This web page was produced as an assignment for an undergraduate course at Davidson College.

Myasthenia Gravis

       Myasthenia gravis literally means "grave muscular weakness" (Howard, 1997). Myasthenia gravis (MG) is a neuromuscular disorder marked by fluctuating weakness of voluntary muscle groups. MG-related muscle weakness generally becomes more pronounced following activity and improves following rest. An MG patient's muscle strength fluctuates on a daily or even hourly basis. Frequently, MG-related muscle weakness is asymmetric (i.e. worse on one side of the body) (Kessey & Sonshine, 1997). Any striated muscle group can be affected by MG (Zweiman & Levinson, 1992), with the muscles controlling eye movement, eyelid movement, chewing, swallowing, coughing, facial expression, breathing, arm movement, and leg movement most likely to be affected (Howard, 1997; Kessey & Sonshine, 1997). MG patients do not typically experience general (non-muscle specific) fatigue. In ocular MG, the weakness is limited to the muscles controlling eye and eyelid movement. In generalized MG, weakness is present in multiple muscle groups. MG is usually painless, but pain may occur if the neck muscles that support the head become weak and spasm (Howard, 1997). Weakness of the muscles required for breathing can create a life-threatening breathing impairment (Howard, 1997; Kessey & Sonshine, 1997). If this occurs, the patient is said to be in respiratory crisis, and hospitalization for mechanical breathing assistance is necessary. Progressive difficulties in swallowing, talking, and breathing usually proceed an MG-related respiratory crisis (Kessey & Sonshine, 1997).
 
 

        About 14 out of every 100,000 people in the US have been diagnosed with MG (Howard, 1997). Men and women of all races and ages suffer from MG, with symptom-onset most common in women of childbearing age and middle-aged men (Kessey & Sonshine, 1997).  In general, MG patients have normal life spans.
 
 

        By far the most common form of MG is autoimmune myasthenia, which is a chronic disorder (Howard, 1997). The majority of these MG patients present with ocular MG. Fifty percent of these patients progress to generalized MG within a year of symptom onset, and another 30% progress to generalized MG within two years of symptom onset. About 15% of patients with autoimmune ocular MG never progress to generalized MG. Within 5 to 7 years of symptom onset, autoimmune MG generally ceases to be progressive, and weakness is there after extremely unlikely to occur in previously unaffected muscle groups (Kessey & Sonshine, 1997).
        Congenital myasthenia is a rare form of MG diagnosed in infants who have a genetic defect in neuromuscular transmission (Kessey & Sonshine, 1997). Twelve percent of babies born to mothers with autoimmune MG have neonatal myasthenia, a form of MG marked by a feeble cry,  a weak sucking response, respiratory distress, and muscle "floppiness". The symptoms of neonatal myasthenia can be reversed by anticholinesterase medication or plasmapheresis (described under the "Treatments" heading) (Howard, 1997; Kessey & Sonshine, 1997). Neonatal myasthenia disappears spontaneously within the first few months of life (Howard, 1997; Kessey & Sonshine, 1997). During this time-period, the maternal antibodies that were present in the infantís body at birth are slowly degraded (Janeway, Travers, Walport, & Capra, 1999). Autoimmune MG is not directly inheritable (Kessey & Sonshine, 1997). However, people with a family member who has autoimmune MG are at a higher risk of developing MG themselves. No form of MG is contagious.
 
 

The Neuromuscular Junction

        Voluntary muscles are controlled by nerve impulses that travel down nerves from the brain to the neuromuscular junctions, the empty space between the final nerve of the pathway and a muscle fiber (Howard, 1997; Drachman, 1994). The arrival of the nerve impulse at the nerve ending causes acetylcholine (ACh), a chemical neurotransmitter, to be released. ACh diffuses across the neuromuscular junction and binds to an acetylcholine receptor (AChR) located on the post-synaptic membrane of the muscle fiber. This binding opens the AChRís cation channel temporarily, producing a localized electrical potential. When enough AChR/ACh bindings have occurred to create a sufficient electric potential, an action potential is generated (Drachman, 1994). This action potential spreads along the muscle fiber, causing the muscle to contract.

Anti-AChR Antibodies

        The immune systems of people with autoimmune MG make antibodies that bind to AChRs (Drachman, 1994; Zweiman & Levinson, 1992). Anti-AChR antibodies of the isotype immunoglobulin G (IgG) can be found in the blood stream of 89-90% of autoimmune generalized MG patients  (Zweiman & Levinson, 1992). These anti-AChR IgGs have been found primarily in the postsynaptic junction of MG-affected muscles (Drachman, 1994; Zweiman & Levinson, 1992).  The injection of IgGs from MG patients into mice results in the appearance of MG symptoms in the mice (Drachman, 1994).
        The binding of anti-AChR antibody to an AChR accelerates its (the AChR's) degradation, blocks its ability to bind ACh, and causes complement-mediated damage to it and to other nearby cells (Drachman, 1994; Aweiman & Levinson, 1992). The injection of antibodies from MG patients into cultured muscle cells, causes the AChRs on these cells to be degraded at 2-3 times the normal rate (Drachman, 1994). Antibody-linked AChRs are cross-linked and drawn together in clusters. The clustering of the AChRs causes them to be endocytosed and degraded (Drachman, Adams, Josifek, & Self, 1982; Howard, Lennon, Finley, Matsumoto, & Elveback; 1987). Some researchers theorize that IgG-tagged AChRs  could also possibly be engulfed by macrophages with receptors for the constant regions of the anti-AChR IgGs, but experimental evidence to support this theory has not yet been found (Zweiman & Levinson, 1992). The most significant abnormality in MG is a decrease in the number of AChRs, with autoimmune MG patients having about one third as many AChRs in affected muscle tissue as healthy controls (Drachman, 1994). The degree of reduction in the number of AChRs is positively correlated with MG severity.
        Anti-AChR antibodies primarily bind to the alpha sub-unit of  AChRs, which is the same subunit that ACh binds (Abboud, Moe, Johnson, Harms, & Ellison, 1996; Drachman et al., 1982;  Howard et al., 1987). Serum IgGs from 50-88% of autoimmune MG patients can block ACh /AChRs binding on cultured muscle cells (Drachman et al., 1982; Howard et al., 1987). This blockade is believed to be due to steric hindrance created by the anti-AChR IgGs binding near the ACh binding site (Drachman, 1994). However, the exact binding site of the anti-AChR IgGs is unknown.

Figure 1: AChR receptor. The alpha sub-unit is believed to contain the binding sites for both ACh (shown on diagram) and the anti-AChR antibody (exact site location not yet known) (Abboud et al., 1996).

        In addition to having fewer and less effective AChRs, the neuromuscular junctions in autoimmune MG patients differ from those of normal controls in other ways (Drachman, 1984; Novella, 1998). Specifically, the neuromuscular junctions in MG patients have a more simplified pattern of postsynaptic muscle membrane folding and a larger gap between the nerve terminal and the postsynaptic muscle membrane.

Figure 2:  Neuromuscular junctions. Embedded in approximately the center of this web page is a diagram of an MG-affected neuromuscular junction (on the right) and a normal neuromuscular junction (on the left) The MG-affected neuromuscular junction displays a larger junctional gap and more shallow muscle membrane folding (Novella, 1998).

    The anti-AChR antibodies are believed to damage the post-synaptic membrane and thus create these abnormalities through the complement pathway (Zweiman & Levinson, 1992).  The binding of an antibody to its target may trigger the classical complement pathway (Janeway et al., 1999). The small peptide fragments C3a, C4a, and C5a that are released during complement activation bind to specific receptors and produce local inflammatory responses. This  inflammation, which will be chronic because the pathway triggering AChR/anti-AChR antibody binding will occur repeatedly, is believed to damage the post-synaptic membrane of the muscle fiber over time (Novella, 1998).

Relation to Clinical Symptoms

        The changes at the neuromuscular junction create the clinical features of MG (Drachman, 1994; Howard, 1997). These changes make it more difficult for ACh to successfully reach and activate AChRs which in turn makes it more difficult to generate an action potential in the muscle fiber. When repeated muscle contractions are attempted, muscle power declines as a result of the failure to generate action potentials at more and more neuromuscular junctions. This creates the muscle weakness associated with MG.

The Role of Lymphocytes

         B cells directly produce the anti-AChR antibodies (Drachman, 1994; Janeway et al., 1999). T cells are also implicated in MG (Drachman, 1994). Both AChR-specific B cells and AChR-specific T cells have been found in the blood and in the thymuses of MG patients. Helper T (Th) cells are considered more likely to be involved in the MG-related immune response than are effector T cells. Th cells respond to antigen that has been degraded by antigen presenting cells (APCs)  and that is bound to major histocompatibility complex (MHC) class molecules on the APCs' surfaces (Janeway et al., 1999). The most likely MG pathway is that CD4 T cells recognize peptide:MHC class II complexes presented by an APC and are thus activated. Activated Th class 2 (Th 2) cells then recognize the peptide:MHC class II complex presented on the surface of the antigen-specific B cells and activate these B cells to make antibody. The majority of T cell recognition sites on the AChRs of MG patients are on the AChR alpha subunit (Drachman, 1994). However, the T cells of MG patients have been shown to respond to a variety of peptides taken from AChRs.The Th 2 cells of MG patients have been shown to augment the production of anti-AChR antibodies in vivo.

Origins of the Autoimmune Response

         The origins of the MG autoimmune response are not yet known. Researchers theorize that the thymus is involved in either the initiation or perpetuation of autosensitization (Zweiman & Levinson, 1992). A variety of evidence supports this theory. About 85% of autoimmune MG patients have thymic abnormalities with 70-75% of all autoimmune MG patients displaying thymic hyperplasias (an increased number of cells in the thymus) and 10-15% of all autoimmune MG patients developing a thymic tumor called a thymoma (Abboud, et al., 1996; Drachman, 1994; Howard, 1997; Kessey & Sonshine, 1997). Further, the B cells and T cells in the thymus of MG patients are more responsive to AChR than are the B cells and T cells in the periphery (Drachman, 1994).
        One model suggests that myoid cells (muscle-like cells with AChRs that are located in the thymus) are involved in the origination of the MG-related autoimmune response (Abboud et al., 1996; Drachman, 1994). Because they are located in the thymus, myoid cells are surrounded by APCs and helper T cells, which could increase their (the myoid cells') vulnerability to immune attack. A random alteration in the myoid cells (Abboud et al., 1996; Drachman, 1994) or  the lymphocytes (Drachman, 1994) could disrupt self-tolerance and lead to an immune response to the myoid cellsí AChRs.

Figure 3: The myoid-cell-mediated model. This diagram offers a hypothetical myoid-cell-mediated mechanism for the development of an anti-AChR immune response (Abboud et al., 1986).

        An alternative model suggests that MG is triggered by molecular mimicry (i.e. an infecting agent with peptides that are similar to the peptides in AChR triggers an immune response which generalizes to AChR) (Abboud et al., 1996; Drachman, 1994). The herpes simplex virus is known to have some amino acids in common with the alpha subunit of the AChR (Abboud et al., 1996), and antibodies taken from MG patients have bound to this virus in vitro (Drachman, 1994). The AChR has also been found to cross-react with some species of bacteria (Stefansson, Dieperink, Richman, Gomex, & Marton, 1985). This suggests that either a bacterial infection or a herpes simplex virus infection could contribute to the development of MG.

Figure 4:  The molecular mimicry model. This diagram offers a herpes-infection-mediated mechanism for the production of an anti-AChR immune response (Abboud et al., 1986).
 
 

        There are many disorders that are characterized by muscle weakness, making diagnosis of MG difficult in some cases (Dobkin, 1994). A complete medical and neurological evaluation is usually required to diagnosis MG (Drachman, 1994; Howard, 1997). Use of a blood test for abnormal antibodies, a single fiber electromyography (EMG) study, or an edrophonium chloride test can aid in the diagnosis of MG (Howard, 1997). If a high number of the anti-AChR antibodies are found in a blood serum test, MG is indicated (Howard, 1997; Kessey & Sonshine, 1997). In an EMG study, a nerve adjacent to a neuromuscular junction is repeatedly electrically stimulated. A weakening of the muscle response with time suggests a diagnosis of MG. An improvement in strength immediately after edrophonium chloride is injected into the blood stream strongly supports a diagnosis of MG. The exact reason why an injection of endrophonium chloride temporarily reduces MG-related muscle weakness is unknown. (Kessey & Sonshine, 1997). Negative results on any or all of these tests does not rule out a diagnosis of MG (Howard, 1997).
 

        There is currently no cure for autoimmune MG (Drachman, 1994). However, treatment options including lifestyle change, intravenous human immunoglobulin therapy, plasmapheresis, treatment with an anticholinesterase agent, thymectomy, and treatment with an immunosuppresant agent are available (Drachman, 1994; Kessey & Sonshine, 1997). No controlled clinical studies have been done to determine a preferred treatment (Howard, 1997). The patientís degree of muscle weakness, degree of impairment, age, and sex may influence which treatment option is chosen. With treatment, most patients have significant improvement in muscle strength and are able to live relatively normal lives. About 20% of autoimmune MG patients go into a spontaneous remission that lasts longer than one year (Kessey & Sonshine, 1997).

Lifestyle Change

     Favorable lifestyle factors, especially adequate rest and a well-balanced diet, can decrease or even help reverse the symptoms of MG (Howard, 1997; Kessey & Sonshine, 1997). Symptoms of MG can be managed by pacing daily activities to avoid unnecessary muscle fatigue (Howard, 1997). Depending on the severity of their muscle weakness and impairment, MG patients may need to simplify daily activities and adopt a daily schedule which optimizes the amount of activity undertaken at times of maximum strength and minimizes the amount of activity undertaken at other times (Howard, 1997; Kessey & Sonshine, 1997). Exposure to infections and stress can worsen the symptoms of autoimmune MG  (Howard, 1997). A variety of substances such as anesthetic agents, muscle relaxants, steroids, some thyroid medications, steroids, magnesium salts, and anticonvulsant medications increase symptom severity in some autoimmune MG patients (Kessey & Sonshine, 1997).

Short-Term Treatments

        In plasmapheresis, or plasma exchange, several liters of the autoimmune MG patientís blood are withdrawn intravenously and centrifuged  (Drachman, 1994; Howard, 1997; Kessey & Sonshine, 1997). The patientís red blood cells are then added either to plasma pooled from several healthy donors or to artificial plasma (plasma made of albumin and saline solution). This plasma/red blood cell mixture is then returned to the patient's blood stream.  Plasmapheresis removes the abnormal anti-AChR antibodies from the patientís body. A striking but short-lived improvement in muscle strength generally follows a plasmapheresis treatment session (Howard, 1997; Kessey & Sonshine, 1997). The improvement is short-lived because the patientís immune system continues to produce anti-AChR antibody. Plasmapheresis is typically conducted every other day for two weeks when a short-term improvement is critical due to an impending respiratory crisis or surgery (Howard, 1997).
        In intravenous human immunoglobulin (IVIG) therapy, the gamma globulin antibodies of many donors are pooled and delivered intravenously into the patient (Drachman, 1994; Howard, 1997; Kessey & Sonshine, 1997). IVIG is used to treat a variety of autoimmune disorders (Howard, 1997). The exact mechanism of IVIGís action is not know, but IVIG probably non-specifically down regulates all antibody production (including anti-AChR antibody production) (Howard, 1997; Kessey & Sonshine, 1997). Improvement usually occurs within a week of IVIG treatment and lasts for several weeks (Howard, 1997). IVIG is a relatively expensive treatment. Moreover, the down-regulation of antibody production weakens the immune system, placing the patient at increased risk for opportunistic infection. IVIG is typically only used when a short-term improvement is critical due to an impending respiratory crisis

Long-Term Treatments

        Anticholinesterase agents block the function of anticholinesterase, the enzyme that normally breaks down acetylcholine  (Drachman, 1994; Howard, 1997; Kessey & Sonshine, 1997). This allows ACh to remain in the neuromuscular junction for a longer period of time. This extra time allows a single ACh molecule to activate more AChRs than it normally could. An increase in the number of activated AChRs should increase the odds of an action potential successfully being generated (Drachman, 1987). Anticholinesterase agents are administered orally, with the dosage schedule varrying with the agent and with the patient (Howard 1997; Kessey & Sonshine, 1997). The effects of most anticholinesterase agents last for several hours, with the maximum symptomatic relief occurring one hour after ingestion (Howard, 1997).
        Thymectomy, the surgical removal of the thymus, frequently decreases the severity of and in some cases eliminates autoimmune MG symptoms (Drachman, 1994; Howard, 1997; Kessey & Sonshine, 1997). Symptomatic improvement generally occurs gradually following the surgery, with peak effect reached within several months or years of surgery (Howard, 1997).  Autoimmune MG patients with a thymoma (thymic tumor) are almost always treated with thymectomy (Drachman, 1994; Howard, 1997; Kessey & Sonshine, 1997). Thymomas are usually benign, but a thymectomy is still performed due to the risk of malignancy (Howard, 1997; Kessey & Sonshine, 1997). Of the autoimmune MG patients without a thymoma who undergo thymectomy, about 30%  eventually go into a complete remission and an additional 50% experience a significant improvement in symptom severity (Howard, 1997). Thymectomys are typically only done on individuals past the age of puberty, since the removal of the thymus during childhood can lead to a severely suppressed immune system, making the patient vulnerable to opportunistic infections.  As long as the patient is past puberty, thymectomy rarely worsens the course of autoimmune MG or impairs the immune system (Howard, 1997). The exact reason why thymectomy improves symptom severity is unknown. However, evidence suggests that the thymus may somehow aid in the perpetuation of the autoimmune response (Zweiman & Levinson, 1992).
        Immunosuppressive agents are a group of drugs that act to generally suppress the bodyís immune system (Janeway et al., 1999). This decreases the autoimmune reaction responsible for MG symptoms, but it also makes the patient vulnerable to opportunistic infection (Kessey & Sonshine, 1997; Howard, 1997). Immunosuppressive agents are rarely the treatment of choice for MG.

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