Myasthenia gravis a review

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1 Myasthenia gravis a review toni ivičić university of zagreb school of medicine x DOI: Summary: Myasthenia gravis is the best studied example of a neuromuscular junction disease. The most important form is the autoimmune form of the disease, which is caused by the binding of autoantibodies to proteins involved in neuromuscular transmission the nicotinic ACh receptor or (less commonly) the muscle-specific tyrosine kinase. These interactions reduce the number of functional receptors and alter the neuromuscular junction morphology. Prevalence rates have increased to cases per million in the last decades. Acquired myasthenia gravis is characterized by skeletal muscle weakness that worsens with exertion, and improves with rest. The involvement of extrinsic ocular muscle presents as the initial symptom in about two-thirds of patients, usually progressing and affecting other bulbar muscles and limb muscles, which is called generalized myasthenia gravis. During the past decades, remarkable progress has been made in understanding of myasthenia gravis, and as nowadays this disease is highly treatable. Early recognition and diagnosis is crucial. Keywords: Eyelid ptosis, Muscle weakness, Myasthenia gravis, Neuromuscular junction, Thymoma Myasthenia gravis is the most common and extensively studied disease affecting the neuromuscular junction (NMJ) in skeletal muscle. The term myasthenia gravis, which is Latin and Greek in origin, means serious muscle weakness. The disease has two basic forms: the acquired autoimmune form, which is the most prevalent one, and congenital form of which fewer than 500 cases have been identified and will not be discussed in this review. In autoimmune myasthenia gravis, antibodies are produced against the nicotinic acetylcholine receptor in skeletal muscles, resulting in a weakened communication between the motor neuron and the muscle. Epidemiology and historical aspect Myasthenia gravis (MG) affects about in 100,000 people worldwide and is a relatively uncommon disease. The prevalence has been on the increase in the past few decades, probably as a result of improved diagnostics. In about two-thirds of patients, the first symptom is weakness of extrinsic ocular muscles (EOMs). In 1 of 10 MG patients, symptoms remain limited to the EOMs (ocular myasthenia gravis, omg). However, in the majority of patients, the symptoms progress and proceed to affect other bulbar muscles as well as limb muscles (generalized myasthenia gravis. gmg). 1 The incidence is age- and sex-related; below the age of 40, females are three times more likely to be diagnosed with myasthenia gravis. Between the ages of 40 and 50 and during puberty the chances are roughly equal, but over the age of 50, it occurs more commonly in males. 2 The first recognized case of myasthenia gravis is probably the illness of Indian Chief Opechankanough, who died in As historical accounts state, he was so weak as to be unable to walk, his eyelids were so heavy they had to be raised by his attendants and his muscle weakness improved with rest. 3 In 1672, the English physician Thomas Willis described a patient with the fatiguable weakness of limbs and bulbar muscles characteristic of MG. Attempts to treat myasthenia gravis were unsuccessfull until 1934, when Mary Walker realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine the administration of physostigmine to an MG patient promptly improved their myasthenic symptoms. In 1937, a female patient was noted to improve after a thymectomy was performed due to thymus pathology (which is common in MG patients). After these discoveries, cholinesterase inhibitors and thymectomy became the standard treatment for MG. 1,4 Immunopathogenesis in MG Physiology of the neuromuscular junction. The neuromuscular junction (NMJ) consists of α-motor neuron axon terminals, the synaptic cleft and the postsynaptic membrane of target muscle fibers (Figure-1). As it enters the muscle and approaches its target fibers, the motor axon ramifies into several fine branches. Each branch loses its myelin sheath and forms multiple swellings called synaptic boutons, which contain ACh-loaded synaptic vesicles and lie over a specialized region of the muscle fiber membrane the end-plate. NMJ postsynaptic membrane has characteristic deep folds, with nicotinic ACh receptors at the top of these folds. As the wave of depolarization opens voltage-gated Ca2+ channels on the presynaptic membrane, discrete packages (quanta) of ACh are released into the synaptic cleft. Until it is hydrolyzed by ACh esterase, ACh reaches and binds to AChR, opens its cation channels and produces end-plate potential (EPP), which activates voltage-gated Na + channels and spreads the action potential along the muscle fiber. 1,5 One other component of the NMJ is highly important in the pathogenesis of MG muscle-specific tyrosine kinase (MuSK). It is a postsynaptic transmembrane protein which forms part of the receptor for agrin, a protein synthesized by motor neurons and secreted into synaptic basal lamina. Agrin and MuSK-mediated 168 Gyrus Vol III No 3 September 2015

2 Origin of the autoimmune response in MG. The thymus is believed to be a possible site of origin because approximately 75% of MG patients have thymic abnormalities. Of the patients with thymus pathologies, 85% have hyperplasia and 15% have thymomas. 16 The observation that a thymectomy results in an improvement in most patients further supports this hypothesis.17 Both normal and myasthenic thymus glands contain myoid cells which express AchR on their surface. It is believed that some alteration of the myoid cells or the lymphocytes may lead to an autoimmune response. 18 Clinical features Figure-1: Structure of the NMJ.1 signaling triggers and maintains clustering of AChR and other postsynaptic proteins. 6,7 Role of anti-achr antibodies. The basic pathology in MG is a decrease in the number of AChR at NMJ, which reduces the probability that a molecule of ACh will bind to the receptor before it is hydrolyzed by AChE. 8 Studies of muscle-biopsy specimens showed that the muscles of MG patients had only one-third as many AChR as those of healthy controls. 9 The degree of reduction of AChR, in general, is proportional to the severity of myasthenic symptoms. Additionally, in MG the geometry of the end-plate is disturbed, with a reduction of normal membrane infolding and enlargement of synaptic cleft. 10 At myasthenic junctions, the decreased number of AChR results in end-plate potentials that are insufficient to trigger an action potential in some fibers. When transmission fails at many junctions, the power of the whole muscle is reduced. That is clinically manifested as muscle weakness. How do antibodies cause the symptoms of myasthenia? They do not simply occupy the ACh binding site. Anti-AChR antibodies affect neuromuscular transmission by at least 3 mechanisms. They appear to react with epitopes elsewhere on the receptor molecules and cross-link the receptors, which induces endocytosis and accelerates their degradation. Complement activation results in formation of membrane attack complexes and destruction of the postsynaptic membrane, which is probably the most important mechanism that alters end-plate morphology. Last and perhaps least, antibodies block the ACh-binding site and prevent normal ACh from attaching and acting on AChR. 1 (Figure-2) Role of anti-musk antibodies. In approximately one-fifth of patients with myasthenia, anti-achr antibodies are not present. These patients are consequently called seronegative. In most of them, MuSK is the main autoantigen and they produce anti-musk antibodies. MuSK helps to organize the nicotinic ACh receptors into clusters at the NMJ and is important both during development and in the adult. Anti-MuSK antibodies affect the agrin-dependent maintenance of AChR clusters, leading to reduced AChR numbers. 1,6,11,12 This can be seen in animal models, where myasthenic symptoms were induced after immunization with MuSK fragments. 13 The crucial feature of MG is fluctuating weakness of skeletal muscles that is fatiguable. It worsens with repetitive activities and improves with rest, as opposed to Lamber-Eaton syndrome. Moreover, heat, infection and stress have a negative impact on myasthenic symptoms. Specific skeletal muscle groups are typically involved. MG often selectively affects cranial muscles ocular, facial, bulbar muscles, neck muscles and proximal extremities. In some patients, it also involves respiratory muscles. The most common initial symptom of MG is ocular muscle weakness. It occurs in approximately 85% of patients and presents with severe drooping of the eyelids (ptosis), double vision (diplopia) and sometimes blurred vision (Figure-3a). The ptosis can be severe enough to totally occlude vision if it is bilateral. As mentioned earlier, weakness remains localized to the extraocular and eyelid muscles in about 15% of patients. When the bulbar muscles are involved (60% of the patients), the patient may look expressionless, present with a flattened smile (snarl) and, if the palate muscles are affected, may produce nasal speech and nasal regurgitation of food (especially liquids). There may be difficulties in chewing and swallowing, particularly with solid food. Severe jaw weakness may cause the jaw to hang open. Weakness involving respiratory muscles can be life-threatening and require mechanical ventilation. The patient is then said to be in myasthenic crisis. Limb muscle weakness predominantly involves proximal muscles and is similar to other myopathies, with the arms more often affected than the legs. Dropped head syndrome is also common; the weight of the head may overcome the affected neck extensor and flexor muscles. The symptoms are limited to the motor system, without loss of reflexes or damage of sensation or coordination. 14,15 The Myasthenia Gravis Foundation of America (MGFA) Clinical Classification divides MG into 5 main classes and several subclasses: 15 Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IIa: Predominantly affecting limb, axial muscles, or both; Class IIb: Predominantly affecting oropharyngeal, respiratory of limb, axial muscles, or both Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IIIa: Predominantly affecting limb, axial muscles, or both; September 2015 Gyrus Vol III no

3 Figure-2: Effector mechanisms of anti-achr antibodies.1 Class IIIb: Predominantly affecting oropharyngeal, respiratory of limb, axial muscles, or both Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IVa: Predominantly affecting limb, axial muscles, or both; Class IVb: Predominantly affecting oropharyngeal, respiratory of limb, axial muscles, or both; use of a feeding tube without intubation Class V: Defined by the need for intubation, with or without mechanical ventilation, except when used during routine postoperative management A combination of cholinesterase inhibitors, immunosuppressive drugs, plasmapheresis, immunotherapy, and supportive care in an intensive care unit setting (when appropriate), provides nearnormal life span for most of the patients with MG, with general improvement in 57% and remission in 13% after the first two years. Mortality is now 3-4%; compared to 30-40% in the past - a the key indicator of effective treatment. Nowadays, the only truly life-threatening manifestation is when weakness involves the respiratory muscles, as mentioned earlier. Intermittent impairment of muscle strength results in increased incidence of aspiration pneumonia, falls, and respiratory failure if not treated. In addition, the medication used to control the disease may produce adverse effects, which will be discussed in Treatment section. 19 Myasthenia gravis is a relatively rare disease and therefore unfamiliar to many doctors. That is the reason why delayed or missed diagnoses are not rare. The diagnosis of MG relies on the anticholinesterase test, serological tests that detect anti-achr or anti- MuSK antibodies and electrodiagnostic tests that detect alteration in neuromuscular transmission. Laboratory tests.the anti acetylcholine receptor antibody test is highly specific (as high as 100%) and therefore very reliable for diagnosing autoimmune MG. Results are positive in 85% of patients who have generalized MG but in only 50% of those who have only ocular MG (class I MG), meaning that false negatives are common in cases of ocular MG. Anti-AChR antibody concentrations cannot be used to predict the severity of disease in individual patients since the concentration of the antibodies does not correlate with severity of symptoms. About 40% of the patients with seronegative MG may have positive test results for antibody to muscle-specific kinase (MuSK). 15,20 Anticholinesterase test. Anticholinesterases are a class of drugs that reversibly inhibit the enzyme acetylcholinesterase from breaking down acetylcholine, thereby increasing both the level and duration of action of acetylcholine. This improves the chance for interactions between ACh and the decreased number of receptors in myasthenic patients, therefore reducing myasthenic symptoms. Edrophonium chloride is a short (~10 minutes)-acting AChE inhibitor with an effect of prolonged duration of ACh action at the NMJ. After intravenous administration, the patient is observed for objective improvement in muscle strength, particularly the eyelid ptosis and/or extraocular muscle movement (Figure-3b). Edrophonium is commonly used for the anticholinesterase test (often referred to as Tensilon test, after the trade name for edrophonium), because of its rapid onset and short duration of action. In that way, the chances of serious complications due to excessive cholinergic stimulation, such as bradycardia and hypotension, are reduced. Atropine, a muscarinic receptor antagonist, should be available at the bedside while the test is being performed to quickly counteract potential adverse effects. Tensilon test has a sensitivity of 71.5% 95% for the diagnosis of MG, with a notably lower sensitivity in ocular MG (50%). Because of that, electromyography and ocular tonography should be combined to increase Tensilon test sensitivity in omg patients. Other anticholinesterases, such as neostigmine, could be 14,15, 21 used in the diagnosis of MG. Electrophysiological testing. Two main electrophysiological tests for the diagnosis of MG are the repetitive nerve stimulation test and single fiber electromyography (SFEMG). In repetitive nerve stimulation, electric shocks are delivered to the nerve at a rate of 3 Hz. A rapid reduction in the amplitude of the evoked action potentials is diagnostic for MG. SFEMG is the most sensitive diagnostic test for MG that detects delayed or failed neuromuscular transmission by recording action potentials of two muscle fibers innervated by the same motor axon simultaneously. 14,15 Imaging studies. Chest radiography may identify a thymoma as an anterior mediastinal mass. CT scan is required if the radiograph is negative, as it does not rule out smaller thymoma. Chest CT or MRI is done in all patients with confirmed MG to exclude the presence of thymoma. 15 Diagnosis 170 Gyrus Vol III No 3 September 2015

4 (a) Photograph of a patient with MG showing partial right ptosis. (b) Post-Tensilon test: note the improvement in ptosis.15 Treatment As mentioned earlier, the outlook for patients with myasthenia gravis has improved dramatically in recent years. With optimal care, the mortality rate has significantly decreased, and the great majority of patients lead relatively normal lives. Because of that, early recognition, diagnosis and management of the disease is very important. There are two basic approaches to management of MG: targeting the physiological effects or targeting the underlying autoimmune mechanism of the disease increasing the amount of ACh in synaptic cleft or using immunosuppressive drugs. Anticholinesterase inhibitors. Anticholinesterase inhibitors, especially pyridostigmine, are the first-line treatment in patients with MG. They provide symptomatic relief, but do not alter the basic disease progression or outcome. Response to treatment varies, from obvious improvement in some patients to little or no improvement in others. Depending on the severity and current activity of the disease, the dosage and schedule of administration must be tailored to the patient s needs. The improvement is usually incomplete and often wanes after weeks or months of treatment. Most patients require additional immunomodulating therapy. Adverse side effects of pyridostigmine are mostly due to the cholinergic stimulation, which results in abdominal cramping, diarrhea, increased salivation and bronchial secretions, nausea, sweating, and bradycardia. 14,15,22 Immunosuppressive treatment. Immunosuppressive therapies include corticosteroids and azathioprine or related drugs that supress antibody synthesis. Corticosteroids were the first and most commonly used immunosuppressant drugs in MG. Prednisone is generally used when symptoms of MG are not sufficiently controlled by cholinesterase inhibitors alone. Corticosteroids suppress the immune system at many levels. In myasthenia gravis, steroid treatment may reduce acetylcholine-receptor antibody levels and decrease the anti-acetylcholine receptor reactivity of peripheral blood lymphocytes. Improvement usually begins in 2 to 4 weeks, with maximal benefit realized after 6 to 12 months. Long-term corticosteroid use also carries a risk of various complications, such as osteoporosis, cataracts, hyperglycemia, weight gain, hypertension. 14,15,23 Other medication, such as nonsteroidal immunosuppressive agents, that are used to treat more difficult cases of MG are azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and rituximab. However, the effectiveness of many of these medication is far from proven, and they should be administered cautiously due to their serious side effects. Azathioprine, a purine analog, interferes with T-and B-cell proliferation by reducing nucleic acid synthesis. It is effective in 70% 90% of patients with MG, but it usually takes up to 15 months to detect clinical response. Adverse side effects include hepatotoxicity and leukopenia. 14,15 (Table-1) Short-term immunotherapies. Removing the plasma and anti- AChR/anti-MuSK antibodies (plasmapheresis) and infusion of immunoglobulin (IVIg) often improve symptoms within few days or weeks. Plasmapheresis and IVIg are primarily used to stabilize the condition of patients in myasthenic crisis or for the short-term treatment of patients undergoing thymectomy. 15 Surgical treatment. Thymectomy is strongly recommended for patients with thymoma and is advised as soon as the patient s degree of weakness is sufficiently controlled to permit surgery. It is also indicated for patients aged without thymoma, but with generalized MG. In the absence of thymoma, 85% of patients experience improvement, and 35% of these patients achieve drugfree remission. The rate of remission in the presence of thymic hyperplasia was 42% compared to 18% in patients with thymoma. Thymectomy is not recommended in patients with anti-musk antibodies, because of the typical thymus pathology, which is very different than in the more common type of MG. 15,24,25 During the past decades, significant progress has been made in our understanding of myasthenia gravis. Nowadays, it is one of the best understood autoimmune disorders. Perhaps the most important aspect of this is that the new knowledge has been applied directly to the clinical diagnosis and management of this formerly grave disease. With current therapies, most cases of myasthenia gravis are not as grave as the name suggests. Early and accurate diagnosis is essential for obtaining a good clinical outcome Most individuals with this disease are able to lead normal, productive lives and have normal life span. Despite these remarkable advances, there are still important gaps in our knowledge of the origin of myasthenia gravis, the factors that maintain the autoimmune response, and the way to permanently cure the disease. September 2015 Gyrus Vol III no

5 Table 1: Immunotherapy in Myasthenia Gravis. 14 Literature: 1. B. M. Conti-Fine, M. Milani, and H. J. Kaminski, Myasthenia gravis: past, present, and future, Journal of Clinical Investigation, vol. 116, no. 11, pp , D. Grob, N. Brunner, T. Namba, and M. Pagala, Lifetime course of myasthenia gravis, Muscle and Nerve, vol. 37, no. 2, pp , Marsteller, H.B The first American case of myasthenia gravis. Arch. Neurol. 45: Pascuzzi, R.M The history of myasthenia gravis. Neurol. Clin. 12: Hughes, B.W., Kusner, L.L., Kaminski, H.J Molecular architecture of the neuromuscular junction. Muscle Nerve. 33: Hoch, W., et al Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat. Med. 7: D. J. Glass, D. C. Bowen, T. N. Stitt et al., Agrin acts via a MuSK receptor complex, Cell, vol. 85, no. 4, pp , Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science 1973;182: Pestronk A, Drachman DB, Self SG. Measurement of junctional acetylcholine receptors in myasthenia gravis: clinical correlates. Muscle Nerve 1985;8: Engel AG, Tsujihata M, Lindstrom JM, Lennon VA. The motor end plate in myasthenia gravis and in experimental autoimmune myasthenia gravis: a quantitative ultrastructural study. Ann N Y Acad Sci 1976;274: Vincent, A., McConville, J., Farrugia, M.E., Newsom-Davis, J Seronegative myasthenia gravis. Semin. Neurol. 24: Vincent, A., Leite, M.I Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. Curr. Opin. Neurol. 18: Shigemoto, K., et al Induction of myasthenia gravis by immunization against muscle-specific kinase. J. Clin. Invest. 116: Daniel B. Drachman, Myasthenia gravis. N Engl J Med 1994; 330: Annapurni Jayam Trouth, Alok Dabi, Noha Solieman, Mohankumar Kurukumbi, and Janaki Kalyanam, Myasthenia Gravis: A Review, Autoimmune Diseases, vol. 2012, Article ID , 10 pages, Castleman B. The pathology of the thymus gland in myasthenia gravis. Ann N Y Acad Sci1966;135: Buckingham JM, Howard FM Jr, Bernatz PE, et al. The value of thymectomy in myasthenia gravis: a computer-assisted matched study. Ann Surg 1976;184: Kao I, Drachman DB. Thymic muscle cells bear acetylcholine receptors: possible relation to myasthenia gravis. Science 1977;195: Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev Jan 23. CD Padua L, Stalberg E, LoMonaco M, Evoli A, Batocchi A, Tonali P. SFEMG in ocular myasthenia gravis diagnosis. Clin Neurophysiol Jul. 111(7): Phillips LH 2nd, Melnick PA. Diagnosis of myasthenia gravis in the 1990s. Semin Neurol Mar. 10(1): Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol Mar. 24(1): Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev Apr 18. CD Leite MI, Strobel P, Jones M, et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol Mar. 57(3): Nieto IP, Robledo JP, Pajuelo MC, et al. Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg Jun. 67(6): Mijastenija gravis - pregled Sažetak: Mijastenija gravis najbolje je proučeni primjer bolesti neuromuskularne spojnice. Najznačajniji je autoimunosni oblik ove bolesti koji je posljedica stvaranja autoantitijela usmjerenih na proteine koji sudjeluju u neuromuskularnoj transmisiji nikotinski receptor za ACh ili rjeđe tirozin-kinazu specifičnu za mišiće (MuSK). Te interakcije smanjuju broj funkcionalnih receptora i dovode do promjene morfologije neuromišićne spojnice. Posljednjih desetljeća došlo je do porasta prevalencije bolesti na slučajeva na milijun stanovnika. Stečena mijastenija gravis karakterizirana je slabošću skeletnih mišića koja se pogoršava radom mišića, a ublažava prilikom odmora. U oko dvije trećine bolesnika bolest najprije zahvaća vanjske očne mišiće te obično napreduje i zahvaća bulbarne mišiće, mišiće vrata i mišiće gornjih i donjih udova, što se naziva generalizirana mijastenija gravis. Proteklih desetljeća ostvaren je značajan napredak u razumijevanju ove bolesti, što je izravno dovelo do poboljšanja u liječenju. Zbog toga je rano prepoznavanje i dijagnoza bolesti od iznimne važnosti. Ključne riječi: Mijastenija gravis, Mišićna slabost, Neuromišićna spojnica, Ptoza, Timom 172 Gyrus Vol III No 3 September 2015