Review
Myasthenia gravis: subgroup classi?cation and therapeutic strategies
Nils Erik Gilhus, Jan J Verschuuren
Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-speci?c kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classi?ed into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are ?rst-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis.
Lancet Neurol 2015; 14: 1023–36 Department of Clinical Medicine, University of Bergen, Bergen, Norway (Prof N E Gilhus MD); Department of Neurology, Haukeland University Hospital, Bergen, Norway (Prof N E Gilhus); and Department of Neurology, Leiden University Medical Center, Leiden, Netherlands (Prof J J Verschuuren MD) Correspondence to: Prof Nils Erik Gilhus, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway nils.gilhus@helse-bergen.no
Introduction
Dysfunction at the neuromuscular junction underlies several disorders that are characterised by skeletal muscle weakness usually involving some but not all muscle groups. Genetic forms of these disorders are termed congenital myasthenic syndromes. Some toxins, like botulinum toxin and curare, can cause neuromuscular dysfunction; acquired antibody-mediated forms include autoimmune and neonatal myasthenia gravis, Lambert– Eaton myasthenic syndrome, and neuromyotonia. Myasthenia gravis forms the largest disease group of neuromuscular junction disorders and is caused by pathogenic autoantibodies to components of the postsynaptic muscle endplate (?gure 1).1–4 Fluctuations in severity of muscle weakness are typical. Some, but not all, muscles are a?ected and not necessarily symmetrically. Increased weakness with continued muscle activity represents a diagnostic clue for myasthenia gravis, but these clinical features can vary. Patients with myasthenia gravis should be classi?ed into subgroups, with implications for diagnosis, optimum therapy, and prognosis. In myasthenia gravis guidelines and consensus reports, subgrouping is recommended,1–5 but exact de?nitions vary and new subgroups are emerging as a result of increased knowledge. As this subgrouping takes into account myasthenia gravis autoantibodies, epidemiology, clinical presentation, and comorbidities, the subgroups are discussed after these sections in this Review. For a few patients, subgrouping is not possible owing to insu?cient precise information, including suboptimum autoantibody testing and pathological changes of the thymus below the detection threshold of imaging. Autoantibodies against the acetylcholine receptor (AChR), muscle-speci?c kinase (MUSK), and lipoproteinrelated protein 4 (LRP4) are well established as sensitive and speci?c diagnostic markers and pathogenic factors, and these autoantibodies are instrumental for subgrouping patients with myasthenia gravis. A
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prerequisite for optimum diagnosis and treatment, therefore, is access to autoantibody testing.1–5 With modern immunosuppressive, symptomatic, and supportive treatments, the prognosis for patients with myasthenia gravis is good. Most patients with mild-tomoderate symptoms will obtain full remission or substantial improvement. Full remission is rare in severe cases, some variation over time is common, and steady progression is unusual. Daily life functions of individuals with myasthenia gravis are not, or only modestly, a?ected and life expectancy is not reduced.6 Long-term drug treatment is necessary for nearly all patients with myasthenia gravis.2,7 In 10–15% of these patients, full control of the disease is not possible or is only at the cost of severe side-e?ects of immunosuppressive therapy.8 Treatment protocols at leading centres are not based purely on results from well controlled studies or guidelines based on such studies, because well controlled studies are sparse for this disease, and do not take into account the variation in therapeutic response among the diagnostic subgroups. Myasthenia gravis is a rare disease, and most patients do well on existing treatments, both aspects that are a challenge for new trials. We will combine information from controlled studies, consensus reports, and expert views with insights from theoretical and experimental studies relevant for myasthenia gravis subgroups, with the aim of assessing the evidence base for the use of treatments, including interventions directed at the pathophysiological process.
Autoantibodies in myasthenia gravis
AChR antibodies are highly speci?c for myasthenia gravis, and their presence combined with muscle weakness con?rms the disease. Further diagnostic investigation is necessary only to de?ne the subgroup and disease severity. The value of repeated AChR antibody testing in patients with this disorder is debated,
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A
Schwann cell Nerve
ACh Vesicles
Muscle
B
Nerve Synapse
Agrin LRP4–MUSK complex
C
Nerve Synapse
Acetylcholine AChR
Muscle
Muscle
Figure 1: The neuromuscular junction (A) The AChR and MUSK are expressed at the top of the junctional folds. (B) Trophic signal: binding of agrin to the LRP4–MUSK complex activates aggregation of AChRs and promotes transition from the plaque to pretzel form of the neuromuscular junction. (C) Activation signal: binding of acetylcholine to the AChR induces a brief opening of the central ion channel causing membrane depolarisation, which in turn elicits a muscle action potential that leads to contraction of the muscle ?bre. AChR=acetylcholine receptor. MUSK=muscle-speci?c kinase. LRP4=lipoprotein-related protein 4.
but changes in antibody concentration might predict disease severity in patients given immunosuppressive drugs and therefore can support therapeutic decisions. No correlation has been shown between AChR antibody concentration and disease severity. AChR antibodies are directly pathogenic through crosslinking of AChRs leading to accelerated degradation of these receptors, through complement binding and activation, and by inducing AChR conformational changes or blocking acetylcholine binding.1–4 Radioimmunoprecipitation is the standard commercial test and gives a quantitative AChR antibody measure. Cell-based assays can have an even higher sensitivity than radioimmunoprecipitation, but are not yet commercially available and standardised.9 Tests avoiding radioactive ligands are also in use such as ELISA and ?uorescence tests based on immunoprecipitation,10 but they tend to be less sensitive than assays with radioactive ligands.
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Standard tests for MUSK antibodies use radioimmunoprecipitation or an ELISA. Cell-based assays used for research can increase sensitivity. MUSK antibodies are directly pathogenic in experimental animal models,11–13 even if the predominant IgG4 antibodies do not bind complement. Any value of repeated tests in the follow-up of patients has not been established because prospective, high-quality studies have not been done. LRP4 antibodies bind to the membrane protein in vivo, block the agrin–LRP4 interaction and thereby also inhibit AChR clustering in the membrane. Interference with the LRP4–MUSK interaction might also be a relevant disease mechanism for this subgroup. Mice immunised with LRP4 develop typical myasthenia gravis.14 Thus, LRP4 antibodies are directly pathogenic through interference with AChR function. Agrin antibodies have been detected in a few patients with myasthenia gravis and AChR, MUSK, or LRP4 antibodies.15,16 Agrin is essential for AChR function, but whether these antibodies contribute to the muscle weakness in this disease is still unclear. Similarly, cortactin autoantibodies have been reported in patients with myasthenia gravis, both with and without other neuromuscular autoantibodies.17 Titin and ryanodine receptor antibodies occur in some patients with AChR-associated myasthenia gravis. Titin maintains the ?exibility of the cell structure, whereas the ryanodine receptor is a sarcoplasmic reticulum calcium channel that mediates contraction of the muscle cell. Titin and ryanodine receptor antibodies probably do not enter the muscle cell in vivo and might not mediate any muscle weakness, but rather could be disease markers.18 These antibodies are present with a high frequency in thymomaassociated myasthenia gravis, with an intermediate frequency in late-onset myasthenia gravis, and very rarely in early-onset and ocular myasthenia gravis; they are not detected by standard testing in MUSK, LRP4, or antibodynegative myasthenia gravis.7,19 Titin and ryanodine receptor antibodies can be used to diagnose a thymoma in patients younger than 50 years.19 These antibodies have been proposed as markers for severe myasthenia gravis with a need for long-term immunosuppression and no response to thymectomy. Commercial tests with ELISA are available for titin but not for ryanodine receptor antibodies.
Epidemiology
Autoimmune myasthenia gravis has a reported worldwide prevalence of 40–180 per million people, and an annual incidence of 4–12 per million people.20–23 Recently collected ?gures of prevalence and incidence tend to be higher than older ones, especially for lateonset myasthenia gravis, partly explained by increased case ?nding and more widespread autoantibody testing. Population demographics with an increased number of elderly people and reduced myasthenia gravis mortality a?ect incidence and prevalence. AChR-associated
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myasthenia gravis has a bimodal age pattern of incidence, with a peak in young adults aged about 30 years and then a steady increase in incidence with increasing age older than 50 years.20,21 The incidence peak in young adults is mainly because of the high frequency in women, typical for many autoimmune disorders, although late-onset myasthenia gravis is slightly more frequent in men. No evidence suggests that the occurrence of this disease is increasing as a result of a change in external causative factors such as infections or diet.24 Overall, myasthenia gravis incidence and prevalence shows little geographical variation; however, this distribution is not the case for all subgroups of the disease. Juvenile myasthenia gravis, a subtype of early-onset disease, has a high frequency in east Asia, in which up to 50% of all cases have onset before age 15 years, many of them with ocular symptoms only.22,25 Myasthenia gravis incidence in children (aged <15 years) in a mixed population from Canada was 1–2 per million per year, and highest in those of Asian ethnicity, especially for the ocular subgroup. LRP4 antibodies were recorded in 19% of patients without AChR antibodies,5 and MUSK antibodies in a third of patients without AChR antibodies.3,4,26 Epidemiological data suggest that LRP4-associated myasthenia gravis is half as frequent as the MUSK form of the disease. MUSK-associated myasthenia gravis incidence is estimated at 0·3 patients per million per year, with a prevalence of 2·9 per million people, and is more common in southern than northern Europe.27 Genetic predisposition and external factors linked to infections or diet are potential explanations for some geographical variation in this disease and its subtypes.
Subtype
AChR myasthenia gravis
MUSK myasthenia gravis
LRP4 myasthenia gravis
Seronegative myasthenia gravis
LEMS
Relative prevalence
80%
4%
2%
5%
4%
Figure 2: Distribution of weakness and relative prevalence of subtypes of myasthenia gravis AChR=acetylcholine receptor. MUSK=muscle-speci?c kinase. LRP4=lipoprotein-related protein 4. LEMS=Lambert–Eaton myasthenic syndrome.
Comorbidities
Patients with early-onset and ocular subgroups of myasthenia gravis have increased frequency of organspeci?c and general autoimmune disorders, especially thyroiditis.29 Patients with thymoma-associated myasthenia gravis are at an increased risk of developing haematological autoimmune disorders. Thymectomies have not been shown to increase the risk of infections, autoimmune disease, or cancer. Myasthenia gravis muscle weakness might increase the risk of respiratory infections and osteoporosis, becoming overweight, and developing other complications. A widespread autoimmune in?ammatory myopathy can occur in myasthenia gravis.30 AChR antibodies and myasthenia gravis-like features have been described occasionally in patients with amyotrophic lateral sclerosis.31 Several studies32–34 have investigated the cancer risk in patients with myasthenia gravis and its subgroups. Methodological challenges due to myasthenia gravis patient selection, sensitivity in cancer detection, follow-up time, and types of control groups have led to varying conclusions. Thymomas in general seem to confer a moderately increased risk for other cancer types,32 whereas myasthenia gravis and its immunoactive treatment, according to a Danish population-based study33 with a long-term follow-up and relevant controls, was not associated with a signi?cantly increased risk, perhaps with the exception of non-melanoma skin cancer.34 AChR, MUSK, and LRP4 antibodies do not cross-react with the heart muscle. In population studies,6 no increased mortality or morbidity related to cardiac factors have been established. However, cardiophysiological function can be marginally a?ected by these antibodies.35 Many case reports of severe cardiomyositis and heart conduction abnormalities in thymoma-associated myasthenia gravis and late-onset myasthenia gravis have been noted, most probably induced by heart muscle autoimmunity.36,37 Heart function monitoring is recommended during severe myasthenia gravis exacerbations, especially in patients with various antimuscle antibodies.38
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Clinical presentation
Muscle weakness is a major symptom and sign in myasthenia gravis. The combination of weakness localisation, variation in weakness over time, and exerciseinduced weakness usually gives strong clues to the diagnosis of the disease for all subgroups. In older individuals with eye muscle weakness and bulbar symptoms, cerebrovascular disease of the brainstem is sometimes suspected. In younger individuals, unspeci?c fatigue disorders can be part of the di?erential diagnoses.1,3,7 Weakness in myasthenia gravis arises in the extraocular, bulbar, limb, and axial muscles (?gure 2). 60% of patients present with ptosis or diplopia, or both, and in 20% of patients, the disease is restricted to ocular myasthenia gravis.1–4 Weakness of external eye muscles is nearly always asymmetrical (?gure 3), whereas limb weakness is symmetrical and more proximal than distal (?gure 2).28 The variability in symptoms in skeletal muscles is surprising because they all express the autoimmune target protein. This variation results from many subtle factors a?ecting neuromuscular transmission, muscle cell depolarisation or contraction, resistance to an immunological attack, and regenerative capacity of muscle structures.2,17
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A
B
C
Figure 3: Two patients with AChR-associated myasthenia gravis Female patient with ophthalmoplegia (note adduction of right eye) and ptosis of the left eye (A). Male patient with opthalmoplegia (note the upward position of the left eye) and ptosis of the right eye before treatment (B) and 1 year after immunosuppressive treatment (C).
Myasthenia gravis subgroups
Early-onset myasthenia gravis with AChR antibodies
Patients with early-onset myasthenia gravis have, by de?nition, onset of their ?rst symptom before age 50 years (table 1).1,7,39 Serum AChR antibodies are detected by standard diagnostic testing. Patients with a thymoma detected on imaging or during surgery are excluded from this myasthenia gravis subgroup. Thymic follicular hyperplasia occurs often but is not a prerequisite, and this group responds to thymectomy. Female cases outnumber male cases by three to one.20,22 Early-onset myasthenia gravis has an association with HLA-DR3, HLA-B8, and other autoimmune risk genes (table 1),40,41 and all autoimmune disorders are more widely reported in relatives of patients in this myasthenia gravis subgroup.42 These ?ndings suggest subgroup di?erences in the pathogenesis of myasthenia gravis.
thymoma develop myasthenia gravis, and even more have AChR antibodies without myasthenia gravis.44
MUSK-associated myasthenia gravis
MUSK is a protein expressed in the postsynaptic muscle membrane that is functionally linked to AChR and necessary to maintain AChR function. Overall, 1–4% of patients with myasthenia gravis have serum MUSK antibodies, but more cases will probably be identi?ed with increasingly sensitive test assays. MUSK and AChR antibodies rarely coexist in the same patient. MUSKassociated myasthenia gravis is usually reported in adults, and rarely in the very old or in children.45 No thymus pathological changes are reported and patients usually have no response to thymectomy. IgG4 antibodies have an important role in the pathogenesis, and there is an HLA association with HLA-DQ5,46–48 unlike in other myasthenia gravis subgroups. MUSK-associated myasthenia gravis shows predominant involvement of cranial and bulbar muscles. About a third of the patients present with ptosis and diplopia.27 In more than 40% of patients with MUSKassociated myasthenia gravis, bulbar weakness is a ?rst symptom, with facial, pharyngeal, and tongue weakness, often associated with neck and respiratory involvement. Limb weakness is not common, and ocular muscles are often una?ected.27 Little variation in muscle strength is reported during the day, and muscle atrophy might occur.
Late-onset myasthenia gravis with AChR antibodies
Patients with late-onset myasthenia gravis are de?ned as having their ?rst onset of symptoms after age 50 years. In this group, serum AChR antibodies are present, thymoma is not evident on imaging or during surgery, and thymic hyperplasia occurs only rarely; these patients most often will not respond to thymectomy. The disease is slightly more frequently reported in males than females, and weak HLA associations occur with HLADR2, HLA-B7, and HLA-DRB1*15:01.43
Thymoma-associated myasthenia gravis
Thymoma-associated myasthenia gravis is a paraneoplastic disease. Myasthenia gravis is by far the most widely reported autoimmune disease associated with a thymoma, although pure red aplasia and neuromyotonia are also associated with thymoma; this association does not occur in other autoimmune disorders. A thymoma is recorded in 10–15% of all patients with myasthenia gravis. Nearly all have detectable AChR antibodies and generalised disease. About 30% of patients with a
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LRP4-associated myasthenia gravis
LRP4 is expressed in the postsynaptic muscle membrane; it is a receptor for nerve-derived agrin and an activator of MUSK, and is necessary to maintain AChR function. LRP4 antibodies have been detected in 2–27% of patients with myasthenia gravis without AChR and MUSK antibodies, with a female preponderance.49,50 Most of these patients present with ocular or generalised mild myasthenia gravis, and about 20% of patients have only ocular weakness for
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more than 2 years. Respiratory insu?ciency occurs very rarely, except in a subgroup with additional MUSK antibodies. In two-thirds of patients with LRP4associated myasthenia gravis, the thymus is atrophic and normal for age, but hyperplasia has been reported.5 Commercial tests are not yet available for LRP4 antibody testing, meaning that this group can be identi?ed only by a few institutions.
Myasthenia gravis subgroup Active immune response AChR AChR AChR Early onset Late onset Thymoma MUSKmyasthenia gravis LRP4myasthenia gravis
Age at onset
Sex
HLA Thymus associations pathological changes DR3-B8-A1 Diverse ·· DR14, DR16, DQ5 ·· Hyperplasia Normal or hyperplasia Lymphoepithelioma Normal
<50 years >50 years Variable Variable
More female than male More male than female ·· Substantially more female than male ··
Antibody-negative generalised myasthenia gravis
Myasthenia gravis without detectable AChR, MUSK, or LRP4 antibodies represents a heterogeneous group pathogenically. Some patients have low-a?nity antibodies or low concentration of antibodies to AChR, MUSK, or LRP4 antigen targets, identi?ed by cell-based methods only, that are not detectable in routine assays.51,52 Low-a?nity antibodies are pathogenic in vivo, and the disease in patients with such antibodies is probably similar to that in the myasthenia gravis subgroup with detectable antibodies. Low-a?nity antibodies seem to account for 20–50% of patients in the antibody-negative generalised myasthenia gravis subgroup.51,52 Antibodies to agrin and cortactin often occur in combination with other autoantibodies.15,17,52 Their functional relationship to other targeted proteins is not clear. Some patients with myasthenia gravis probably have pathogenic antibodies against yetunde?ned antigens in the postsynaptic membrane. The diagnosis is more challenging in patients in whom no speci?c autoantibodies are detected. In such patients, non-myasthenia gravis myasthenic syndromes and other muscle and non-muscle disorders should also be considered.3
MUSK
LRP4
Variable
Normal
Unknown SNMG
Variable
··
··
Normal or hyperplasia None
Passive transfer of antibodies AChR, or MUSK, or LEMS Neonatal myasthenia gravis Neonate Equal proportion of female to male ··
AChR=acetylcholine receptor. MUSK=muscle-speci?c kinase. LRP4=lipoprotein-related protein 4. SNMG=seronegative myasthenia gravis. LEMS=Lambert-Eaton myasthenic syndrome.
Table 1: Myasthenia gravis antibody and subgroup characteristics
Ocular myasthenia gravis
In some patients with myasthenia gravis, the weakness is restricted to the ocular muscles. Patients with purely ocular weakness are at risk of developing generalised myasthenia gravis, especially early in the disease. 90% of those who have had the ocular form for more than 2 years will remain in this subgroup.53 Half of patients with ocular myasthenia gravis have detectable AChR antibodies, whereas MUSK antibodies very rarely occur.53
elements of the thymus and are active in early-onset myasthenia gravis, whereas thymoma cells contain muscle-speci?c antigens and have antigen-presenting properties.54 AChR expression can be activated in thymic epithelial cells through cytokine and receptor signalling, potentially triggered by a virus;3,55 however, no speci?c virus has been identi?ed so far. MicroRNAs can mediate immunoregulatory processes, be induced by environmental events, and seem to be abnormally expressed in myasthenia gravis.56 Autoreactive T cells, speci?c for AChR, escape the normal intrathymic surveillance and are exported to the periphery where they stimulate B cells to produce antibodies. Di?erences in autoantibody pattern, HLA associations, thymic pathological changes, cytokine intrathymic pattern, and T-cell subsets and clones all point to di?erences in induction mechanisms for early-onset, late-onset, and thymoma-associated myasthenia gravis.44
Thymus pathological changes
Thymoma, but no other thymic tumours, is associated with myasthenia gravis. Thymic hyperplasia is reported in most patients with early-onset myasthenia gravis and in some patients with late-onset, ocular, and antibodynegative disease. CT scanning or MRI of the mediastinum should be undertaken in all patients with myasthenia gravis to assess for a thymoma.1–4,7 Both sensitivity and speci?city are challenges for imaging. Experimental and clinical evidence strongly suggests that early-onset and thymoma-associated myasthenia gravis are initiated within the thymus.44 Myoid musclelike cells and professional antigen-presenting cells are
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Neurophysiological testing
Neurophysiological tests are unnecessary in patients with typical myasthenia gravis symptoms because diagnosis can be con?rmed by speci?c antibody tests; these tests are also not helpful for myasthenia gravis subgroup classi?cation. However, they are important for correct diagnosis in patients with myasthenia gravis without detectable autoantibodies. Repetitive nerve stimulation and single-?bre electromyography for an increased jitter are useful tests for patients with myasthenia gravis. Single-?bre testing is the most sensitive, whereas decrement at repetitive stimulation is the most speci?c.1 Both sensitivity and
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speci?city rely on investigation quality. Even after combined neurophysiological and antibody testing, myasthenia gravis can be di?cult to rule out. Most
Drug Corticosteroids Mount (1964)58 Howard et al (1976)59 Lindberg et al (1998)60 Benatar et al (2015)61 Assistance Publique— H?pitaux de Paris (2009–2015) Azathioprine Bromberg et al (1997)62 Palace et al (1998)63 Ciclosporin Tindall et al (1987)64 Tindal et al (1993)65 Tacrolimus (FK506) Nagane et al (2005)66 Yoshikawa et al (2011)67 Mycophenolate Meriggioli et al (2003)68 Ho?mann-La Roche (2004–07) Ho?mann-La Roche (2004–07) Mycophenolate mofetil Mycophenolate mofetil Mycophenolate mofetil Placebo Placebo Placebo Placebo 14 136 136 80 FK506 Tacrolimus Placebo Placebo Placebo 34 80 83 Ciclosporin Ciclosporin Placebo Placebo 20 39 Azathioprine Prednisolone and azathioprine Prednisone Prednisolone and placebo 10 34 Corticotropin Alternate-day prednisone Pulse methylprednisone Prednisolone Slow decrease of prednisolone plus azathioprine Placebo Placebo Placebo Placebo Rapid decrease of prednisolone plus azathioprine 43 13 19 11 118 Control or comparator Number of Duration participants
patients for whom some doubt about diagnosis remains after testing, from our experience, do not have autoimmune myasthenia gravis.
Primary outcome measure Eye movements Clinical score Muscle fatigue test Treatment failure Minimal manifestation ClinicalTrials. gov number ·· ·· ·· NCT00995722 NCT00987116 Result
12 weeks 24 weeks 2 weeks 16 weeks 60 weeks
No signi?cant di?erence No signi?cant di?erence p<0·01 Completed Ongoing
52 weeks 156 weeks
Observational Prednisone dose
·· ··
Descriptive p=0·02
52 weeks 26 weeks 52 weeks 28 weeks 24 weeks 20 weeks 36 weeks 12–52 weeks 12 weeks
QMGS, AChR titre QMGS, AChR titre Prednisone dose Prednisone dose QMGS QMGS Responder status Adverse events QMGS
·· ·· ·· NCT01325571 ··
Only QMGS signi?cant p=0·004 p<0·05 Ongoing No signi?cant di?erence, except SFEMG (p=0.03)
NCT00309088 No signi?cant di?erence
Astellas Pharma Inc (2011–14) Tacrolimus
NCT00683969 Completed NCT00408213 NCT00285350 Completed No signi?cant di?erence
FDA O?ce of Orphan Products Mycophenolate mofetil Development/Duke University, NC, USA (2008) Sanders et al (2008)69 Qualitix Clinical Research Co Ltd (2009–11) Methotrexate Pasnoor et al (2013)70 Gajdos et al (1997)71 Methotrexate Plasma exchange vs intravenous immunoglobulin Intravenous immunoglobulin Intravenous immunoglobulin (two doses) Intravenous immunoglobulin Intravenous immunoglobulin Intravenous immunoglobulin (GB-0998) Mycophenolate mofetil Mycophenolate mofetil
Placebo Azathioprine
176 40
36 weeks 52 weeks
Myasthenia gravis composite Remission
·· NCT00997412
No signi?cant di?erence Completed
Placebo ··
50 87
36 weeks 15 days
Prednisone dose Myasthenic muscular score QMGS Myasthenic muscular score QMGS
NCT00814138 ··
Ongoing No signi?cant di?erence
Immunoglobulin or plasma exchange
Wolfe et al (2002)72 Gajdos et al (2005)73
Placebo Placebo
15 173
6 weeks 2 weeks
·· ··
No signi?cant di?erence No signi?cant di?erence
Zinman et al (2007)74
Placebo
50
4 weeks
NCT00306033
Intravenous immunoglobulin e?ective (p<0.047) Equally e?ective Completed
Barth et al (2011)75 Benesis Corporation (2007–10)
Plasma exchange Plasma exchange
84 46
2 weeks 4 weeks
QMGS QMGS
NCT01179893 NCT00515450
(Table 2 continues on next page)
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Drug (Conintued from previous page) Rituximab Yale University, CT, USA (2014–17) Eculizumab Howard et al (2013)76 Alexion Pharmaceuticals (2013–16) Belimumab GlaxoSmithKline (2013–14) Le?unomide First A?liated Hospital, Sun Yat-Sen University, China (2012–15) Tirasemtiv (CK-2017357) Sanders et al (2015)77 Thymectomy University of Alabama at Birmingham, AL, USA/ National Institute of Neurological Disorders and Stroke, USA (2008) Thymectomy plus prednisolone CK-2017357 Le?unomide Belimumab Eculizumab Eculizumab Rituximab
Control or comparator
Number of Duration participants
Primary outcome measure
ClinicalTrials. gov number
Result
Placebo
50
52 weeks
Prednisone dose reduction QMGS, adverse events Myasthenia gravis ADL score QMGS Clinical response
NCT02110706
Ongoing
Placebo Placebo
14 92
18 weeks 26 weeks
NCT00727194 NCT01997229
p=0·0144 Ongoing
Placebo Azathioprine
42 158
24 weeks 48 weeks
NCT01480596 Ongoing NCT01727193 Ongoing
Placebo Prednisolone
32 150
2 days 3 years
QMGS, VC, MMT AU QMGS
NCT01268280
Completed
NCT00294658 Ongoing
QMGS=quantitative myasthenia gravis score. AChR=acetylcholine receptor. SFEMG=Single-?bre electromyography. ADL=activities of daily living. VC=vital capacity. MMT=manual muscle test. AU=area under the curve. Table 2: Randomised trials of treatments for autoimmune myasthenia gravis
Treatment of myasthenia gravis
Symptomatic drug treatment
Drugs that increase the amount of acetylcholine at neuromuscular endplates after motor nerve stimulation improve muscle weakness in all myasthenia gravis subgroups; pyridostigmine is the preferred drug for symptomatic treatment.7 Other acetylcholinesterase inhibitors, such as neostigmine and ambenonium chloride, have di?erent durations of action and can di?er regarding side-e?ects. The improvement reported in patients with these drugs is so speci?c that it is used as a diagnostic clue in patients who are antibody negative. Reduction of acetylcholine breakdown by acetylcholinesterase inhibition is the most e?ective symptomatic treatment in myasthenia gravis, and is better than increasing acetylcholine release presynaptically, although a mild bene?cial e?ect of ephedrine or 3, 4-diaminopyridine might be seen. The observational e?ects are so clear that randomised studies have not been undertaken and are di?cult to justify.57 In MUSK-associated myasthenia gravis, acetylcholinesterase inhibitors are less e?ective and induce frequent sidee?ects.27 The optimum dose is a balance between increased muscle strength and side-e?ects due to cholinergic stimulation in the autonomic nervous system. Glycopyrronium bromide, atropine sulfate, and loperamide can be used to treat muscarinergic side-e?ects. Long-term treatment with acetylcholinesterase inhibitors is safe and habituation or cumulative side-e?ects have not been
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reported. Some patients with no or only very mild symptoms choose to continue to take an acetylcholinesterase inhibitor. This continuation might be out of habit or concern of disease, or because the inhibitors induce a substantial subjective improvement in these patients.
Immunosuppressive drug treatment
For patients with myasthenia gravis in all subgroups who do not have a fully satisfactory functional result with symptomatic treatment alone, immunosuppressive drugs should be initiated (tables 2,3, and ?gure 4). Both treatment e?ects and side-e?ects are dose dependent. Finding the optimum drug dose for each patient is as important as selecting the optimum drug. To maximise e?ect and minimise side-e?ects, a combination of immunosuppressive drugs is preferable for most patients. Placebo-controlled studies and those comparing alternative treatments are rare. Recommendations are generally based on the sum of many studies with weak evidence, or on guidelines, clinical experience, and consensus reports.78 Formal standards for patient assessment can be helpful to assess treatment response.79 Prednisone and prednisolone improve muscle strength in all myasthenia gravis subgroups. Prednisone and prednisolone are used in the same manner and are equally e?ective. Prednisone is activated by the liver into prednisolone. The bene?cial e?ect manifests after 2–6 weeks, faster than for most other treatments. In a few
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Number of participants Bortezomib GM-CSF Plasmapheresis Rituximab Rituximab Stem-cell therapy Subcutaneous intravenous immunoglobulin Subcutaneous intravenous immunoglobulin Tacrolimus 18 12 10 10 30 10 25
Duration 6 months 120 days 14 weeks 12 months 12 months 5 years 12 weeks
Study design Open Open Observational Open Open Open, phase 1 Open, phase 2
https://www.doczj.com/doc/f22565081.html, number NCT02102594 NCT01555580 NCT01927692 NCT00619671 NCT00774462 NCT00424489 NCT02100969
Study period 2014–16 2012–13 2013–14 2004–09 2008–11 2002–16 2014–17
10
6 months
Open
NCT01828294
2011–15
11
28 weeks
Open
NCT00309101
2006–09
GM-CSF=granulocyte-macrophage colony stimulating factor.
Table 3: Ongoing non-randomised trials of treatments for autoimmune myasthenia gravis registered in https://www.doczj.com/doc/f22565081.html,
Myasthenia gravis diagnosis con?rmed
Start acetylcholine esterase inhibitor and undertake thymectomy (if early onset or thymoma)
Clinical remission? No
Yes
Continue with acetylcholine esterase inhibitor
Start prednisolone and azathioprine
Very good clinical e?ect? No
Yes
Continue with prednisolone (lowest possible dose) and azathioprine
Start mycophenolate mofetil (mild, moderate symptoms) or rituximab (severe symptoms) Yes
Su?cient e?ect? No
Continue treatment
A Start other immunosuppressive drugs (methotrexate, ciclosporin, tacrolimus) B Re-evaluate myasthenia gravis
Figure 4: Treatment of generalised myasthenia gravis
patients, initial deterioration of generalised myasthenia gravis has been reported lasting for up to 3 weeks.7,54,80 The starting dose is most often 0·75–1·0 mg/kg per day1 for prednisone and prednisolone and is gradually increased; alternate-day dosing is thought to reduce side-e?ects and is recommended by some treatment guidelines.2,3,81 After optimum improvement has been induced, the drug dose should be gradually reduced, and continued at the lowest dose necessary to obtain maximum e?ect. Prednisone or
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prednisolone should not be given as an alternate-day treatment to patients with diabetes because ?uctuations in glucose concentrations result from this treatment approach. If muscle strength di?ers for o?-treatment days and on-treatment days, a low dose (5–10 mg) of prednisone or prednisolone can be added on o?-days. For ocular myasthenia gravis, observational studies53,82 suggest that prednisolone treatment reduces the risk of developing generalised myasthenia gravis, although this observation has not been con?rmed. For patients who take long-term corticosteroids, speci?c precautions should be taken to reduce the risks of glucose intolerance, gaining excess bodyweight, hypertension, and development of osteoporosis. A UK registry-based study83 did not report an increased fracture risk in patients with myasthenia gravis. Azathioprine is an e?ective drug for all myasthenia gravis subgroups, with 2–3 mg/kg being the most e?ective dose in combination with prednisolone.62,63,84 This combination is often recommended as a ?rst-choice treatment for patients with generalised myasthenia gravis who need immunosuppression, and is more bene?cial than corticosteroids alone with fewer sidee?ects. The azathioprine e?ect is delayed and from clinical experience is usually seen after 6–15 months, and might further increase during the subsequent 1–2 years.63 This makes the combination with prednisolone convenient, and prednisolone can be reduced when the azathioprine e?ect has been established. Regular followup is necessary because of the risk of leucopenia and hepatotoxic e?ects, especially during the ?rst months of treatment. Low thiopurine methyltransferase activity increases the risk for azathioprine toxic e?ects, and can be tested before the start of treatment. Long-term treatment is also safe and e?ective in young individuals.85 Azathioprine and corticosteroids in combination are e?ective in almost all patients with myasthenia gravis. Patients with ocular myasthenia gravis often respond well to a small dose (10–30 mg on alternate days) of corticosteroids alone. Mycophenolate mofetil is a prodrug that after conversion blocks purine synthesis and interferes with B-cell and T-cell proliferation. Most guidelines recommend the drug for mild and moderate myasthenia gravis if the initial immunosuppressive therapy fails,2–4 often together with prednisolone. This recommendation is based on retrospective studies1–3,8 and clinical experience. Mycophenolate mofetil is not recommended as ?rst-line treatment. In two prospective and controlled trials,69,86 mycophenolate mofetil did not show additional bene?t when given as initial treatment combined with prednisone. The studies had short durations of only 12 weeks and 9 months. There were no stopping rules for the use of corticosteroids and the lowest prednisone dose was 7·5 mg per day, which might have obscured an e?ect of mycophenolate mofetil. Little is known about myasthenia gravis subgroup responses for this drug.87
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Side-e?ects are rare, with mild headache, nausea, and diarrhoea the most commonly reported. Rituximab has emerged as a potentially e?ective drug in myasthenia gravis.81,88,89 It is a chimeric IgG1 monoclonal antibody that depletes all types of B lymphocytes through speci?c binding to the transmembrane CD20 antigen. This drug should, in our opinion, be considered in moderate and especially severe myasthenia gravis that does not respond su?ciently to ?rst-line immunosuppressive treatment. However, controlled studies have not been done, and rituximab is not regarded as a fully established treatment. About twothirds of patients with severe myasthenia gravis and insu?cient response to prednisolone and azathioprine have a substantial improvement on this treatment.81,88–91 Open and uncontrolled studies90–92 show that patients with MUSK-associated myasthenia gravis in particular have a favourable response, which is especially important as this myasthenia gravis subgroup often has a lower response to the ?rst-line symptomatic and immunosuppressive treatment. In most reports, the induction treatment recommended for rheumatological diseases has been used, which is two doses of rituximab 1000 mg, and then another two doses of 1000 mg after 2 weeks.81,88–91 Lower doses have been suggested for myasthenia gravis.88 Most centres would give additional rituximab doses only to patients with deterioration after a substantial and longlasting response, and then in the lowest e?ective dose.92 Rituximab is most often combined with prednisolone and the combination with prednisolone and azathioprine is also regarded as safe. Severe side-e?ects have been reported as rare events with rituximab for other autoimmune disorders, including JC-virus-related progressive multifocal leukoencephalopathy, and have restricted the use of rituximab in myasthenia gravis. Even in the absence of controlled prospective studies and with high drug costs, rituximab has, in our opinion, a place as an early treatment for an increasing number of patients with MUSK and AChR-associated myasthenia gravis. Prospective and controlled studies have shown that ciclosporin and methotrexate are e?ective as secondary drugs for myasthenia gravis.65,70,93 The e?ect occurs in all myasthenia gravis subgroups. Although comparative studies have not been undertaken, ciclosporin and methotrexate are thought to be as e?ective as azathioprine.1–4,7 Patients should be monitored for potential side-e?ects, especially nephrotoxic e?ects and hypertension. Tacrolimus has similarities to ciclosporin. A small (34 patients) randomised but unblinded study66 showed that prednisone could be given at a reduced dose after 52 weeks when combined with tacrolimus. However, a large double-blind study67 comprising of 80 patients did not con?rm this ?nding. The length of this study was only 28 weeks and the therapeutic e?ect of prednisone alone was better than expected.94 A new trial comparing tacrolimus with placebo for patients with an insu?cient
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response to glucocorticoids is in progress (NCT01325571). Tacrolimus has an additional e?ect on ryanodine receptormediated calcium release from the sarcoplasmic reticulum, which theoretically could lead to improvements in muscle strength in patients with myasthenia gravis.
Thymectomy
Many studies have reported a substantial e?ect of thymectomy in myasthenia gravis. These studies have included control groups, but prospective and randomised studies have not been done.1–3,7,95,96 For early-onset myasthenia gravis, we recommend a thymectomy early after symptom onset. All thymus tissue needs to be removed. Video-assisted thoracoscopic and roboticassisted methods are well established, used by an increasing number of centres, and are usually preferred by patients.97 Thymectomy can be safe for juvenile myasthenia gravis, down to an age of about 5 years.98 Improvement in response to thymectomy occurs gradually after some months, and according to follow-up studies, continues for up to 2 years postoperatively.95 No other autoimmune disorders have been shown to improve after thymectomy. Thymectomy should be undertaken as an oncological intervention when a thymoma is detected or is strongly suspected to avoid local compression and spread to the thoracic cavity. Any positive e?ect on myasthenia gravis is more unpredictable for the thymoma than for the early-onset subgroup. Use of thymectomy in late-onset myasthenia gravis is debated. For patients with late-onset disease with an atrophic thymus or onset at age 60–65 years or older, thymectomy is not recommended because no convincing data support surgery for this group. However, some guidelines7 recommend treating young patients (up to age 60–65 years) with late-onset disease who have an enlarged thymus on imaging and no antibodies to muscle titin or the ryanodine receptor, similar to patients with early-onset myasthenia gravis. For younger patients with late-onset myasthenia gravis, the thymus is most probably involved in the pathogenesis and the response to thymectomy would be expected to be similar to that for early-onset disease. Thymectomy is not recommended for patients with MUSK, LRP4, or ocular forms of myasthenia gravis as no therapeutic e?ect has been shown. For patients with generalised myasthenia gravis and low-a?nity AChR antibodies, thymus hyperplasia is usually impossible to establish by imaging. Such patients would be expected to respond to thymectomy but cannot be distinguished from other patients with myasthenia gravis who are found to be antibody negative. Thymectomy should be done early, but is never an emergency; patients should be in a stable condition. Intravenous immunoglobulin or plasma exchange immediately before surgery will improve the myasthenia gravis symptoms, reduce the risk of complications, and contribute to a faster recovery.
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Supportive treatment
Physical activity and low intensity and medium intensity training provide short-term and long-term bene?ts for patients with myasthenia gravis. Weakness increases with repetitive muscle use, but patients with myasthenia gravis can still ?nd activities for which they can adjust intensity and duration to increase their long-term physical ability. Rest after such exercise is needed. No controlled studies of myasthenia gravis training programmes have been published. Bodyweight control is important, as for other disorders with muscle weakness. Such control is especially relevant in patients with involvement of respiratory muscles. Infections in patients with myasthenia gravis should be treated early and vigorously because they can lead to myasthenia gravis exacerbation and add to respiratory impairment.1–4,7 Drugs that interfere negatively with neuromuscular transmission should be avoided. D-penicillamine and telithromycin should not be given to patients with myasthenia gravis, and ?uoroquinolones, aminoglycosides, macrolides, and neuromuscular blocking drugs will often cause worsening of the disease. Neuromuscular blockade should be used with care during anaesthesia. Sedatives that could suppress respiration should be avoided in the treatment of patients with severe myasthenia gravis. If a patient deteriorates when given a new drug, this drug should be withdrawn. However, most patients with myasthenia gravis with mild-to-moderate disease, or in stable remission, tolerate drugs that have a relative warning, and most drugs can be used with caution.
Severe, generalised myasthenia gravis
Treatment of myasthenia gravis crisis
Crisis is de?ned as a need for intubation for respiratory support caused by muscle weakness related to the disease. Treatment includes intensive care with respiratory support, treatment of infections, and monitoring of vital functions and mobilisation (?gure 5). Intravenous immunoglobulin and plasma exchange are speci?c immunosuppressive treatments with a rapid e?ect occurring after 2–5 days, and either one should be given to patients with severe myasthenia gravis exacerbations and always for crisis.99–103 These two treatment alternatives are equally e?ective, and can be given in sequence if necessary, as patients can respond to one but not to the other. Standard protocols include treatment for 3–6 consecutive days. Intravenous immunoglobulin is often slightly more convenient and with a lower risk of severe side-e?ects, whereas plasma exchange might have a slightly faster e?ect. Catheter placement procedures for plasma exchange can be complex because access to large veins is necessary. The treatment e?ect is usually restricted to 2–3 months, owing to continuing antibody synthesis. Plasma exchange and intravenous immunoglobulin can be repeated when the e?ect tapers o?. To secure long-term improvement, this treatment is usually combined with standard immunosuppressive drugs, in higher doses than before the crisis or with add-on drugs. In patients with an acute exacerbation that does not respond to intravenous immunoglobulin or plasma exchange, corticosteroids in high doses can be tried. Myasthenia gravis crisis is a reversible condition. Sometimes the treatment response is delayed, but intensive care and vigorous immunosuppression should be continued for as long as necessary, sometimes for several weeks.
Start intensive care, respirator if necessary, start intravenous immunoglobulin or plasma exchange
Treatment of myasthenia gravis in pregnancy
Pregnancy does not a?ect myasthenia gravis in any consistent way, with no increased risk of severe deterioration or myasthenia gravis crisis.85,104,105 During the ?rst weeks and few months post partum, the risk of symptom worsening is moderately increased, mainly because of stress and new demands. Pyridostigmine and corticosteroids are regarded as safe treatments for pregnant women.85 These drugs do not increase the risk of fetal malformations or delayed fetal development. Plasma exchange and intravenous immunoglobulin can be used safely for exacerbations in pregnancy, and also as preparation for women giving birth. Evidence for potential teratogenic e?ects of other immunosuppressive drugs is sparse. However, caution is recommended for use of these drugs, and the manufacturers of immunosuppressive drugs generally advise against their use in pregnancy. Azathioprine has been widely used for many years by young women with AChR, MUSK, or LRP4 forms of myasthenia gravis. The general view is that this drug has very low, if any, increased teratogenic risk.85 Lactation should be encouraged in
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Improvement? No
Yes
Start or continue and intensify long-term immunosuppressive treatment
Start plasma exchange or intravenous immunoglobulin Start corticosteroids in high-dose methylprednisolone*
Improvement? No
Yes
Continue and intensify long-term immunosuppressive treatment
Start rituximab (outside intensive care unit), continue intensive care and treat complications
Figure 5: Treatment of severe myasthenia gravis exacerbations *1000 mg a day for 3 days.
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patients with myasthenia gravis, also for women on immunosuppressive drugs,105 but the passage of some medications into breastmilk should be taken into account. Mycophenolate mofetil and methotrexate have teratogenic potential. Methotrexate might also reduce female fertility. These two drugs should only rarely be used in young women, and not in pregnancy. Most female patients with myasthenia gravis give birth in an uncomplicated way. Apart from the risk of neonatal myasthenia gravis, no precautions are usually needed. Caesarean section is not recommended as a routine for these women, but should be considered in prolonged births for women with moderate or severe generalised myasthenia gravis because of muscle fatigue.
Search strategy and selection criteria We searched MEDLINE and the Cochrane Library with the terms “myasthenia gravis”, “myasthenic syndromes”, and “myasthenia” from January 1995, to April, 2015. Guideline and review papers were assessed in detail, and controlled studies sought for in particular. Papers were selected by title and abstract. Only papers in English were included. Randomised trials on established and emerging therapies for myasthenia gravis are often scarce, so our recommendations are based on the best available evidence or clinical experience, where stated.
Treatment of neonatal myasthenia gravis
Neonatal myasthenia gravis occurs in 10–15% of babies of mothers with the disease. The cause of this transient muscular weakness in these babies is transfer of the mother’s AChR or MUSK antibodies of the IgG class across the placenta. This weakness usually lasts for only days or a few weeks and is typically mild but can interfere with feeding and respiration. Mothers with myasthenia gravis should always give birth at hospitals experienced in respiratory support treatment for newborn babies. The fact that neonatal myasthenia gravis does not occur in all babies and that occurrence in babies is not correlated with maternal disease severity or AChR antibody concentration might be explained by variation in AChR epitopes, epitopebinding a?nity, and non-AChR factors.105 Transplacental AChR antibodies can, in rare cases, produce arthrogryposis due to severe intrauterine movement inhibition. Such skeletal malformations were reported in three of 127 babies in an unselected national cohort.106 Arthrogryposis, AChR-antibody induced stillbirths, and repeated spontaneous abortions can be avoided by intravenous immunoglobulin infusions or plasma exchange before and during pregnancy. This treatment should be given in female patients with myasthenia gravis who have already experienced such a pregnancy outcome.
Conclusions and future directions
Most patients with myasthenia gravis do well and have well controlled disease. However, most need long-term and often life-long drug treatment with acetylcholinesterase inhibitors and usually low-dose immunosuppression. Pathogenic autoantibodies are well characterised and myasthenia gravis subgroups are de?ned accordingly. However, treatment is far from antibody speci?c and is not even speci?c to the disease subgroup. Many new and more traditional drugs that have not been tested properly in myasthenia gravis have modes of action that are expected to suppress autoantibody production directly or indirectly, and therefore might bene?t patients with myasthenia gravis. For patients with severe symptoms that do not respond su?ciently to standard treatment, with a diagnosis con?rmed by the presence of
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autoantibodies and no comorbidity as the symptom cause, such drugs could be tried, o?-label, and with strict monitoring. These include monoclonal antibody drugs with a proven e?ect for other autoimmune disorders. Complement inhibition is one of several potential strategies,76 with a focus on several factors in the complement system. Eculizumab, belimumab, le?unomide, and etanercept are drugs that might have the potential to become new myasthenia gravis treatment options,76,107–109 although some immunoactive drugs can precipitate or worsen myasthenia gravis.110 Tirasemtiv (CK-2017357) selectively sensitises fast skeletal muscle to calcium by binding to its troponin complex and ampli?es the muscle response when neural input is diminished secondary to neuromuscular disease.111 A dose-related, short-term improvement was reported in a phase 2a randomised placebo-controlled trial.77 Any functionally relevant long-term bene?t to patients is still to be proven. Several non-antibody factors linked to the immune system and skeletal muscle a?ect the individual’s muscle strength and immune responses, and thereby each patient’s myasthenia gravis manifestations. The high number of factors associated with muscle function in myasthenia gravis should drive future research towards an individually adapted treatment approach based on biomarker (autoantibody) assessment and monitoring. The aim should be to suppress the antiAChR, anti-MUSK, or anti-LRP4 immune response without a?ecting other immune reactions. An alternative approach could be treatment that promotes tolerance to the antigens (AChR, MUSK, and LRP4) that induce myasthenia gravis.112 Patients with myasthenia gravis without detectable antibodies probably have pathogenic antibodies against unde?ned antigens in the neuromuscular junction; many proteins a?ect AChR function, synthesis, and maintenance that could potentially underlie antibody-negative disease. Autoimmune myasthenia gravis with a T-cell-mediated and non-antibody mechanism a?ecting neuromuscular transmission could theoretically exist. When the causes of myasthenia gravis can be identi?ed, they might be possible to avoid or prevent, potentially, for example, by vaccination. Until antigen-speci?c treatment is available, however, research e?orts should target new
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immunosuppressive drugs and drug combinations for the myasthenia gravis subgroups. Prospective and controlled studies should be encouraged and supported. Severe myasthenia gravis is a reversible disorder that should be treated with intensity and optimism.
Contributors NEG planned the Review and wrote the ?rst draft. JJV edited and rewrote the ?rst draft. Both authors searched primary sources for information, produced tables and ?gures, and ?nalised the text. Declaration of interests NEG has received speaker’s honorarium from Octapharma, Baxter, and Merck Serono. JJV is a partner in an FP7 European grant that is associated with Curavac. The Department of Neurology at Leiden University Medical Center has received fees from BioMarin for JJV’s consultancy work and royalties from antibody tests. JJV received research grants from Prinses Beatrix Spierfonds and National Institutes of Health. References 1 Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 2009; 8: 475–99. 2 Gilhus NE. Myasthenia and neuromuscular junction. Curr Opin Neurol 2012; 25: 523–29. 3 Querol L, Illa I. Myasthenia and the neuromuscular junction. Curr Opin Neurol 2013: 26: 459–65. 4 Verschuuren JJ, Huijbers MG, Plomp JJ, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-speci?c kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013; 12: 918–23. 5 Zisimopoulou P, Brenner T, Trakas N, Tzartos SJ. Serological diagnostics in myasthenia gravis based on novel assays and recently identi?ed antigens. Autoimmun Rev 2013; 12: 924–30. 6 Owe JF, Daltveit AK, Gilhus NE. Causes of death among patients with myasthenia gravis in Norway between 1951 and 2001. J Neurol Neurosurg Psychiatry 2006; 77: 203–07. 7 Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010; 17: 893–902. 8 Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med 2013; 86: 255–60. 9 Jacob S, Viega S, Leite MI. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol 2012; 69: 994–1001. 10 Yang L, Maxwell S, Leite MI, et al. Non-radioactive serological diagnosis of myasthenia gravis and clinical features of patients from Tianjin, China. J Neurol Sci 2011; 301: 71–76. 11 Cole RN, Ghazanfari N, Ngo ST, et al. Patient autoantibodies deplete postsynaptic muscle-speci?c kinase leading to dissembly of the ACh receptor sca?old and myasthenia gravis in mice. J Physiol 2010; 17: 3217–29. 12 Y, Ito M, Hirayama M, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77: 1819–28. 13 Plomp JJ, Huijbers MG, Maarel SMVD, Verschuuren JJ. Pathogenic IgG4 subclass autoantibodies in MuSK myasthenia gravis. Ann NY Acad Sci 2012; 1275: 114–22. 14 Shen C, Lu Y, Zhang B, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest 2013; 123: 5190–202. 15 Gasperi C, Melms A, Schoser B, et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology 2014; 82: 1976–83. 16 Zhang B, Shen C, Bealmear B, et al. Autoantibodies to agrin in myasthenia gravis. PLoS One 2014; 9: e91816. 17 Gallardo E, Martinez-Hernandez E, Titulaer MJ, et al. Cortactin autoantibodies in myasthenia gravis. Autoimmun Rev 2014; 13: 1003–07. 18 Skeie GO, Mygland A, Treves S. Ryanodine receptor antibodies in myasthenia gravis: epitope mapping and e?ect on calcium release in vitro. Muscle Nerve 2003; 27: 81–89. 19 Romi F, Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur J Neurol 2007; 14: 617–20.
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Heldal AT, Owe JF, Gilhus NE, et al. Seropositive myasthenia gravis; a nationwide epidemiologic study. Neurology 2009; 73: 150–51. Andersen JB, Engeland A, Owe JF, et al. Myasthenia gravis requiring pyridostigmine treatment in a national population cohort. Eur J Neurol 2010; 17: 1445–50. Carr AS, Cardwell CR, McCarron PO, et al. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010; 10: 46 Pakzad Z, Aziz T, Oger J. Increasing incidence of myasthenia gravis among elderly in British Columbia, Canada. Neurology 2011; 76: 1526–28. Pedersen EG, Hallas J, Hansen K, et al. Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996–2009. Eur J Neurol 2012; 20: 942–48. VanderPluym, J, Vajsar J, Jacob FD, et al. Clinical characteristics of pediatric myasthenia: a surveillance study. Pediatrics 2013; 132: e939–44. Niks EH, Kuks JBM, Verschuuren JJGM. Epidemiology of myasthenia gravis witht anti-muscle speci?c kinaase antibodies in the Netherlands. J Neurol Neurosurg Psychiatry 2007; 78: 417–18. Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis; clinical ?ndings and response to treatment in two large cohorts. Muscle Nerve 2011; 44: 36–40. Rodolico C, Toscano A, Autunno M, et al. Limb-girdle myasthenia; clinical, electrophysiological and morphological features in familial and autoimmune cases. Neuromuscul Disord 2002; 12: 964–69. Gilhus NE, Nacu A, Andersesn JB, Owe JF. Myasthenia gravis and risks for comorbidity. Eur J Neurol 2015; 22: 17–23. Liewluck T. Immune-mediated rippling muscle disease; another in?ammatory myopathy in myasthenia gravis. Arch Neurol 2010; 67: 896–97. Mehanna R, Patton EL, Phan CL, Harati Y. Amyotrophic lateral sclerosis with positive anti-acetylcholine receptor antibodies; case report and review of the literature. J Clin Neuromuscul Dis 2012; 14: 82–85. Filosso PL, Galassi C, Ru?ni E, et al. Thymoma and the increased risk of developing extrathymic malignancies: a multicentre study. Eur J Cardiothor Surg 2013; 44: 219–24. Pedersen EG, Pottegard A, Hallas J, et al. Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide casecontrol study in Denmark. Eur J Neurol 2013; 20: 942–48. Pedersen EG, Pottegard A, Hallas J, et al. Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine. Eur J Neurol 2014; 20: 942–48. Owe JF, Davidsen ES, Eide GE, et al. Left ventricular long-axis function in myasthenia gravis. J Neurol 2008; 255: 1777–84. Suzuki S, Utsugisawa K, Yoshikawa H, et al. Autoimmune targets of heart and skeletal muscles in myasthenia gravis. Arch Neurol 2009; 66: 1334–38. Kumagai S, Kato T, Ozaki A, et al. Serial measurements of cardiac troponin I in patients with myasthenia gravis-related cardiomyopathy. Int J Cardiol 2013; 168: e79–80. Suzuki S, Utsugisawa K, Suzuki N. Overlooked non-motor symptoms in myasthenia gravis. J Neurol Neurosurg Psychiatry 2013; 84: 989–94. Alkhawajah NM, Oger J. Late-onset myasthenia gravis; a review when incidence in older adults keeps increasing. Muscle Nerve 2013; 48: 705–10 Gregersen PK, Kosoy R, Lee AT, et al. Risk for myasthenia gravis maps to a (151) pro-ala change in TNIP1 and human leukocyte antigen-B*08. Ann Neurol 2012; 72: 927–35. Renton AE, Piner HA, Provenzano C, et al. A genome-wide association study of myasthenia gravis. JAMA Neurol 2015; 72: 396–404. Klein R, Marx A, Str?bel P, et al. Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum Immunol 2013; 74: 1184–93. Maniaol AH, Elsais A, Lorentzen ?R, et al. Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLoS One 2012; 7: e36603. Marx A, P?ster P, Schalke B, et al. The di?erent roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 2013; 12: 875–84.
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48
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Skjei KL, Lennon VA, Kuntz NL. Muscle speci?c kinase autoimmune myasthenia gravis in children: a case series. Neuromuscul Disord 2013; 23: 874–82. Bartoccioni E, Scuderi F, Augugiaro A, et al. HLA class II allele analysis in MuSK-positive myasthenia gravis suggests a role for DQ5. Neurology 2009; 72: 195–97. Klooster R, Plomp JJ, Huijbers MG, et al. Muscle-speci?c kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 2012; 135: 1081–101. Alahgholi-Hajibehzad M, Yilmaz V, Guisen-Parman Y, et al. Association of HLA-DR131*14,-DR131*16 and –DQB1*05 with MuSK-myasthenia gravis in patients from Turkey. Hum Immunol 2013; 74: 1633–35. Higuchi O, Hamuo J, Motomura M, et al. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011; 69: 418–22. Zhang B, Tzartos JS, Viegas S, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-negative myasthenia gravis. Arch Neurol 2012; 69: 445–51 Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to acetylcholine receptors in ”seronegative” myasthenia gravis. Brain 2008; 131: 1940–52. Cossins J, Belaya K, Zoltowska K, et al. The search for new antigenic targets in myasthenia gravis. Ann N Y Acad Sci 2013; 1275: 123–28. Kerty E, Elsais A, Argov Z, Evoli A, Gilhus NE. EFNS/ENS guidelines for the treatment of ocular myasthenia gravis. Eur J Neurol; 2014: 21: 687–93. Romi F, Bo L, Skeie GO, et al. Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J Neuroimmunol 2002; 128: 82–89. Cu? P, Dragin N, Weiss JM, et al. Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis. Ann Neurol 2012; 73: 281–93. Panse RL, Berrih-Aknin S. Autoimmune myasthenia gravis: autoantibody mechanisms and new developments on immune regulation. Curr Opin Neurol 2013; 26: 569–76. Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev 2014; CD006986. Mount, FW. Corticotropin in treatment of ocular myasthenia; a controlled clinical trial. Arch Neurol 1964; 11: 114–24. Howard FM Jr, Duane DD, Lambert EH, Daube JR. Alternate-day prednisone: preliminary report of a double-blind controlled study. Ann N Y Acad Sci 1976; 274: 596–607. Lindberg C1, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand 1998; 97: 370–73. Benatar M, McDermott MP, Sanders DB, et al, for the Muscle Study Group (MSG). E?cacy of Prednisone for the Treatment of Ocular Myasthenia (EPITOME): a randomized controlled trial. Muscle Nerve 2015; published online July 14. DOI:10.1002/ mus.24769. Bromberg MB, Wald JJ, Forshew DA, et al. Randomized trial of azathioprine or prednisone for initial immunosuppressive treatment of myasthenia gravis. J Neurol Sci 1997; 150: 59–62. Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 1998; 50: 1778–83. Tindall RS, Rollins JA, Phillips JT, Greenlee RG, Wells L, Belendiuk G. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 1987; 316: 719–24. Tindall RS, Philips JT, Rollins JA, et al. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci 1993; 681: 539–51. Nagane Y, Utsugisawa K, Obara D, et al. E?cacy of low-dose FK506 in the treatment of myasthenia gravis; a randomized pilot study. Eur Neurol 2005; 53: 146–50. Yoshikawa H, Kiuchi T, Saida T, et al. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011; 82: 970–77.
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73
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77
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Meriggioli MN, Rowin J, Richman JG, Leurgans S. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. Ann N Y Acad Sci 2003; 998: 494–9. Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008; 71: 400–06. Pasnoor M, He J, Herbelin L, et al. Phase II trial of methotrexate in myasthenia gravis. Ann N Y Acad Sci 2013; 1275: 23–28. Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997; 41: 789–96. Wolfe GI, Barohn RJ, Foster BM, et al, for the Myasthenia Gravis-IVIG Study Group. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002; 26: 549–52. Gajdos P, Tranchant C, Clair B, et al, for the Myasthenia Gravis Clinical Study Group. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol 2005; 62: 1689–93. Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology 2007; 68: 837–41. Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 2011; 76: 2017-23. Howard JF, Barohn PJ, Cutter GR, et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve 2013; 48: 76–84. Sanders DB, Rosenfeld J, Dimachkie MM, et al. A double-blinded, randomized, placebo-controlled trial to evaluate e?cacy, safety and tolerability of single doses of tirasemtiv in patients with acetylcholine receptor-binding antibody-positive myasthenia gravis. Neurotherapeutics 2015; 12: 455–60. Hart IK, Sthasiam S, Sharshar T. Immunosuppressive agents for myasthenia gravis (review). Cochrane Database Syst Rev 2007; CD005224. Jaretzki III A, Barohn RJ, Ernsto? RM et al. Myasthenia gravis: recommendations for clinical research standards. Ann Thorac Surg 2000; 70: 327–34. Benatar M, Sanders DB, Wolfe GI, McDermott MP, Tawil R. Design of the e?cacy of prednisone in the treatment of ocular myasthenia (EPITOME) trial. Ann N Y Acad Sci 2012; 1275: 17–22. Benveniste O, Hilton-Jones D. The role of rituximab in the treatment of myasthenia gravis. Eur Neurol Rev 2010; 5: 95–100. Benatar M, Kaminski H. Medical and surgical treatment for ocular myasthenia. Cochrane Database Syst Rev 2012; CD005081. Pouwels S, Boer AD, Javaid MK, et al. Fracture rates in patients with myasthenia gravis; the general practice research database. Osteoporos Int 2013; 24: 467–76. Marinkovic G, Kroon J, Hoogenboezem M, et al. Inhibition of GTPase rac1 in endothelium by 6-mercaptpurine results in immunosuppression in nonimmune cells; new target for an old drug. J Immunol 2014; 192: 4370–78. Norwood F, Dhanjal M, Hill M, et al. Myasthenia in pregnancy; best practice guidelines from a UK multispeciality working group. J Neurol Neurosurg Psychiatry 2014; 85: 538–43. The Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008; 71: 394–399. Hehir MK, Burns TM, Alpers J, et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis; outcomes in 102 patients. Muscle Nerve 2010; 41: 593–98. Blum S, Gillis D, Brown H, et al. Use and monitoring of low dose rituximab in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011; 82: 659–63. Maddison P, McConville J, Farrugia ME, et al. The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2011; 82: 671–73. Diaz-Manera J, Martinez-Hernandez E, Querol L, et al. Long-lasting treatment of rituximab in MuSK myasthenia. Neurology 2012; 78: 189–93.
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Keung B, Robeson KR, DiCapua DB, et al. Long-term bene?t of rituximab in MuSK autoantibody myasthenia gravis patients. J Neurol Neurosurg Psychiatry 2013; 84: 1407–09. 92 Yi JS, DeCroos EC, Sanders DB et al. Prolonged B-cell depletion in MuSK myasthenia gravis following rituximab treatment. Muscle Nerve 2013; 48: 992–93. 93 Heckmann JM, Rawoot A, Bateman K, et al. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol 2011; 11: 97. 94 Benatar M, Sanders D. The importance of studying history; lessons learnt from a trial of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011; 82: 945. 95 Gronseth GH, Barohn RJ. Thymectomy for autoimmune myasthenia gravis (an evidence-based review). Neurology 2000; 55: 7–15. 96 Cea G, Benatar M, Verdugo RJ, Salinas RA. Thymectomy for nonthymomatous myasthenia gravis. Cochrane Database Syst Rev 2013; cd008111. 97 Ye B, Tantal J-C, Li W, et al. Video-assisted thoracoscopic surgery versus robotic-assisted thoracoscopic surgery in the surgical treatment of Masaoka stage I thymoma. World J Surg Oncol 2013; 11: 157–62. 98 Liew WKM, Kang PB. Update on juvenile myasthenia gravis. Curr Opin Pediatr 2013; 25: 694–700. 99 Gajdos P, Chevret S, Toyka KV. Plasma exchange for generalised myasthenia gravis. Cochrane Database Syst Rev 2002; CD002275. 100 Mandawat A, Kaminski H, Cutter G, et al. Comparative analysis of therapeutic options used for myasthenia gravis. Ann Neurol 2010; 68: 797–805. 101 Barth D, Nabavi N, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 2011; 76: 2017–23. 102 Gilhus NE. Acute treatment for myasthenia gravis. Nat Rev Neurol 2011; 7: 132–34.
103 Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 2012; CD002277. 104 Ferrero S, Pretta S, Nicoletti A, et al. Myasthenia gravis: management issues during pregnancy. Eur J Obst Gynecol Reproduct Biol 2005; 121: 129–38. 105 Ho? JM, Daltveit AK, Gilhus NE. Myasthenia gravis in pregnancy and birth: identifying risk factors, optimising care. Eur J Neurol 2007; 14: 38–43. 106 Ho? JM, Loane M, Gilhus NE, et al. Arthrogryposis multiplex congenital: an epidemiologic study of nearly 9 million births in 24 Eurocat registers. Eur J Obst Gynecol Reproduct Biol 2011; 159: 347–50. 107 Ragheb S, Lisak R, Lewis R, et al. A potential role for B-cell activating factor in the pathogenesis of autoimmune myasthenia gravis. Arch Neurol 2008; 65: 1358–62. 108 Gomez AM, Vrolix K, Martinez-Martinez P, et al. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J Immunol 2011; 186: 2503–13. 109 Rowin J, Thiruppathi M, Arrebamen E, et al. Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis; e?ects on regulatory T cells. Muscle Nerve 2012; 46: 449–53. 110 Fee DB, Kasarskis EJ. Myasthenia gravis associated with etanercept therapy. Muscle Nerve 2009; 39: 866–70. 111 Russell AJ, Hartman JJ, Hinken AC, et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 2012; 18: 452–56. 112 Steinman L. The road not taken: antigen-speci?c therapy and neuroin?ammatory disease. JAMA Neurol 2013; 70: 1100–01.
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#include "reg52.h" unsigned char count; //0.5ms次数标识 sbit pwm =P2^7 ; //PWM信号输出 sbit jia =P2^4; //角度增加按键检测IO口 sbit jan =P2^5; //角度减少按键检测IO口 unsigned char jd=5; //角度标识 void delay(unsigned char i)//延时 { unsigned char j,k; for(j=i;j>0;j--) for(k=125;k>0;k--); } void Time0_Init() //定时器初始化 { TMOD = 0x01; //定时器0工作在方式1 IE = 0x82; TH0 = 0xfe; TL0 = 0x33; //11.0592MZ晶振，0.5ms TR0=1; //定时器开始 } void Time0_Int() interrupt 1 //中断程序 { TH0 = 0xfe; //重新赋值 TL0 = 0x33; if(count< jd) //判断0.5ms次数是否小于角度标识 pwm=1; //确实小于，PWM输出高电平 else pwm=0; //大于则输出低电平 count=(count+1); //0.5ms次数加1 count=count%40; //次数始终保持为40 即保持周期为20ms } void keyscan() //按键扫描 { if(jia==0) //角度增加按键是否按下 { delay(10); //按下延时，消抖 if(jia==0) //确实按下 { jd++; //角度标识加1 count=0; //按键按下则20ms周期从新开始 if(jd==6) jd=5; //已经是180度，则保持 while(jia==0); //等待按键放开
摘要：本设计主要针对目前城市公交公司，银行等场所对于钱币分类处理的问题，目前许多地方对于钱币的分离都依赖于人工，人力成本高，且效率较低，本次设计就是对于硬币的分类整理的。本次设计的产品比较实用，精准，而且方便，可以代替人工，减少成本。 本次设计创新（1）可以将不同大小的硬币进行有效的分离（2）此作品结构严谨，能够精准的分离，整理硬币。 关键词：硬币的分离整理识别 1.1硬币清分机的课题背景 银行等一些特殊部门要对大量的硬币进行高效的处理，如计数、分类、包装等以使其再流通，无人售票车、投币电话等需要对硬币进行实时识别，自动售货机除了识别之外，还要提供找零功能等。而且在目前在世界范围内，硬币以其成本低，流通次数多、耐磨损、易回收等无可替代的优势将占领小面额货币市场是大势所趋。市场需要一种成熟可靠的硬币自动处理机具。鉴于此需要，我们研制用于处理上述问题的机具。 硬币清分机是金融行业设备中的用于清点硬币的技术产品，它的主要功能是硬币的计数和硬币币种的清分。目前主要适用于超市、公交、自动售货行业，零售业等行业。硬币清分机外型简单大方，设备原理清晰。操作简单易懂，价格适中，在超市，零售等行业颇受欢迎。 硬币清分机的最大优点在于它不仅可以清点硬币的数目，更能将各币种清分开来，并且面对不同的国家的硬币不需要调整软件，只需要调整机器的硬件设备就可以满足不同的国家的硬币清点需求。因此不仅占据了很大的市场份额，而且对于生产成本也有所降低。 1.1.1硬币分离器的简介 硬币分离器是对高速通过的硬币进行识别，计数，同时对伪币，残币进行剔除的系统，在这领域国外已经开展了研究，并做了了大量的工作，开发的产品大多分三个档次，低档，中档，高档。低档的清分速度在1000枚/rain以下，中档为1000-1500枚/rain，高档在1500枚/rain以上。所使用的分离方法注意就有两大类，一类物理技术清分，二类是性能指标清分。 1.2国内外硬币清分机发展现状 1.2.1国外硬币清分发展现状 硬币清分机至今已有30年的历史，发展到今天，硬币清分机已具有可靠的传动系统和先进的计数清分功能，其智能化的设计为解决硬币清点的困难提供了完美的选择。国外著名厂家有日本的荣光瑞典的SCANCOIN AB。
控制思想 该模块的程序框图如图4.5 所示。车模在行驶过程中不断采样赛道信息，并通过分析车模与赛道相对位置判断车模所处赛道路况，是弯道还是直道，弯道时是左转还是右转。直道时小车舵机状态保持不变，弯道时左转或右转，计算转弯半径。我们所用舵机的标准PWM 周期为20ms,转动角度最大为左右90度，PWM调制波如图7.2所示。
当给舵机输入脉宽为0.5ms，即占空比为0.5/20=2.5%的调制波时，舵机右转90度；当给舵机输入脉宽为1.5ms，即占空比为1.5/20=7.5%的调制波时，舵机静止不动；当给舵机输入脉宽为2.5ms，即占空比为2.5/20=12.5%的调制波时，舵机左转90度。可以推导出舵机转动角度与脉冲宽度的关系计算公式为： 注：其中t为正脉冲宽度（ms）；θ为转动角度；当左转时取加法计算，右转时取减法计算结果。 当我们根据赛道弯度计算出转动角度以后便可以根据舵机的参数计算出脉冲宽度，控制舵机转动，舵机转角与PWM脉宽关系如表4-1所示。
在具体操作中PWM调制波的周期可以设置在20ms左右一定范围内，比如设置为10ms 或是30ms均可以使舵机正常转动，但是设置周期较长时，系统延迟时间较多，舵机转向会出现滞后，导致赛车冲出跑道；设置周期如果过短，系统输出PWM 调制波不稳定，舵机转动也会受影响，不能实现赛车的精确转向。经过反复测试，最终把输出PWM 调制波周期设定为13ms (用计数器实现)。 运行电机的转速以及舵机的转角，在软件上都是通过对PWM 波占空比进行设置来相应控制的。前面提到，舵机转角控制需要将两个
八位寄存器合成为一个十六位寄存器。程序中的舵机位置信号，当PWM调制波周期设为13ms时，因为总线频率为24MHz,用时钟SB，可计算得到16进制参数为9870H，舵机中间位置时占空比16进制参数为1680H，要分配给PWM6和7，分配时这2个端口的赋值必须是16进制，那么PWM模块初始化赋值为 PWMPER6= 0x98，PWMPER7= 0x70，PWMDTY6= 0x16，PWMDTY7= 0x80，因此这就牵涉到如何将1个十进制数分配为2个十六进制数问题。有2种方案，一种是除法取余，另一种是移位操作，前者编译生成的代码比后者要多，所以采用移位操作来实现，即取高位时与0xFF00先作“&”计算，然后将所得到的数向右移8位（>>8），即可取得高8位；同理，取低8位时只要与0x00FF作“&”计算即可（算法）。 2、结构和控制 一般来讲，舵机主要由以下几个部分组成，舵盘、减速齿轮组、位置反馈电位计5k、直流电机、控制电路板等。 工作原理：控制电路板接受来自信号线的控制信号（具体信号待会再讲），控制电机转动，电机带动一系列齿轮组，减速后传动至输出舵盘。舵机的输出轴和位置反馈电位计是相连的，舵盘转动的同时，带动位置反馈电位计，电位计将输出一个电压信号到控制电路板，进行反馈，然后控制电路板根据所在位置决定电机的转动方向和速度，从而达到目标停止。
雅马哈12路调音台的使用方法 当最初接触调音台的时候，很容易会被它面板上花花绿绿、数目众多的旋钮和推杆唬住。首先我们来看一下左边的面板。实际上，左边每一路的推杆和旋钮的意义都是一样的。所以你只需要集中精力了解一个通道的操作方法就可以通盘掌握。较少路数的调音台有4路和8路的输入控制，而路数最多的有96路甚至更多的。这个调音台有8路输入控制，我们只取其中一个来讲解各部分的作用。 1.MIC：麦克风输入接口 麦克风输入经由XLR 母座，可接受平衡式或非平衡式低电平讯号，使用专业动圈式、电容式或丝带式低阻抗麦克风，如果使用非平衡式麦克风需要尽量使用愈短愈好的麦克风线，以避免电波噪音的干扰。 2.LINE：高电平输入接口 高电平输入通常经由TRS 1/4" 立体Phone Jack 或TRS 1/4" Mono Phone Jack 送入，麦克风音源以外的讯号都可经由高电平输入至混音机，立体Phone Jack 的输入是平衡式的，相同于XLR 的方式，但是如果一定要用非平衡式器材时，可用Mono Phone Jack ，其接线不能太长（4.5m 以内）。 3.LINE -20DB：衰减20 分贝按键 按下此键可以对输入电平衰减20 分贝。一般在环境噪音较大，设备电平噪音较大或电平过高的时候使用该按键。使用该键将对音频输入信号的所有频率进行衰减，以达到将音量较小的杂音或电噪音过滤掉的目的。有时会出现输入电平信号过高的现象，如不进行衰减，则衰减器的控制范围就会大大降低，只能在一个很小的区域内滑动，造成对音量输出控制很难操作。此时应按下此键，以增大衰减器的有效控制范围。 4.PEAK：峰值指示灯 Peak 灯亮时，警告使用者输入信道内的讯号过强。发现Peak 灯亮时，并且任由这种情况持续的话，调音台会启动自我保护功能，切断音源输出。所以，此时应调整输入音量大小，否则，调音台的音频输出将被自动切断。可使用的控制包括： Line －20 DB、减小Gain、拉低衰减器，一般以减小Gain为宜。 5.GAIN：增益旋钮 它是用来调节输入信号电平大小的。输入的信号以多大的电平来输出是由该旋钮和该输入单元的推子共同决定的。显然，旋钮顺时针方向角度越大、推子越高，输入信号的输出电平的提升就越大，或者说该路输入的音频信号在输出中的响度就越大。增益范围为20 分贝到60 分贝。值得注意的是，增益太高会使声道负荷过载，导致声音失真；太低则背景噪音明显，可能也无法获得足够的讯号电平提供混音输出。使用高电平输入时要将增益转小。增益旋钮是作为声音输入调音台的关口，调整适当，即可保证调音台下一级的处理电路能接收到充分且“干净”的信号。 6.HIGH、MIDDLE、LOW：三段均衡器旋钮 High、Middle、Low 分别可以对高频、中频、低频进行增强或衰减，控制范围为正负15 分贝。中频控制收人声时尤其有用，可以非常准确地修饰演出者的声音。低音：20 Hz ～500 Hz 适当时，低音张弛得宜，声音丰满柔和。不足时声音单薄，过度提升时会使声音发闷，明亮度下降，鼻音增强。中音：500 Hz ～2 KHz 适当时声音透彻明亮。不足时声音朦胧，过度提升时会产生类似电话的声音。高音：2 KHz ～8 KHz 是影响声音层次感的频率。不足时声音的穿透力下降，过强时会掩蔽语言音节的识别，使齿音加重、音色发毛。 7.MONITOR：总监听音量旋钮调节该通路在监听线路中的音量大小。如不使用额外接入调音台的总监听设备，则此旋钮可置于0 处。 8.EFFECT：输出至效果器旋钮调节该旋钮决定该路输出至效果器的电平大小。如不使用外接的效果器，则此旋钮可置于0 处。 9.PANPOT: 声像旋钮 它用来调整该通道信号在左右声道之间的立体声位置。调节范围左声道5 ～右声道5 ，如不需要制作特殊效果，一般置于0 处。 10.PFL：衰减器前监听按键当衰减器前监听按键按下时，监听输出送出的仅为该路信号，使用该键可有效地判别出杂音的来源。当有多路输入的PFL 被按下时，监听输出送出的将是这些通路的混音。 11.FADER：衰减器(音量推子)决定该通道信号发送给总线输出的音量大小。音量推子实际上是一个衰减器，用于对该通道的输出信号进行衰减。当推子位于最下端（或音量旋钮位于最左端）时，信号被无穷衰减。这时，该通道没有信号输出。调节范围－∞～＋6 分贝，一般以推到0 处适宜，超过0 则会使声音产生一定程度的失真。如果一定要提高电平讯号，一般采用适当提高Gain的办法，而不会将衰减器提升超过0 。由于音乐输入为连续，而人声输入为间断，故在操作上有一定区别。在对音乐的输入轨道操作时，一般使用“淡
目录 一.设备安全使用须知 (1) 二.机床简介 (3) 三.主要技术参数和连接尺寸 (4) 四.机床的吊运、安装及试车 (5) 五.主要部件结构性能及调整 (5) 六.液压系统 (6) 七.机床的润滑 (6) 八.机床的冷却－排屑系统 (7) 九.机床的调试与维修 (7) 十.易损件清单 (8) 十一.机床的工作环境 (28) 注： 图一.HTC6330b机床地基图 (9) 图二.机床占地面积图 (10) 图三.机床外观图 (11) 图四.机床吊运图 (12) 图五.HTC6330b数控车床加工尺寸及刀具干涉图 (13) 图六.主轴箱结构图 (14) 图七.X轴滑板 (17) 图八.液压卡盘系统 (18) 图九.Z轴丝杠连接图 (19) 图十.主轴连接尺寸 (20) 图十一.卡盘座尺寸图 (22) 图十二.液压原理图 (24) 图十三.导轨润滑装置 (25) 图十四.主轴润滑 (26) 图十五.冷却装置 (27)
HTC6330b 使用说明书一、设备安全使用须知 对于生产企业来讲，没有什么比安全工作更重要的了。为此，在机床使用说明书正文之前，制定本安全说明。 请尊敬的用户，在读正文之前，认真阅读并能领会，那将是我们的共同的幸福。 1．设备的使用 除非之前已受过培训并授权的人员进行特殊维修工作时，否则不得在设备防护罩松动或被取掉的情况下使用该机床。 该机床是为完成一系列具体操作而设计的。在质量保证期内，未经生产厂家授权，不得对设备进行任何形式的改装或用于其它超出机床使用范围的用途。 该机床是自动循环起动的，不得在机床的任何部位（尤其是机床移动部位）放置工具、工件及其它物品。刀具及其它设置一定要在处于夹紧状态时才可使用。 2．人员培训 机床若由人员不恰当的使用将会是很危险的，所以，在机床的安全使用，调整，操作及维修方面对其人员进行充分培训是完全必要的。 3．人员防护服 为了安全起见，应使用并爱护好您的防护服装及用具。在该机床工作事，切勿穿松垮的衣服，应去掉珠宝首饰并将长发挽到后面，戴安全防护眼镜并穿安全工作鞋。 4．防护罩--包括观察窗 在机床工作期间，所有的防护罩始终都应在位并处于牢固安全状态。防护罩上所带的观察窗应始终保持清洁，该观察窗是用特殊安全材料制成的，不得用其它材料替代。全部防护罩的目的在于最大程度减小加工时液体和铁屑飞溅的危险但并不能完全消除。 5．互锁及保护装置 为了保证您的安全，该机床配备了各种安全互锁及保护装置，切勿以任何方式干扰这类装置。紧急情况时，应立即使用紧急停止按扭。 6．安全用电 电是一种危险的物质并可致人于死命。 机床在进行清洁、检查故障、或停机以及进行任何调整之前一定要将主电源置于关闭（OFF）状态，这不会影响计算机存储器的存储功能，因为里面装有后备电池。 当机床突然断电时需重新送电之前，机床转塔刀架务必要先行返回原点位置。 7．液压系统 机床液压系统是在高，中压状态下工作的，其中有些部件即使是在机床停机的情况下也处于压力状态。所以对液压系统及其部件进行修理时一定要小心谨慎。 皮肤长期与液压油接触有可能会导致皮炎及过敏反应，当必需与其接触时，必须陪带整齐的防护用品。 8. 切削液 切削液里很容易滋生大量的细菌，设备上可能由此生成大量的粘液，机油和淤泥，并带有相关的异味因此要经常更换切削液。清除切削液及油污时应配带安全的防护设备和服装。尽量避免接触污油和切削液。9．润滑油 当不可避免地要接触油品时，则应使用维护很好的人体防护设备，护手霜并穿戴防护服。要严格遵守车间卫生纪律，尽快的将油从皮肤上清洗干净。切勿穿戴经油污浸泡过的衣物，且不要在口袋里装有油的碎纸布或手帕。 10．除油剂的使用 皮肤长期与除油剂接触有可能会导致皮炎。所以应避免与任何除油剂不必要的接触，当不可避免地要接触除油剂时，则应使用维护很好的人体防护设备，护手霜并穿戴防护服。要严格遵守车间卫生纪律，尽快的将油从皮肤上清洗干净。 11．压缩空气 2沈阳第一机床厂
YAMAHA GA32/12、GA24/12调音台 使用手册 为使调音台保持良好的工作状态,应注意以下几点: ○1. 避免调音台过热、潮湿、尘土堆积和振动。 ○2. 避免物体阻挡，在通风孔保持空气流通。 ○3. 避免硬物碰撞，搬运时要小心谨慎。 ○4. 不要打开调音台或尝试修理或更改，维修应由有资格的Yamaha维修人员进行。 ○5. 在连接或拔出电缆线时，关闭调音台电源，这对防止调音台自身以及其它同调音台连接的设备的损坏是非常重要的。 ○6. 插拔电缆线包括AC交流电源线时，请握持插头插拔，不要握持电缆线插拔。○7. 用柔软干燥的织物清洁调音台，决不使用溶剂，例如汽油或稀释剂清洁调音台。 ○8. 使用在调音台后面板上指明的当地的AC交流电压，对调音台正确供电。在系统中使用所有的设备，AC交流电源应有足够的供电电流。 绪言 感谢你选择YAMAHA GA32/12或GA24/12调音台，请详细阅读使用手册，对你使用YAMAHA GA32/12或GA24/12调音台有很大的帮助。 注意: 这本手册假定你已经知道调音台的基本操作及调音台的技术术语。 对GA24/12调音台技术规格如果同GA32/12有不同，在括号{}中描述。 特点:
? GA32/12调音台提供28路单声道｛GA24/12调音台提供20路单声道｝、2组立体声输入模块。输出通道包含立体声ST1 OUT、ST2 OUT输出；10个混音MIX OUT 1–10输出和2个矩阵MATRIX OUT1－2输出。 ? 每个单声道输入通道提供26 dB定值衰减pad开关、高通滤波器HPF、倒相开关、4段均衡EQ(其中，高－中HI－MID和低－中LO－MID频段的中心频率可变)、100 mm长音量控制器(推拉电位器)。还有供每4个输入通道为1组的+48 V幻象电源通断开关。 ? 提供4个立体声辅助返回AUX RETURN1L/1R－4L/4R和立体声磁带输入TAPE IN L/R输 入口。 ? 主控部分位于调音台中间区域，便于操作。 ? 主控部分为混音母线MIX buses1－10提供输出通道，具有均衡EQ和100 mm长音量控制器(推拉电位器)。. ? 每个输入通道和4个立体声辅助返回通道均包含1个PFL监听开关。立体声母线、混音母线1－10和矩阵1－2输出通道有1个AFL监听开关，能使你方便快速地监听输入/输出信号。? 用GA(GROUP/AUX)编组/辅助功能，能使你各自地设置到混音母线MIX1－4上的信号为可调(Variable)模式或固定(Fix)模式。 在可调(Variable)模式中，从输入通道输出的信号到混音母线MIX VARIABLE 1－4上的电平可调，这个信号路程通常作辅助(AUX)母线。 在固定(Fix)模式中，从输入通道输出的信号到混音母线MIX FIX 1－4上的电平不可调即此时从输入通道输出的信号到混音母线MIX FIX 1－4上的电平固定不变，这个信号路程通常作编组(GROUP)母线。 由此可见，用这种方式配置混音母线MIX1－4为编组或辅助功能，作特殊的用途。 ? 调音台有2个独立的矩阵输出。可各自地混合混音母线MIX1－4和立体声母线ST L/R上的信号，在你希望的电平从矩阵输出MATRIX OUT1－2插座(1/4″茄克插座)上输出混合后的信号。这个混音信号路程可为返送监听系统或为单独的音箱(如中间放置的音箱)及功放。? 所有单声道输入通道、立体声母线ST L/R输出通道、混音母线MIX1－4输出通道均配有插入INSERT I/O插座(1/4″茄克插座)，如果需要，可插入外部的音频周边设备，对信号进行处理。 ? 对讲信号可输送到任意的混音母线MIX1－4、混音母线MIX5－10和立体声母线ST L/R。? 控制室监听通道输出C－R MONITOR OUT可选择监听PFL/AFL或磁带输入TAPE IN处信号。 1 YAMAHA GA32/12、GA24/12调音台输入通道部分
#i n c l u d e"r e g52.h" unsigned char count; //0.5ms次数标识 sbit pwm =P2^7 ; //PWM信号输出 sbit jia =P2^4; //角度增加按键检测IO口 sbit jan =P2^5; //角度减少按键检测IO口 unsigned char jd=5; //角度标识 void delay(unsigned char i)//延时 { unsigned char j,k; for(j=i;j>0;j--) for(k=125;k>0;k--); } void Time0_Init() //定时器初始化 { TMOD = 0x01; //定时器0工作在方式1 IE = 0x82; TH0 = 0xfe; TL0 = 0x33; //11.0592MZ晶振，0.5ms TR0=1; //定时器开始 } void Time0_Int() interrupt 1 //中断程序 {
TH0 = 0xfe; //重新赋值 TL0 = 0x33; if(count< jd) //判断0.5ms次数是否小于角度标识 pwm=1; //确实小于，PWM输出高电平 else pwm=0; //大于则输出低电平 count=(count+1); //0.5ms次数加1 count=count%40; //次数始终保持为40 即保持周期为20ms } void keyscan() //按键扫描 { if(jia==0) //角度增加按键是否按下 { delay(10); //按下延时，消抖 if(jia==0) //确实按下 { jd++; //角度标识加1 count=0; //按键按下则20ms周期从新开始 if(jd==6) jd=5; //已经是180度，则保持 while(jia==0); //等待按键放开 }
目录1. 1. 概述 1-1.系统名称 1-2.生产线工作内容 1-3.生产能力 1-4.必备条件 1-5.机器油漆颜色 1-6.设计标准 2. 2. WD615/WD415发动机装配线组成 2-1. 系统简介 2-2. 结构说明 3.3. 装配线工作过程简述及主要注意事项 3-1. 工作过程简述 3-2. 主要注意事项 4. 4. 安装 4-1. 装配线安装 4-2. 升降机安装 4-3. 180°（90°）翻转机的安装 4-4. 缸盖装配线的安装 5. 5. 维护 5-1. 传送线辊子维护 5-2. 线体维护 5-3. 气动系统维护 5-4. 润滑期 5-5. 润滑油 6. 6. 排故与检修 7.7. 电气控制系统 8.8. 图纸资料
1. 概述 1-1. 系统名称: WD615/WD415发动机装配线 1-2. 生产线完成内容: 欧III机型、欧II机型、直列四缸柴油机装配线，完成发动机上各零部件的装配，包装前的准备工作。 1-3. 生产能力 -生产量(生产目标) : 6万台/年(2班制) -每年工作日: 250 日 -日工作时间 : 16小时 -生产效率：85％ -节拍：≤3分钟 1-4. 必备条件 1) 压缩空气 在端点处空气供应为5 Kg/cm2 2)提供电源 AC220V;50Hz 1-5.设备油漆颜色 1)机用: RAL 9002 1-6. 设计标准 1) GB (中国标准) 2) KS (韩国工业标准) 3) JIS (日本工业标准) 4) ISO (国际标准化组织) 2. 装配线组成 装配线线长270m，为柔性直线环行输送，单层滚道及地下输送线。单层滚道为装配作业输送滚道，托盘用上线吊车在起始工位上线，单层线设有92个装配工位，单层线起始端和末端人工通过自行小车上下料，中间由两个180°翻转机、两个90°翻转机半自动翻转，实现
在机器人机电控制系统中，舵机控制效果是性能的重要影响因素。舵机可以在微机电系统和航模中作为基本的输出执行机构，其简单的控制和输出使得单片机系统非常容易与之接口。 舵机是一种位置伺服的驱动器，适用于那些需要角度不断变化并可以保持的控制系统。其工作原理是：控制信号由接收机的通道进入信号调制芯片，
获得直流偏置电压。它内部有一个基准电路，产生周期为20ms，宽度为1.5ms的基准信号，将获得的直流偏置电压与电位器的电压比较，获得电压差输出。最后，电压差的正负输出到电机驱动芯片决定电机的正反转。当电机转速一定时，通过级联减速齿轮带动电位器旋转，使得电压差为0，电机停止转动。舵机的控制信号是PWM信号，利用占
空比的变化改变舵机的位置。一般舵机的控制要求如图1所示。 图1 舵机的控制要求 单片机实现舵机转角控制可以使用FPGA、模拟电路、单片机来产生舵机的控制信号，但FPGA成本高且电路复杂。对于脉宽调制信号的脉宽变换，常用的一种方法是采用调制信号获取有源滤波后的直流电压，但是需要50Hz(周期是20ms)的信号，这对运放 器件的选择有较高要求，从电路体积和功耗考虑也不易采用。5mV 以上的控制电压的变化就会引起舵机的抖动，对于机载的测控系统而言，电源和其他器件的信号噪声都远大于5mV，所以滤波
电路的精度难以达到舵机的控制精度要求。 也可以用单片机作为舵机的控制单元，使PWM信号的脉冲宽度实现微秒级的变化，从而提高舵机的转角精度。单片机完成控制算法，再将计算结果转化为PWM信号输出到舵机，由于单片机系统是一个数字系统，其控制信号的变化完全依靠硬件计数，所以受外界干扰较小，整个系统工作可靠。 单片机系统实现对舵机输出转角的控制，必须首先完成两个任务：首先是产生基本的PWM周期信号，本设计是产生20ms的周期信号；其次是脉宽的调整，即单片机模拟PWM信号的输出，并且调整占空比。当系统中只需要实现一个舵机的控制，采用的控制方式是改变单片机的一个定时器中断的初值，将20ms分为两次中断执行，一次短定时中断和一次长定时中断。这样既节省了硬件电路，也减少了软件开销，控制系统工作效率和控制精度都很高。 具体的设计过程： 例如想让舵机转向左极限的角度，它的正脉冲为2ms，则负脉冲为 20ms-2ms=18ms，所以开始时在控制口发送高电平，然后设置定时器在
废水处理设备 系统操作说明书 苏州万科环境工程有限公司 2014年2月（第一版） 操作和维护该系统时，必须遵守该手册中的操作程序。本手册仅针对本系统，如对其它水处理系统按照本手册操作引起损失，本公司恕不负责。 目录 1 人身安全注意事项.............................................................................................. 1.1电气................................................................................................................ 1.2机械................................................................................................................ 1.3开停机............................................................................................................ 1.4通道............................................................................................................... 1.5安全用具....................................................................................................... 1.6安全检查表................................................................................................... 2 废水处理工艺...................................................................................................... 3处理设备构筑物的运行与控制参数................................................................... 3.1地坑................................................................................................................ 3.2调节池............................................................................................................ 3.3气动隔膜泵.................................................................................................... 3.4管道混合器.................................................................................................... 3.5沉淀池............................................................................................................ 3.6回用水池........................................................................................................ 3.7除油过滤器.................................................................................................... 4加药系统............................................................................................................... 4.1加碱系统....................................................................................................... 4.2混凝剂加药系统........................................................................................... 4.3絮凝剂加药系统........................................................................................... 5. 压滤机系统........................................................................................................ 6. 触摸屏操作说明................................................................................................
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机械停车设备 使用说明书PSH类二层升降横移式
目录 一、前言 二、设备型号表示方法及基本参数 三、主要结构组成及特点 四、设备的安全装置及安全措施 五、设备的运行及操作说明 六、一般故障分析查找及排除 七、用户操作须知 八、系统维护与保养
一、前言 随着我国国民经济的高速发展，小型客车及家庭轿车的发展已进入了快速增长期。大、中城市停车场地不足的问题日益突出，特别是都市繁华地带、写字楼、宾馆、大厦、商场、住宅小区、旅游景点等都已出现车满为患的局面。为适应市场经济的快速发展，满足广大用户对停车库的急需，我公司技术开发出PSH型多层升降横移式机械式立体停车设备，并已形成系列化的停车设备产品体系。立体停车设备可以充分利用空间，在占用相同土地面积的情况下提供尽可能多的停车位置，对于改善城市繁华地段的停车状况具有重大意义。 本说明书适合于本公司生产的通用型二层升降横移式停车设备，主要介绍设备的操作方法及使用过程中的维护保养。请用户在使用前仔细阅读本说明书，并按本说明书的要求正确使用。为保证本停车设备能长期、可靠地为您服务，提高设备的使用效率，请用户在使用过程中按照本说明书定期对设备进行维护保养。 我公司从事机械式立体停车设备已有多年的历史，本产品精心设计，精心制造，质量可靠。我公司承诺二年保修，终身服务。在使用过程中如发现设备的不足之处或您对设备有特殊的要求，欢迎来人、来函与我公司联系。
二、设备型号表示方法及基本参数 1、表示方法： P S H-10D-QY 公司名称开头字母简称 设备能停放的客车数量及车尺寸代号 机械式停车设备类别代号 机械式停车设备总代号 2、基本参数 组别代号 汽车长×车宽×车高 （mm ×mm ×mm ） 重量 （kg ） D ≤5000×1850×1550 ≤ 2019 注：表中参数为标准系列，实际参数以定货合同为准。 3使用环境条件：可安装于室内，地下室和地上面等场所。 3.1正常使用环境条件 环境温度：+55℃ -5℃ 非使用最低温度：-15℃ 环境湿度：35%～98%（无凝露），日平均湿度≤90% 抗地震等级：地震烈度不超过8级 周围空气应不受腐蚀性或者可燃性气体、水蒸气等明显污染。 无严重污秽及经常性的剧烈振动。严酷条件下严酷设计满足Ⅰ类要求。 3.2特殊工作条件：在超过GB3906规定的正常环境条件下使用时，由用户和制造商协商解决。
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MIXING CONSOLE 用户手册 C
Lea detenidamente antes de conectar la lámpara a la toma bilateral LAMP . (página 18) ?No utilice una lámpara que ponga a tierra la patilla 2 o la patilla 3 en la carcasa. El uso de un tipo de lámpara inco-rrecto puede provocar averías en la mesa de mezclas. Lámparas recomendadas: lámparas ?exo Littlite, serie X-HI.?No conecte accidentalmente un micrófono bilateral a la toma LAMP . Un micrófono se puede averiar si se conecta a esta toma. Lámparas admitidas: 12 V (CA o CC), máx. 5 W. Suministra 12 V a las patillas 2 y 3. La patilla 1 no está conectada. ? ? Aviso importante – Conectar una l ámpara – Tipo de lámpara incorrecto Tipo de lámpara correcto S J ? 2004 Yamaha Corporation WE16440
忆飞工作室 https://www.doczj.com/doc/f22565081.html, 忆飞电子淘宝店欢迎进入 设计者：曾传辉 时间2012年8月13号 手机：134******** QQ：36439133 旺旺：epiapl_cn 程序名称：按键控制舵机控制 程序效果：单片机两个按键控制左右转，转角90度单片 #include #define Sevro_moto_pwm P1_0 //接舵机信号端输入PWM信号调节速度 #define k1 P2_5 //按键控制舵机左转 #define k2 P2_6 //按键控制舵机右转 unsigned char pwm_val_left = 0;//变量定义 unsigned char push_val_left;// =14;//舵机归中，产生约，1.5MS 信号 unsigned int timer=0; //延时基准变量 unsigned char timer1=0; //扫描时间变量 void pwm_Servomoto(void); //函数申明 unsigned int val,val2,fl1,fl2; //变量申明 /************************************************************************/ void delay(unsigned int k) //延时函数 { unsigned int x,y; for(x=0;x 课程设计项目说明书 舵机控制型机器人设计 学院机械工程学院 专业班级2013级机械创新班 姓名吴泽群王志波谢嘉恒袁土良指导教师王苗苗 提交日期 2016年4 月1日 华南理工大学广州学院 任务书 兹发给2013级机械创新班学生吴泽群王志波谢嘉恒袁土良 《产品设计项目》课程任务书，内容如下： 1. 题目：舵机控制型机器人设计 2.应完成的项目： 1.设计舵机机器人并实现运动 2.撰写机器人说明书 3.参考资料以及说明： [1] 孙桓.机械原理[M].北京.第六版;高等教育出版社，2001 [2] 张铁，李琳，李杞仪.创新思维与设计[M].国防工业出版社，2005 [3] 周蔼如.林伟健.C++程序设计基础[M].电子工业出版社.北京.2012.7 [4] 唐增宏.常建娥.机械设计课程设计[M].华中科技大学出版社.武汉.2006.4 [5] 李琳.李杞仪.机械原理[M].中国轻工业出版社.北京.2009.8 [6] 何庭蕙.黄小清.陆丽芳.工程力学[M].华南理工大学.广州.2007.1 4.本任务书于2016 年2 月27 日发出，应于2016 年4月2 日前完 成，然后提交给指导教师进行评定。 指导教师（导师组）签发2016年月日 评语： 总评成绩： 指导教师签字： 年月日 目录 摘要 (1) 第一章绪论 (2) 1.1机器人的定义及应用范围 (2) 1.2舵机对机器人的驱动控制 (2) 第二章舵机模块 (3) 2.1舵机 (3) 2.2舵机组成 (3) 2.3舵机工作原理 (4) 第三章总体方案设计与分析 (6) 3.1 机器人达到的目标动作 (6) 3.2 设计原则 (6) 3.3 智能机器人的体系结构 (6) 3.4 控制系统硬件设计 (6) 3.4.1中央控制模块 (7) 3.4.2舵机驱动模块 (7) 3.5机器人腿部整体结构 (8) 第四章程序设计 (9) 4.1程序流程图 (9) 4.2主要中断程序 (9) 4.3主程序 (11) 参考文献 (13) 附录 (14) 一．程序 (14) 二．硬件图 (17)舵机控制型机器人设计要点
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