the number of muscle fibers firing is what causes weakness.

Structural Changes

The chronic inflammation of MG causes several changes in the structure of the Neuromuscular Junction which also inhibit transmission and contribute to weakness. These include flattening out of the junctional folds, spreading out of AChR and Acetylcholinesterase, a 66% decrease in number of AChR, and an increased junctional gap.

Thymus

The thymus gland plays some role in the pathogenesis of MG, although it is not yet clear exactly what this role is. Evidence for the thymus playing a role includes the fact that the thymus contains myoid cells which can express AChR. B and T lymphocytes taken from MG thymus are reactive to AChR. 65% of patients with MG are found to have thymic dysplasia and 15% of cases are associated with thymoma. Finally, there is definite clinical improvement if the thymus gland is removed.

There are several other interesting pathological features of MG. MG is associated with certain HLA types, specifically B8, DRW3, DQW2, A1, A3, B7, DRW2. There is also an association with other autoimmune diseases. These two facts suggest a heritable defect in immune regulation. Some speculate that there might also be a viral trigger, although this has not been proven. This means that a viral infection may cause an autoimmune response against AChR through molecular mimicry, or a chance similarity between proteins on the virus and the ACh receptor. Homology found between herpes simplex virus and antibody from 6/40 MG patients is some evidence for a possible viral association.

Diagnosis

The diagnosis of MG is often very challenging. The clinical history and exam always provides the first clue to the diagnosis, but laboratory studies must be used for confirmation. Three studies are used for the diagnosis of MG, anti-AChR antibody titers, the Tensilon test, and electromyography, including both the Jolly test and single fiber EMG. Used together, these three studies are almost 100% sensitive for MG.

Anti-AChR antibody titers are positive in 85-95% of patients with systemic MG, and somewhat fewer in ocular MG. When positive, however, this is the most specific test for MG. There are rare false positives in the elderly population and those with other autoimmune disorders. The titers do not correlate with severity of disease between patients, but will rise and fall with activity of disease in a single patient.

The edrophonium, or Tensilon Test is both less specific and less sensitive than antibody titers. Edrophonium is a short acting acetylcholinesterase inhibitor, which improves strength in MG by increasing binding of ACh to its receptor. Adequately performing this test requires the presence of an unambiguous clinical marker, such as ptosis, diplopia, or clear weakness. A test dose of 2mg of edrophonium followed by 4-8mg is given to the patient and should result in an improvement in the clinical marker within 30-60 seconds in myasthenics. Improvement should subside within 4-5 minutes. A saline control is also used and both the clinical evaluator and the patient should not be aware if the patient is getting the edrophonium or the saline. There is some risk to this test and therefore it should only be performed in an appropriate clinical setting.

The Jolly test refers to a sequence of repetitive nerve stimulation (RNS) studies specifically designed to look for neuromuscular junction disease. A positive test on RNS is a >10% decremental response with 3Hz repetitive stimulation. The decrement results from a decreased safety margin to reach threshold depolarization, therefore progressively fewer muscle fibers depolarize as the nerve terminal becomes partially depleted of ACh. This test is 50 - 80% sensitive, increased with severity of disease.

A single fiber EMG looks for increased "jitter," which is variability in the time of neuromuscular transmission measured in a single muscle fiber. The test has a sensitivity of up to 95% is systemic, and 84% in ocular MG, making it the single most sensitive test for this disorder.

Genetics

Although MG is not considered a genetic disease, because it is not directly inherited nor is it the direct result of a genetic mutation, there are certain HLA (human lymphocyte antigens) associations. In people < 40 there is a higher incidence of HLA A1, B8, and DRW3 in patients with MG, and in those > 40 there is a correlation with HLA A3, B7, and DRW2. In patients with thymoma there is no HLA association. Although no direct link has been found, this HLA association, along with the fact the MG patients have a higher incidence of other autoimmune diseases, suggests an inherited defect in immune regulation.

Treatment

Management of MG is primarily pharmacological. The goal of treatment is remission, which can be achieved in about a third of cases. The remaining cases require ongoing medical treatment to keep the disease under control. Some cases remain poorly controlled despite maximal medical treatment.

Mestinon is an acetylcholinesterase inhibitor, just like edrophonium but longer acting. Mestinon increases availability of ACh at the receptor site, thereby increasing strength. This is considered symptomatic treatment only, since it does not affect the underlying cause or course of the disease. The usual maximum dose is 60mg q4 hours and the typical starting dose is 30mg q6 hours. Chronic high doses should be avoided, by giving drug holidays if necessary.

Immunosuppression is the mainstay of treatment. Acute treatment is given for myasthenic crisis or active disease which is severe and not responding to more chronic therapies. Plasmapheresis is the primary means of acute therapy. Plasmaphersis therapy consists of filtering antibody proteins out of the blood, thereby removing the offending anti-AChR antibodies. Intravenous immune globulin (IVIG) is second line acute therapy.

First line chronic immunosuppressive therapy is prednisone, starting at 40-60mg qD for the first 2-3 months of treatment followed by a slow taper to the lowest dose necessary to suppress the disease. Initiating steroid therapy must be done carefully as it can cause increased weakness for 2-3 days. Imuran at 2-3 mg/kg is used together with prednisone because prednisone is quicker acting but Imuran is safer long term. Cyclosporin A is used second line in cases of Imuran failure.

Thymectomy is associated with improved long term outcome, and is performed when the patient is stable on maximal medical therapy to minimize the risk of surgery. There is a definite indication if thymoma is present. Thymectomy should not be performed prior to puberty and is not indicated in older adults ( >60) because the thymus has usually involuted by that age. A CT scan or MRI of the thorax should be performed on all MG patients to assess the status of the thymus gland.

Ocular MG

The indication for thymectomy and immunosuppression in ocular only MG is somewhat controversial. Some practitioners feel that if Mestinon alone is sufficient to eliminate all ocular symptoms than the risks of prednisone or thymectomy are not warranted. There is some evidence, however, that using prednisone may decrease the chance of the disorder becoming systemic, and therefore within the first two years after onset there is justification for immunosuppressive therapy. In any case where ocular symptoms are not adequately treated with Mestinon immunosuppressive treatment should be considered.

Support Groups

Myasthenia Gravis Foundation of America (MGFA)
5841 Cedar Lake Rd., Suite 204
Minneapolis, MN 55416
Phone: 1-952-545-9438 or 1-800-541-5454
Fax: 1-952-646-2028
Email: myasthenia@myasthenia.org
Website: http://www.myasthenia.org

The MGFA is a national organization with over 35 local chapters dedicated to patient support, funding research, and disseminating information on MG.

Muscular Dystrophy Association (MDA)
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718
Phone: 1-800-572-1717

The MDA supports research and patient care for over 40 diseases, including Myasthenia Gravis. They can put patients and families in touch with local chapters and support groups.

Internet Links to other MG sites

Disclaimer

This page is intended for educational purposes only, to provide an overview of MG for patients, their families, and health care providers. It is not intended to recommend any specific treatment, nor should it be used as a guide for self-treatment. Patients with MG should consult their physician before making any changes to their treatment regimen.