myasthenia gravis myasthenia gravis myasthenia gravis (mg) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. the most commonly affected muscles are those of the eyes, face, and swallowing. it can result in double vision, drooping eyelids, trouble talking, and trouble walking. onset can be sudden. those affected often have a large thymus or develop a thymoma. myasthenia graviseye deviation and a drooping eyelid in a person with myasthenia gravis trying to open her eyesspecialtyneurologysymptomsvarying degrees muscle weakness, double vision, drooping eyelids, trouble talking, trouble walkingusual onsetwomen under 40, men over 60durationlong termcausesautoimmune diseasediagnostic methodblood tests for specific antibodies, edrophonium test, nerve conduction studiesdifferential diagnosisguillain–barré syndrome, botulism, organophosphate poisoning, brainstem stroketreatmentmedications, surgical removal of the thymus, plasmapheresismedicationacetylcholinesterase inhibitors (neostigmine, pyridostigmine), immunosuppressantsfrequency50 to 200 per million myasthenia gravis is an autoimmune disease of the neuro-muscular junction which results from antibodies that block or destroy nicotinic acetylcholine receptors (achr) at the junction between the nerve and muscle. this prevents nerve impulses from triggering muscle contractions. most cases are due to immunoglobulin g1 (igg1) and igg3 antibodies that attack achr in the postsynaptic membrane, causing complement-mediated damage and muscle weakness. rarely, an inherited genetic defect in the neuromuscular junction results in a similar condition known as congenital myasthenia. babies of mothers with myasthenia may have symptoms during their first few months of life, known as neonatal myasthenia. diagnosis can be supported by blood tests for specific antibodies, the edrophonium test, or a nerve conduction study. mg is generally treated with medications known as acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine. immunosuppressants, such as prednisone or azathioprine, may also be used. the surgical removal of the thymus may improve symptoms in certain cases. plasmapheresis and high-dose intravenous immunoglobulin may be used during sudden flares of the condition. if the breathing muscles become significantly weak, mechanical ventilation may be required. once intubated acetylcholinesterase inhibitors may be temporarily held to reduce airway secretions. mg affects 50 to 200 per million people. it is newly diagnosed in three to 30 per million people each year. diagnosis has become more common due to increased awareness. mg most commonly occurs in women under the age of 40 and in men over the age of 60. it is uncommon in children. with treatment, most of those affected lead relatively normal lives and have a normal life expectancy. the word is from the greek mys, "muscle" and astheneia "weakness", and the latin gravis, "serious". signs and symptoms the initial, main symptom in mg is painless weakness of specific muscles, not fatigue. the muscle weakness becomes progressively worse during periods of physical activity and improves after periods of rest. typically, the weakness and fatigue are worse toward the end of the day. mg generally starts with ocular (eye) weakness; it might then progress to a more severe generalized form, characterized by weakness in the extremities or in muscles that govern basic life functions. eyes in about two-thirds of individuals, the initial symptom of mg is related to the muscles around the eye. eyelid drooping (ptosis may occur due to weakness of m. levator palpebrae superioris) and double vision (diplopia, due to weakness of the extraocular muscles). eye symptoms tend to get worse when watching television, reading, or driving, particularly in bright conditions. consequently, some affected individuals choose to wear sunglasses. the term "ocular myasthenia gravis" describes a subtype of mg where muscle weakness is confined to the eyes, i.e. extraocular muscles, m. levator palpebrae superioris, and m. orbicularis oculi. typically, this subtype evolves into generalized mg, usually after a few years. eating the weakness of the muscles involved in swallowing may lead to swallowing difficulty (dysphagia). typically, this means that some food may be left in the mouth after an attempt to swallow, or food and liquids may regurgitate into the nose rather than go down the throat (velopharyngeal insufficiency). weakness of the muscles that move the jaw (muscles of mastication) may cause difficulty chewing. in individuals with mg, chewing tends to become more tiring when chewing tough, fibrous foods. difficulty in swallowing, chewing, and speaking is the first symptom in about one-sixth of individuals. speaking weakness of the muscles involved in speaking may lead to dysarthria and hypophonia. speech may be slow and slurred, or have a nasal quality. in some cases, a singing hobby or profession must be abandoned. head and neck due to weakness of the muscles of facial expression and muscles of mastication, facial weakness may manifest as the inability to hold the mouth closed (the "hanging jaw sign") and as a snarling expression when attempting to smile. with drooping eyelids, facial weakness may make the individual appear sleepy or sad. difficulty in holding the head upright may occur. other the muscles that control breathing and limb movements can also be affected; rarely do these present as the first symptoms of mg, but develop over months to years. in a myasthenic crisis, a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. crises may be triggered by various biological stressors such as infection, fever, an adverse reaction to medication, or emotional stress. pathophysiology mg is an autoimmune synaptopathy. the disorder occurs when the immune system malfunctions and generates antibodies that attack the body's tissues. the antibodies in mg attack a normal human protein, the nicotinic acetylcholine receptor, or a related protein called musk, a muscle-specific kinase. other, less frequent antibodies are found against lrp4, agrin, and titin proteins. human leukocyte antigen haplotypes are associated with increased susceptibility to myasthenia gravis and other autoimmune disorders. relatives of people with myasthenia gravis have a higher percentage of other immune disorders. the thymus gland cells form part of the body's immune system. in those with myasthenia gravis, the thymus gland is large and abnormal. it sometimes contains clusters of immune cells that indicate lymphoid hyperplasia, and the thymus gland may give wrong instructions to immune cells. neuromuscular junction: 1. axon 2. muscle cell membrane 3. synaptic vesicle 4. nicotinic acetylcholine receptor 5. mitochondrion a juvenile thymus shrinks with age. the nicotinic acetylcholine receptor in pregnancy for women who are pregnant and already have mg, in a third of cases, they have been known to experience an exacerbation of their symptoms, and in those cases, it usually occurs in the first trimester of pregnancy. signs and symptoms in pregnant mothers tend to improve during the second and third trimesters. complete remission can occur in some mothers. immunosuppressive therapy should be maintained throughout pregnancy, as this reduces the chance of neonatal muscle weakness, and controls the mother's myasthenia. about 10–20% of infants with mothers affected by the condition are born with transient neonatal myasthenia (tnm), which generally produces feeding and respiratory difficulties that develop about 12 hours to several days after birth. a child with tnm typically responds very well to acetylcholinesterase inhibitors, and the condition generally resolves over a period of three weeks, as the antibodies diminish, and generally does not result in any complications. very rarely, an infant can be born with arthrogryposis multiplex congenita, secondary to profound intrauterine weakness. this is due to maternal antibodies that target an infant's acetylcholine receptors. in some cases, the mother remains asymptomatic. diagnosis mg can be difficult to diagnose, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders. three types of myasthenic symptoms in children can be distinguished: transient neonatal myasthenia occurs in 10 to 15% of babies born to mothers afflicted with the disorder, and disappears after a few weeks. congenital myasthenia, the rarest form, occurs when genes are present from both parents. juvenile myasthenia gravis is most common in females. congenital myasthenias cause muscle weakness and fatigability similar to those of mg. the signs of congenital myasthenia usually are present in the first years of childhood, although they may not be recognized until adulthood. classification myasthenia gravis foundation of america clinical classification classdescription iany eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere iieye muscle weakness of any severity, mild weakness of other muscles iiapredominantly limb or axial muscles iibpredominantly bulbar and/or respiratory muscles iiieye muscle weakness of any severity, moderate weakness of other muscles iiiapredominantly limb or axial muscles iiibpredominantly bulbar and/or respiratory muscles iveye muscle weakness of any severity, severe weakness of other muscles ivapredominantly limb or axial muscles ivbpredominantly bulbar and/or respiratory muscles vintubation needed to maintain airway when diagnosed with mg, a person is assessed for his or her neurological status and the level of illness is established. this is usually done using the accepted myasthenia gravis foundation of america clinical classification scale. physical examination during a physical examination to check for mg, a doctor might ask the person to perform repetitive movements. for instance, the doctor may ask one to look at a fixed point for 30 seconds and to relax the muscles of the forehead, because a person with mg and ptosis of the eyes might be involuntarily using the forehead muscles to compensate for the weakness in the eyelids. the clinical examiner might also try to elicit the "curtain sign" in a person by holding one of the person's eyes open, which in the case of mg will lead the other eye to close. blood tests if the diagnosis is suspected, serology can be performed: one test is for antibodies against the acetylcholine receptor; the test has a reasonable sensitivity of 80–96%, but in ocular myasthenia, the sensitivity falls to 50%. a proportion of the people without antibodies against the acetylcholine receptor have antibodies against the musk protein. in specific situations, testing is performed for lambert-eaton syndrome. electrodiagnostics a chest ct-scan showing a thymoma (red circle) photograph of a person showing right partial ptosis (left picture), the left lid shows compensatory pseudo lid retraction because of equal innervation of the m. levator palpabrae superioris (hering's law of equal innervation): right picture: after an edrophonium test, note the improvement in ptosis. muscle fibers of people with mg are easily fatigued, which the repetitive nerve stimulation test can help diagnose. in single-fiber electromyography, which is considered to be the most sensitive (although not the most specific) test for mg, a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers. two muscle fibers belonging to the same motor unit are identified, and the temporal variability in their firing patterns is measured. frequency and proportion of particular abnormal action potential patterns, called "jitter" and "blocking", are diagnostic. jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit. ice test applying ice for 2–5 minutes to the muscles reportedly has a sensitivity and specificity of 76.9% and 98.3%, respectively, for the identification of mg. acetylcholinesterase is thought to be inhibited at the lower temperature, which is the basis for this diagnostic test. this generally is performed on the eyelids when ptosis is present and is deemed positive if a ≥2-mm rise in the eyelid occurs after the ice is removed. edrophonium test this test requires the intravenous administration of edrophonium chloride or neostigmine, drugs that block the breakdown of acetylcholine by cholinesterase (acetylcholinesterase inhibitors). this test is no longer typically performed, as its use can lead to life-threatening bradycardia (slow heart rate) which requires immediate emergency attention. production of edrophonium was discontinued in 2008. imaging a chest x-ray may identify widening of the mediastinum suggestive of thymoma, but computed tomography or magnetic resonance imaging (mri) are more sensitive ways to identify thymomas and are generally done for this reason. mri of the cranium and orbits may also be performed to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles. pulmonary function test the forced vital capacity may be monitored at intervals to detect increasing muscular weakness. acutely, negative inspiratory force may be used to determine adequacy of ventilation; it is performed on those individuals with mg. management treatment is by medication and/or surgery. medication consists mainly of acetylcholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process. thymectomy is a