Myasthenia Gravis 101 Meeting of the Myasthenia Gravis

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A Presentation for the Participants at the Annual Meeting of the Myasthenia Gravis Foundation

April 23, 1999

James F. Howard, Jr., M.D.

Professor of Neurology and

Director, Neuromuscular Disorders Section

Department of Neurology

The University of North Carolina at Chapel Hill

Chapel Hill, NC



Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction. Much has been learned about the pathophysiology and immunopathology of myasthenia gravis during the past 20 years. What was once a relatively obscure condition of interest primarily to neurologists is now the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implications for the treatment of other autoimmune disorders. This overview is designed to familiarize the reader with the basic concepts of Myasthenia Gravis. Other speakers will address specific issues of treatment, thymectomy and research.



HISTORY

In 1672, Sir Thomas Willis described a disease with fluctuating weakness that varied throughout the day and could render patients “mute fish.” Erb described the classic signs of MG in 3 patients in 1879 and recognized that the fluctuating weakness differed from that seen in other diseases. In 1893, Goldflam provided a comprehensive description of the disease and 2 years later, Jolly used the term myasthenia gravis pseudoparalytics to described the condition in a 14 year-old boy. Jolly also showed the visible twitch of muscle induced by electrical stimulation decreased with repetition. The first case of Myasthenia Gravis in the US was probably that of the Chief Opechankanough of the Powatan Tribe in Virginia. Historians describe “excessive fatigue….His eyelids were so heavy that he could not see unless they were lifted up by his attendants…..”.



As association between the thymus gland and MG was first suggested in 1901 when he described a thymoma in a patient with MG. The association of thymus gland and hyperplasia and MG was reported 4 years later in 1913, Schumacher and Roth described the first thymectomy, performed 2 years earlier by Sauerbruck. In 1934, Mary B. Walker treated a 56 year old woman with physostigmine, an acetylcholinesterase inhibitor (a forerunner of Mestinon and Neostigmine), and noted a striking improvement in the patient’s strength. Neostigmine became the first accepted medical treatment after Wall reported its use in 1935.



Lindsley reported variation in the amplitude of single motor unit potentials in patients with MG in 1935. Harvey and Masland confirmed the findings in 1941 and described the decremental muscle response to repetitive nerve stimulation that is the basis for the most commonly used electrodiagnostic test for the disease.



Professor Simpson (of Scotland) noted a frequent associates of MG with diseases that have a presumed autoimmune cause in 1960 and postulated that MG was mediated by an immunological attack on the muscle endplate (neuromuscular junction). In 1964, Swedish scientists demonstrated specific abnormalities in neuromuscular transmission (nerve-muscle communication) in very technical and detailed electrical studies of muscle from patients with this disease.

Hormonal therapy of MG with anterior pituitary extract was first tried by Simon in 1935. The first report of successful therapy with prednisone was by Kjaer in 1971 and the late Dr. T.R. Johns pioneered this therapy in the mid 1970s at the University of Virginia. It was the pioneering work of Dr. Johns and his colleagues that opened the doors for immunosuppressive therapy for MG.

In 1973, Patrick and Lindstrom noted fluctuating, neostigmine-responsive weakness in rabbits immunized with acetylcholine receptor (ACHR) protein. Near simultaneous observations at the University of Virginia and in Sweden led to the animal model, Experimental Autoimmune Myasthenia Gravis. The similarity of this condition to human MG and the demonstration of antibodies to ACHR in the serum of patients with MG were the seminal observations that ultimately led to the current understanding of the immune-mediated basis of MG. It is without question that the experimental model has been the key to our understanding of this disease and the advancement which have occurred.

EPIDEMIOLOGY
The prevalence of MG in the United States is estimated at 14/100,000 population, approximately 36,000 cases in the United States. However, MG is probably under-diagnosed and the prevalence is probably higher. Previous studies showed that women were more often affected than men. The most common age at onset was the second and third decades in women and the seventh and eighth decades in men. As the population ages, the average age at onset has increased correspondingly, and now males are more often affected than females, and the onset of symptoms is usually after age 50.

CLINICAL PRESENTATION
Patients, with MG go to their physician complaining of specific muscle weakness and not of generalized fatigue. Ocular motor disturbances, ptosis or diplopia, are the initial symptom of MG in two-thirds of our patients; almost all had both symptoms within 2 years. Oropharyngeal muscle weakness, difficulty -chewing, swallowing, or talking, was the initial symptom in one-sixth of patients, and limb weakness in only 10%. Initial weakness was rarely limited to single muscle groups such as neck or finger extensors or hip flexors.

The severity of weakness fluctuates during the day, usually being least severe in the morning and worse as the day progresses, especially after prolonged use of affected muscles. Ocular symptoms typically become worse while reading, watching television, or driving, especially in bright sunlight. Many patients find that dark glasses reduce diplopia and hide drooping eyelids. Jaw muscle weakness typically becomes worse during prolonged chewing, especially tough meats or chewy candy. Careful questioning by the physician often reveals evidence of earlier, unrecognized myasthenic features; e.g., frequent purchases of new eyeglasses to correct blurry vision, avoidance of foods that became difficult to chew or swallow, cessation of activities that require prolonged use of specific muscles. Review of family photographs will sometimes demonstrate drooping eyelids which were not previously recognized. Friends may have noted a sleepy or sad facial appearance caused by ptosis or facial weakness. The course of disease is variable but usually progressive if not treated.

Weakness is restricted to the ocular muscles in about 10% of cases. Factors that worsen myasthenic symptoms are emotional upset, systemic illness (especially viral respiratory infections), hypothyroidism or hyperthyroidism, pregnancy, the menstrual cycle, drugs affecting neuromuscular transmission (see below), and increases in body temperature. The unusual distribution and fluctuating weakness of MG often suggests psychiatric illness and many women are initially treated as such. Conversely, ptosis and diplopia suggest increased intracranial pressure and often lead to unnecessary cranial imaging studies or arteriography.

PHYSICAL FINDINGS
Ocular Muscles - Most patients with MG have weakness of ocular muscles. Asymmetrical weakness of several muscles in both eyes is typical. Ptosis is usually asymmetrical and varies during sustained activity. To compensate for ptosis, the frontalis muscle may be chronically contracted, producing a worried or surprised look. This may be the only visible evidence of facial weakness. Patients with ocular muscle weakness usually have weakness of eye closure

Oropharyngeal Muscles - Oropharyngeal muscle weakness causes changes in the voice, difficulty chewing and swallowing, inadequate maintenance of the upper airway, and altered facial appearance. The voice may be nasal, especially after prolonged talking, and liquids may escape through the nose when swallowing because of palatal muscle weakness. Weakness of the laryngeal muscles causes hoarseness. Difficulty chewing and swallowing will cause choking or clearing of the throat or coughing after eating. Myasthenic patients, particularly those with severe or long-standing disease, may have a characteristic facial appearance. At rest, the corners of the mouth droop downward making the patient appear depressed. Attempts to smile produce contraction of the medial portion of the upper lip and a horizontal contraction of the comers of the mouth without the natural upward curling. This gives the appearance of a snarl and that the patient is angry or hostile. A frequent sign of jaw weakness is that the patient holds the jaw closed with the thumb under the chin, the middle finger curled under the nose or lower lip and the index finger extended up the cheek, producing a studious or attentive appearance.

Limb Muscles - Any trunk or limb muscle can be weak but some are more often affected than others. Neck flexors are usually weaker than neck extensors, and the deltoids, triceps and extensors of the wrist and fingers are frequently weaker than other limb muscles.

INHERITANCE OF MG
A small number of patients with the autoimmune form of MG will have an affected primary relative. The vast majority of patients do not. The genetics of this observation are not understood and it may relate to the predisposition of autoimmune disorders in general.

Congenital forms of MG are genetically acquired (see below).

PATHOPHYSIOLOGY OF MG
The human neuromuscular junction is a highly complex system in which the nerve terminal lies in close proximity to a very organized portion The normal neuromuscular junction releases acetylcholine (ACh) from the motor nerve terminal in discrete packages called quanta. The ACh quanta diffuse across the synaptic cleft and bind to highly specialized receptors on the folded muscle endplate membrane. Stimulation of the motor nerve releases many ACh quanta that depolarize (energize) the muscle endplate region causing muscle contraction.

In acquired MG, the concentration of ACh receptors on the muscle endplate membrane is reduced, and antibodies are attached to the membrane. ACh is released normally, but its effect on the postsynaptic membrane is reduced. There are several observation that support the concept that MG is an immune-mediated disease of the ACHR complex:

1. Patients with MG have an increased incidence of other presumed or known immune-mediated diseases, such as rheumatoid arthritis, thyroid disease, vitamin B12 deficiency.

2. A transitory neonatal form of the disease occurs in children born to mothers affected with MG.

3. The weakness of MG improves after removal of serum by including plasma exchange.

5. In-immunosuppressive drug treatment, produces improvement in most patients with MG.

6. An animal model of MG can be produced by immunization with purified ACHR protein.

7. Antibodies against human ACHR are found in the serum of most patients with MG.

8. Myasthenic serum or IgG produces a defect of neuromuscular transmission when injected into animals.

The role of serum antibodies against ACHR in the pathophysiology of the disease is not fully understood. Although antibody levels are usually higher in patients with more severe disease, wide variation of values exists among patients. As many as 25% of patients are seronegative (do not have antibodies which can be measured). Even seronegative patients may improve after plasma exchange, and the neuromuscular abnormality can be transferred to animals by injecting serum from seronegative patients. The antibodies responsible for the neuromuscular abnormality may not always be those that are measured, and the serum antibody level may not reflect the amount of antibody attached to the muscle endplate.

Much of the research in the last 10 years has been directed towards the understanding of the cellular immune system and its role in MG. While T-lymphocytes do not play a role in the damage to antigenic determinants at the neuromuscular junction, they do play a crucial role in the initiation and propagation of the disease. Anti-AChR reactive CD4+ T-cells are found in the serum and thymus glands of myasthenic patients. These can be propagated in vitro and express T helper functions. Thymectomy, a common treatment for MG, results in a reduction in the anti-AChR reactivity of circulating T-cells. Most recently, synthesis of human anti-AChR antibodies and clinical myasthenic symptoms can be transferred to SCID (severe combined immunodeficiency) mice following engraftment of the blood lymphocytes from myasthenic patients if they have not been depleted of CD4+ cells. Our understanding of the cellular immune abnormalities of MG will be the next stepping stone to a new class of treatments.

THE THYMUS IN MG
A detailed discussion of the thymus gland and its role in MG is beyond the scope of this syllabus. Thymic abnormalities are clearly associated with MG but the nature of the association is uncertain. Ten percent of patients with MG have a thymic tumor and 70% have hyperplastic changes (germinal centers) that indicate an active immune response. These are areas within lymphoid tissue where B- cells lymphocytes interact with helper T-cells to produce antibodies. Because the thymus is the central organ for immunological self-tolerance, it is reasonable to suspect that thymic abnormalities cause the breakdown in tolerance that causes an immune-mediated attack on ACHR in MG. The thymus contains all the necessary elements for the pathogenesis of MG: myoid cells that express the ACHR antigen, antigen presenting cells, and immunocompetent T-cells. Thymus tissue from patients with MG produces ACHR antibodies when implanted into immunodeficient mice.

Most thymic tumors in patients with MG are benign and can be removed completely at surgery. It is unlikely that thymomas result from chronic thymic hyperactivity because MG can develop years after thymoma removal and the HLA haplotypes that predominate in patients with thymic hyperplasia are different from those with thymomas.

In our experience, patients with thymoma usually have more severe disease, higher levels of ACHR antibodies, and more severe EMG abnormalities than patients without thymoma. Almost 20% of our patients with MG whose symptoms began between the ages of 30 and 60 years have thymoma; the frequency of thymoma was much lower when symptoms began after age 60.

DIAGNOSTIC PROCEDURES
The Chloride (Tensilonã ) Test - Weakness caused by abnormal neuromuscular transmission characteristically improves after intravenous administration of edrophonium chloride. With the exception of the ocular and pharyngeal muscles, the examiner must rely on the patient to exert maximum effort before and after drug administration to assess its effect. For this reason, the test is most reliable when the patient has ptosis or nasal speech.

The Tensilonã test is positive in more than 90% of patients with MG. However, improved strength after Tensilonã is not unique to MG. It may produce improvement in a number of other neurological disorders. However, this improvement is slight and not to the degree often seen in patients with MG. Some patients who do not respond to intravenous Tensilonã may respond to intramuscular neostigmine, because of its longer duration of action. Intramuscular neostigmine is particularly useful in infants and children whose response to intravenous Tensilonã may be too brief for adequate observation. In some patients, a therapeutic trial of oral pyridostigmine for several days may produce improvement that can not be appreciated after a single dose of Tensilonã or neostigmine.

Antibodies Against ACHR - Eighty percent of our patients with acquired generalized myasthenia and 55% with ocular myasthenia have serum antibodies that bind human ACHR. The serum concentration of ACHR antibody varies widely among patients with similar degrees of weakness and can not predict the severity of disease in individual patients. Rarely ACHR antibodies are elevated in patients with systemic lupus erythematosus, inflammatory neuropathy, amyotrophic lateral sclerosis, rheumatoid arthritis taking D-penicillamine, thymoma without MG, and in normal relatives of patients with MG. In general, an elevated concentration of ACHR binding antibodies in a patient with compatible clinical features confirms the diagnosis of MG, but normal antibody levels do not exclude the diagnosis.

Electromyography - Several different electrodiagnostic studies are performed to more fully understand the patient\'s neuromuscular physiology. The physician must determine whether there are abnormalities of nerve conduction, problems with the muscle membrane and to assess whether there is an abnormality of neuromuscular transmission as seen in Myasthenia Gravis. It is then the physician\'s job to make a determination as to the distribution and severity of the abnormality. Several different studies are used to determine this.

Repetitive Nerve Stimulation (RNS) - The commonest electrodiagnostic study to look for MG involves the repetitive stimulation of the nerve with an electric shock while recording the muscle response. The amplitude of the fourth or fifth response to a train of low frequency nerve stimuli falls at least 10% from the initial value. This decrementing response to RNS is seen more often in proximal muscles, such as the facial muscles, biceps, deltoid, and trapezium than in hand muscles. While this test is highly specific for disorders of neuromuscular transmission such as MG, it is not very sensitive. We have found a significant decrement to RNS in either a hand or shoulder muscle in 61% of patients with MG. Therefore a normal study does not exclude the diagnosis of MG.

Needle EMG - Standard needle electrode EMG is performed to exclude other diseases that either resemble or occur concomitantly with MG, such as myositis or thyroid myopathy.

Single-fiber EMG (SFEMG) is the most sensitive clinical test of neuromuscular transmission and shows increased jitter in some muscles in almost all patients with MG. Jitter is greatest in weak muscles but may be abnormal even in muscles with normal strength. Patients with mild or purely ocular muscle weakness may have increased jitter only in facial muscles. Increased jitter is a nonspecific sip of abnormal neuromuscular transmission and can be seen in other motor unit diseases. The physician must rely on his other testing to make the distinction. Normal jitter in a weak muscle excludes abnormal neuromuscular transmission as the cause of weakness.

Comparison of Diagnostic Techniques - Intravenous edrophonium chloride is often diagnostic in patients with ptosis or ophthalmoparesis, but is less useful when other muscles are weak. An elevated serum ACHR binding antibody level virtually assures the diagnosis of MG, but a normal level does not exclude it. Repetitive nerve stimulation confirms impaired neuromuscular transmission but it is not very sensitive and is frequently normal in patients with mild or purely ocular disease.

The measurement of jitter by SFEMG is the most sensitive clinical test of neuromuscular transmission and is abnormal in almost all patients with MG. A normal test in a weak muscle excludes the diagnosis of MG, but an abnormal test can occur when other motor unit disorders cause defects in neuromuscular transmission.

TREATMENT
The treatment of MG will be discussed by others (Drs. Jaretzki and Zacharias) at this conference and will not be detailed in this syllabus. A controlled clinical trial has never been reported for any medical or surgical modality used to treat MG. All recommended regimens are empirical and experts disagree on treatments of choice. Treatment decisions are based on knowledge of the natural history of disease in each patient and the predicted response to a specific form of therapy. Treatment goals must be individualized according to the severity of disease, the patient\'s age and sex, and the degree of functional impairment. The response to any form of treatment is difficult to assess because the severity of symptoms fluctuates. Spontaneous improvement, even remissions, occur without specific therapy, especially during the early stages of the disease. Successful treatment of MG requires close medical supervision and long-term follow-up.

Cholinesterase Inhibitors - Cholinesterase Inhibitors (ChE) retard the enzymatic hydrolysis of ACh at cholinergic synapses, so that ACh accumulates at the neuromuscular junction and its effect is prolonged. ChE inhibitors cause considerable improvement in some patients and little to none in others. Strength rarely returns to normal.

Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin) are the most commonly used ChE inhibitors. Pyridostigmine is generally preferred because it has a lower frequency of gastrointestinal side effects. Pyridostigmine is available as syrup for children or for nasogastric tube administration in patients with impaired swallowing. A timed-release tablet of pyridostigmine (Mestinon Timespan, 180 mg) is useful as a bedtime dose for patients who are too weak to swallow in the morning. Its absorption is erratic, leading to possible overdosage and underdosage, and it should not be used during waking hours. Even at night, it is sometimes preferable for the patient to awaken at the appropriate dosing interval and take the regular tablet. Overdosage with this class of drugs may produce muscle weakness that may not be distinguishable for myasthenic weakness. No fixed dosage schedule suits all patients. The need for ACh inhibitors varies from day-to-day and during the same day in response to infection, menstruation, emotional stress, and hot weather.

Different muscles respond differently; with any dose, certain muscles get stronger, others do not change, and still others become weaker. The drug schedule should be titrated to produce an optimal response in muscles causing the greatest disability. For example, patients with oropharyngeal weakness need doses timed to provide optimal strength during meals. Ideally, the effect of each dose should last until time for the next, without significant underdosing or overdosing at any time. in practice, this is not possible.

Adverse effects of ChE inhibitors may result from ACh accumulation at muscarinic receptors on smooth muscle and autonomic glands and at nicotinic receptors of skeletal muscle. Central nervous system side effects are rarely seen with the doses used to treat MG.

Gastrointestinal complaints are common; queasiness, loose stools, nausea, vomiting, abdominal cramps, and diarrhea. Increased bronchial and oral secretions are a serious problem in patients with swallowing or respiratory insufficiency. Symptoms of muscarinic overdosage may indicate that nicotinic overdosage (weakness) is also occurring. Gastrointestinal side effects can be suppressed with loperamide HCI (Imodium), propantheline bromide (Pro-Banthine), glycopyrrolate (Robinul), and diphenoxylate HCI with atropine (Lomotil, Mylan, Roxane). Some of these drugs produce weakness at high dosage.

Thymectomy - Thymectomy is recommended for most patients with MG. Most reports do not correlate the severity of weakness before surgery and the timing or degree of improvement after thymectomy. The maximal favorable response generally occurs 2 to 5 years after surgery. However, the response is relatively unpredictable and significant impairment may continue for months or years after surgery. Sometimes, improvement is only appreciated in retrospect. The best responses to thymectomy are in young people early in the course of their disease, but improvement can occur even after 30 years of symptoms. In our experience, patients with disease onset after the age of 60 rarely show substantial improvement from thymectomy. Patients with thymomas do not respond as well to thymectomy as do patients without thymoma. Thymectomy may be followed by improvement even in seronegative patients and we do not base the decision to perform thymectomy on the presence or level of ACHR- antibodies The preferred surgical approach is transthoracic; the sternum is split and the anterior mediastinum explored. Transcervical and endoscopic approaches have less postoperative morbidity, but do not allow sufficient exposure for total thymic removal.

Corticosteroids - Marked improvement or complete relief of symptoms occurs in more than 75% of patients treated with prednisone, and some improvement occurs in most of the rest. Much of the improvement occurs in the first 6 to 8 weeks, but strength may increase to total remission in the months that follow. The best responses occur in patients with recent onset of symptoms, but patients with chronic disease may also respond. The severity of disease does not predict the ultimate improvement. Patients with thymoma have an excellent response to prednisone before or after removal of the tumor. We have found that the most predictable response to prednisone occurs when treatment begins with a daily dose. This dose is given until sustained improvement occurs, which is usually within 2 weeks, and is then changed to an alternate daily schedule beginning with 100 to 120 mg. This dose is gradually decreased over many months to the lowest dose necessary to maintain improvement. The rate of decrease must be individualized: Most patients who respond well to prednisone become weak if the drug is stopped but maintain
strength on very low dosages.

Immunosuppressant Drugs - Several immunosuppressant drugs are effective in MG.

Azathioprine reverses symptoms in most patients but the effect is delayed by 6
to 8 months. Once improvement begins, it is maintained for as long as the drug is given, but symptoms recur 2 to 3 months after the drug is discontinued or the dose is reduced below therapeutic levels. Patients who fail corticosteroids may respond to azathioprine and the reverse is also true. Some respond better to treatment with both drugs than to either alone. Because the response to azathioprine is delayed, both drugs may be started simultaneously with the intent of rapidly tapering prednisone when azathioprine becomes effective.

Cyclosporine inhibits predominantly T-lymphocyte-dependent immune responses and is sometimes beneficial in treating MG. Most patients with MG improve I to 2 months after starting cyclosporine and improvement is maintained as long as therapeutic doses are given. Maximum improvement is achieved 6 months or longer after starting treatment. After achieving the maximal response, the dose is gradually reduced to the minimum that maintains improvement.

Plasma Exchange - Plasma exchange is used as a temporary intervention for patients with sudden worsening of myasthenic symptoms for any reason, to rapidly improve strength before surgery, and as a chronic intermittent treatment for patients who are refractory to all other treatments. The need for plasma exchange, and its frequency of use is determined by the clinical response in the individual patient. Almost all patients with acquired MG improve temporarily following plasma exchange. Most patients who respond to the first plasma exchange will respond again to subsequent courses. Repeated exchanges do not have a cumulative benefit.

Intravenous Immune Globulin (Mg) - Many groups have reported a favorable response to high-dose IvIg. Its mechanisms of action include is not completely understood. Improvement occurs in 50 to 100% of patients, usually beginning within 1 week and lasting for several weeks or months. The indications for IVIG are similar to those for plasma exchange. 'IVIG is an effective alternative to plasma exchange, especially in patients with poor vascular access or when plasma exchange is not available.

ASSOCIATION OF MG WITH OTHER DISEASES
MG is often associated with other immune-mediated diseases, especially hyperthyroidism and rheumatoid arthritis. One-fifth of our myasthenic patients have another disease: 7% have diabetes mellitus before corticosteroid treatment, 6% have thyroid disease, 3% have nonthymus neoplasm, and less than 2% have rheumatoid arthritis.

Treatment of Associated Diseases
The effect of concomitant diseases and their treatment on myasthenic symptoms is an important consideration. Thyroid disease should be vigorously treated; both hypo- and hyperthyroidism adversely affect myasthenic weakness. Intercurrent infections require immediate attention because they exacerbate MG and can be life-threatening in patients who are immunosuppressed.

Drugs that cause neuromuscular blockade must be used with caution. Many antibiotics fall into that category. Ophthalmic preparations of 0-blockers for glaucoma and their use for high blood pressure and migraine headaches should be avoided. Several classes of antibiotics, primarily the aminoglycoside antibiotics (end in micin or mycin), erythromycin or zithromax may cause worsening of muscle strength. D-penicillamine and botulinum toxin should not be used.

Annual immunization against influenza is recommended for all patients with MG, and immunization against pneumococcus is recommended before starting prednisone or other immunosuppressive drugs.

Inactivated polio vaccine rather than attenuated live oral polio vaccine should be used in people who are immunocomprornised, or in children who have household contacts with immunocompromised individuals.

SERONEGATIVE MG
One-quarter of patients with acquired, presumably immune-mediated MG do not have detectable serum antibodies against AChR-Ab. Seronegative patients are more likely than seropositive patients to be male, to have milder disease, have ocular MG, fewer thymomas, less frequent thymic hyperplasia, and more frequent thymic atrophy. In seronegative patients, the diagnosis is based on the clinical presentation, the response to ChE inhibitors and EMG findings. Genetic myasthenia must be considered in all childhood-onset seronegative MG. MG treatment of seronegative, acquired MG is the same as for seropositive patients. The absence of ACHR antibodies does not necessarily mean that an unsatisfactory response to immunosuppression, plasma exchange, or thymectomy is expected.



SPECIAL SITUATIONS
Myasthenic or Cholinergic Crisis - Myasthenic crisis is respiratory failure from disease. Patients in myasthenic crisis who previously had well-compensated respiratory function usually have a definable precipitating event, such as infection, surgery, or rapid tapering of immunosuppression.

Cholinergic crisis is respiratory failure from overdosage of ChE inhibitors. It was more common before the introduction of immunosuppressive therapy when very large dosages of ChE inhibitors were used. Respiratory failure of any cause is a medical emergency and requires prompt incubation and ventilatory support.

Anesthetic Management
The stress of surgery and some drugs used perioperatively may worsen myasthenic weakness. As a rule, local or spinal anesthesia is preferred over inhalation anesthesia. Neuromuscular blocking agents should be used sparingly, if at all. Adequate muscle relaxation can usually be produced by inhalation anesthetic agents alone. These issues must be discussed thoroughly with the patient's anesthesiologist.

Pregnancy
Myasthenic women may improve, worsen, or remain unchanged during pregnancy. Worsening during the first trimester is more common in first pregnancies, whereas third-trimester worsening and postpartum exacerbations are more common in subsequent pregnancies. Therapeutic abortion is rarely, if ever, needed because of MG. The use of intravenous ChE inhibitors is contraindicated during pregnancy because they may produce uterine contractions. Although pregnancy is not usually recommended in patients treated with corticosteroids, adverse outcomes in children born to myasthenic mothers taking even high doses throughout pregnancy are not reported. We do not use cytotoxic drugs during pregnancy because of their potential mutagenic effects.

Labor and delivery are usually normal, and cesarean section is only needed for obstetrical indications. Regional anesthesia is preferred for delivery or cesarean section. Magnesium sulfate should not be used to manage pre-eclampsia because of its neuromuscular locking effects. Barbiturates usually provide adequate treatment. In our experience, breast feeding is not a problem, despite the theoretical risk of passing maternal ACHR antibodies to the newborn.

Transitory Neonatal Myasthenia
A transitory form of MG affects 10% to 20% of newborns whose mothers have immune-mediated MG. The severity of symptoms in the newborn does not correlate with the severity of symptoms in the mother. Affected newborns are hypotonic (floppy) and feed poorly during the first 3 days. They may have a weak cry. Symptoms usually last less than 2 weeks, but may continue for as long as 12 weeks.

Myasthenia gravis does not recur later.

All children of myasthenic mothers should be assessed for transitory neonatal MG. Edrophonium chloride or repetitive stimulation establishes the diagnosis. Affected newborns require symptomatic treatment with ChE inhibitors if swallowing or breathing is impaired. Plasma exchange should be considered in newborns with respiratory weakness.

GENETIC MYASTHENIC SYNDROMES
Genetic forms of myasthenia are not immune-mediated. They are a heterogeneous group of disorders caused by several different abnormalities of neuromuscular transmission. One can think of them as architectural problems in how the neuromuscular junction has been built. Symptoms are typically present at birth or early childhood, but can be delayed until young adult life.

The onset of myasthenic symptoms at birth is always genetic with the exception of the transitory neonatal form of the immune mediated disease. All genetic forms of myasthenia gravis are known or presumed to be transmitted by autosomal recessive inheritance except the slow channel syndrome which is transmitted by autosomal dominant inheritance. Myasthenia that begins in infancy or childhood may be genetic or acquired.

THE FUTURE
The future of Myasthenia Gravis lies in the elucidation of the molecular immunology of the anti- acetylcholine receptor response with the goal of developing a rational treatment for the illness that will cure the abnormality in the immune system that results in the ACHR immune response. To this end, six broad categories of theoretical treatment strategies need to be explored. First, those treatments which target the antigen specific B-cells; Second, those treatments which target the antigen specific CD4+ T-cells; Third, those treatments which interfere with co-stimulatory response for antigen presentation, Fourth, treatments aimed at inducing tolerance or anergy of the CD4+ T-cell to the autoantigen or the CD4+ epitopes; Fifth, those treatments designed to stimulate those immunological circuits which activate CD8+ cells specific for the activation antigens expressed by CD4+ cells and Sixth, those treatments which intervene with cytokine function and discourage autoimmune mediated inflammatory responses.

REVIEW ARTICLES
Conti-Fine BM, Protti, MP, Belone M, Howard JF, Jr.: Myasthenia Gravis and Its Experimental Model: The immunobiology of an Autoimmune Disease. Landes Bioscience Publishers, Georgetown, Texas. 1997.

Engel AG: Congenital myasthenic syndromes. Neurologic Clinics of North America 1994; 12:401-437

Howard JF Jr.: Adverse drug effects on neuromuscular transmission. Seminars in Neurology 1990;10:89-102.

Howard JF Jr.: Myasthenia gravis in the elderly. In Practical Neurology of the Elderly, edit., M. Mark, J. Sage, Marcel Dekker, Inc., Chapter 5 pp. 189-236, 1996.
Howard JF, Sanders DB, Massey JM: The electrodiagnosis of myasthenia gravis and the Lambert- Eaton myasthenic syndrome.

Neurologic Clinics of North America, 12:305-330,1994.

Oosterhuis HJGH: The natural course of myasthenia gravis: a long term follow up study. Journal of Neurology, Neurosurgery, and Psychiatry 1989;52:1121-1127.

Sanders DB, Howard JF Jr.: Disorders of Neuromuscular transmission. In Neurology in Clinical Practice, edit., WG Bradley, RB Daroff, GM Fenichel, CD Marsden, Butterworth Publishers, 2nd edition Chapter 83 pp. 1983-2002, 1995.











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