REVIEWUpdate on myasthenia gravis B R Thanvi, T C N Lo ............................................................................................................................... Postgrad Med J2004;80:690–700. doi: 10.1136/pgmj.2004.018903 Myasthenia gravis is an autoimmune disorder caused byautoantibodies against the nicotinic acetylcholine receptoron the postsynaptic membrane at the neuromuscularjunction and characterised by weakness and fatigability ofthe voluntary muscles. It has a bimodal peak of incidence with first peak in the third decade and the second peak in the sixth decade. It is probably underdiagnosed in the veryold populat ion. Our understandin g of the pathogenes is, immunology, and molecular biology of myasthenia gravis has greatly improved in last three decades. It is almostalways possible to establish the diagnosis of myasthenia gravis with the current tests. The modern treatment is highlysuccessful and the mortality of treated myasthenia gravis is practically zero. However, there are still important gaps in our knowledge of the origin of myasthenia gravis, the factors that contribute to chronic disease, and the way to cure the disease. In this article the current knowledge of the various aspects of myasthenia gravis are outlined. ........................................................................... See end of article forauthors’ affiliations ....................... Correspondenc e to: Dr Bhom Raj Thanvi, Department of Integrated Medicine, Leicester Royal Infirmary, UniversityHospitals of Leicester NHS Trust, Infirmary Square, Leicester LE1 5WW, UK; [email protected]Submitted 7 January 2004 Accepted 26 April 2004 ....................... M yasthenia gravis is a potentially serious but treatable organ specific autoimmune disor der charac teris ed by weaknes s and fat igabil ity of the volunt ary mus cle s that is caused by autoantibod ies against the nicot inic acetylcholine receptor (AChR) on the postsynap- tic membrane at the neuromuscular junction. 1 2 Thomas Willis (1672) was probably the first to describe patients with weakness of limb muscles incr eas ing duri ng the course of the day and progressive tongue weakness provoked by ‘‘long, hasty or labor ious speaking’’. 3 It was more than two centurie s later when another patient with bulbar and limb muscle weakness who died ofrespiratory failure was reported. 4 The lesion was initially thought to be in the medulla oblongata but necropsy did not show any abnormality in the medulla. Subsequently, several case reports descri bing patients with the early or predomi- nant bulbar weakness , and those with the weak- ness worse ning dur ing the course of the day appe ared in the lit erature. Jol ly (18 95) des- cribed a progressive decline in the tetanic tension of the indirectl y sti mul ated mus cles wit h the repeat ed stimu latio ns that improved with rest. He gave the disease its name: myasthenia gravis pseudoparalytica. 5 The earlier reports suggeste d a ‘‘toxi n proba bly of micro bial origin’’ 6 or ‘‘some toxi c, pr obably autotoxi c, agent ’’ 7 causing damage of the lower motor neurons to produce myastheni c weak ness. The demonstra tio n by Da le and Fel dber g of ac e tylc ho li ne as a neuro transmitter at the moto r endplat e paved way for the future developments in pathogenesis, diagnosis, and the treatment of myastheni a gravis. 8 Harvey and Mars land descri bed the decremental response of the evoked muscles to repeat ed stimuli in myasthenia gravi s. 9 Simpson propo sed a new theory that myasthenia gravis was an autoimmune disorder based on its association with the other autoimmune diseases, the thymi c abnor malit ies noted in myasthenia gravis , and the fluctu ati ng cou rse of the dis - ease. 10 That the damage in myasthenia gravis is at the postsy naptic level was demonstrated by Engel and Santa in ultrastructural studies of the motor endplate. 11 Neost igmine , an orall y admi- nis ter ed ant icholi nesteras e, was fir st used in myasthenia gravis in 1935. 12 Subsequently, corti- costeroids 13 and other immunosuppressants 14 were found to be useful in treatment and Blalo ck repor ted benefi cial effects of thyme ct- omy. 15 Lindst orm and his team demonstra ted circulating antibodies directed against the AChRprot ei n in up to 87% of cases of myastheni a gravis. 16 Recently, antibodies that bind to MuSK, a muscle spec if ic prot ei n ki nase, hav e been desc ri bed in a subgroup of pati e nt s wi th myasthenia gravis who do not have antibodi es against AChRs. 17 Mus cul ar weak ness and fat igabil ity are the hallma rks of myasthenia gravis. They are caused by an anti body-media ted aut oimmune att ack directed against AChRs at neuromuscular junc- tio ns. Ther e are several mec hani sms by whi ch the autoantibodies reduce the number of avail- abl e AChRs at neuromusc ular junctions. The mol ecular str uct ure of nic oti nic AChR is now well characterised and the receptor has been pur ifi ed fro m a var iet y of sources, inc lud ing human musc le. An exp erimental model ofmyasthenia gravis has been produced by immu- ni sati on of anima ls wi th A Ch Rs . This has greatly helped our understanding of the disease mechanisms. The re hav e been si gni fi cant adv ances in the di agnosis and treatment ofmyasthenia gravis. It used to be a very disabling and oft en fat al (and, hence, the name gra vis ) disease in the pas t. However, modern immu- notherapy has dramatically improved the prog- nosis and nearly all patients are now able to lead full, productive lives. Despite these advances, there are still impor- tant gaps in our knowledge. We do not kno w the fact o rs that init iate and maintain the autoi mmune response in myasthenia gravis. AAbbreviations: AChR, acetylcholine receptor; EPP, endplate potential; MRI, magnetic resonance imaging; MuSK, muscle specific protein kinase 69 0 www.postg radmedj.com
