Acquired autoimmune myasthenia gravis - Heterogenous entity

Acquired autoimmune myasthenia gravis (MG) is an organ specific autoimmune disorder of the neuromuscular junction. In the majority of the patients (~85%) antibodies are directed to muscle postsynaptic nicotinic acetylcholine receptor (AChR), but in others the target is non-AChRprotein at neuromuscular junction, such as Muscle-specific receptor tyrosine kinase (MuSK), or low density lipoprotein receptor related protein 4 (LRP4).This autoantibodies can be detected by specific assays and implicate different therapeutic strategies and prognosis of the disease. The basic pathophysiological finding in MG is muscle endplate dysfunction with fluctuating fatigue and weakness of skeletal muscles. The clinical presentation of MG is heterogenous, from pure ocular form on the one side, to severe bulbar or respiratory weakness on the other side. The onset of the disease may be in childhood period (under 2 years of age), juvenile period (2-16 years of age), young adult period (between 16 and 50 years of age) and late adult period (after the age of 50 years). Also, the disease is heterogenous in the aspect of thymus pathology. In 60-70% of patients there is thymus hyperplasia, in 10-15% thymic tumor (thymoma), while in the remaining 20% persistent or atrophic thymic tissue. Correspondence/Reprint request: Dr. Lavrnić D., Clinic for Neurology, Clinical Center of Serbia, Belgrade E-mail: [email protected] Lavrnić D. et al. 218 Good knowledge about heterogenity of MG is of outstanding importance, not only because of the better understanding of the disease pathogenesis and differences in interpretation of the conducted diagnostic procedures (for example, prostigmine test in patients with MuSK MG can induce worsening of the symptoms), but also because of the different therapeutic approach to the patients with different forms of MG (for example, in MuSK positive patients, patients with ocular form of MG and in late onset patients with generalyzed form of the disease thymectomy is not recommended). In that way, knowledge about all subentities of the disease contributes to the improved diagnosing and the disease outcome, which is noted in the last ten years and this trend still continues. Myasthenia gravis comprises numerous, heterogenous disorders of the neuromuscular junction, which are in the majority of cases clearly defined and caused by autoimmune processes or genetic mutations. Among these disorders, the most frequent is aquired autoimmune myasthenia gravis (MG) which is caused by the disruption of the postsynaptic muscle membrane by different autoantibodies. The first clinical description of this disease was published by Thomas Willis in 1672 in the journal “De anima brutorum” (1), and its autoimmune origin was assumed by Simpson (in 1960.) on the basis of clinical similarities between MG and systemic lupus erythematodes (2). The major clarifying of the MG pathogenesis is the results of the experiments performed by Patric and Lindrstrom, who registered signs of myasthenic weakness in the experimental rabits imunized by nicotinic acetylcholine receptor (AChR) of Torpedo californica, and detected the presence of anti-acetylcholine receptor antibodies in their sera (anti-AChR Ab) (3). In the later period, lot of studies proved the pathogenetic role of anti-AChR Ab in the structural and functional disruption of the neuromuscular junction (4, 5) and this form of MG is the most frequent clinical presentation. MG is relatively rare disorder with the incidence of 3 to 30 per million and the prevalence of 15 to 200 per million inhabitants (6-8). Disease onset is in most of the patients between 20 and 30 years, predominantly in females in this age group and between 60 and 80 years with the similar incidence in both genders. Alltogether, among patients with MG there is clear female preponderance (6-9). Nevertheless, it is well known that MG presents heterogenous entity in many different aspects. It is neccessary to get informed about all disease variants because of the different diagnostic algorythm, treatment and prognosis. Heterogenity of MG in the clinical presentation MG is clinically characterized by the fluctuating weakness of the striated muscles, which worsens after prolonged or repetitive muscle activation, Acquired autoimmune myasthenia gravis Heterogenous entity 219 while it improves after the rest or treatment with anticholinesterase drug. In over 50% of patients with MG, initial symptom is the weakness of the extraocular muscles (9, 10), and in 5-25% of patients ocular symptoms remain the only clinical presentation. This form of MG is so called ocular form and in the clinical terms it represents the distinct entity (9, 10). In most of the patients (70-80%) symptoms of MG generalize during the course of the disease, with the development of the weakness and fatiguability of other sceletal muscles, which usually happens during the first two years after the disease onset (9-11). It is believed nowdays that this percentage is much lower, because early and adequate immunosupressive therapy decreases the risk of symptom generalization up to 75% (12). Frequent finding in MG patients is bulbar muscle weakness, present in more severe forms of the disease, although in 15-26% of patients this clinical presentation can be initial symptom of MG (9-11). Weakness can affect any other sceletal muscle in the body, for example different extremity muscles, more frequently proximal than distal, respiratory muscles, neck, and rarely auditory muscles or volontary sphincters of the bladder and bowel. Weakness of oropharyngeal and respiratory muscles is present in the most severe forms of the disease (myasthenic crysis) and it often requires assisted ventilation (10). Finally, in relation to the clinical presentation, it is important to mention also focal form of MG, which is characterized by the affection of only one muscle (for example rectus lateralis, obliqus inferior or other muscles) or localized muscle group (for example fingers extensors, with the „dropped fingers” phenomenon, or external urethral sphincter with the urine incontinence (13). Knowledge about this form of the disease is of great importance in the neurological practice because prolonged isolated weakness of only one muscle or the muscle group rarely associates the doctor with the diagnosis of MG, and more frequently to the presence of some other disease, for example the mononeuropathy associated with diabetes. Regarding different clinical presentations of the disease, which direct the further diagnosis and treatment, Osserman and Genkins classification from 1971. has been previously used (14). However, during every day neurological practice, this classification of MG showed significant imperfections in the classification of all MG patients, which is why Myasthenia gravis Foundation of America (MGFA) suggested new clinical classification of the disease (15). This classification enables more precise clinical definition of each patient and is presented in Table 1. Lavrnić D. et al. 220 Table 1. Myasthenia Gravis Foundation of America (MGFA) classification of the MG severity. Form of MG Clinical manifestations of the disease I Exclusively ocular symptoms IIA Mild weakness of the predominantly trunk and/or extremity muscles IIB Mild weakness of the predominantly bulbar and/or respiratory muscles IIIA Moderate weakness of the predominantly trunk and/or extremity muscles IIIB Moderate weakness of the predominantly bulbar and/or respiratory muscles IVA Severe weakness of the predominantly trunk and/or extremity muscles IVB Severe weakness of the predominantly bulbar and/or respiratory muscles V Need for intubation According to this classification, all patients with MG can be classified into 5 different groups: 1) class I – presence of isolated affection of extraocular muscles; 2) class II – presence of mild generalized weakness, with or without affection of extraocular muscles; 3) class III – presence of moderate generalized weakness, with or without affection of extraocular muscles; 4) class IV – presence of severe generalized weakness, with or without affection of extraocular muscles; 5) class V – the most severe form of MG, with the presence of severe generalized weakness, with the affection of the vital muscle groups, oropharyngeal and respiratory muscles, and the need of nasogastric tube feeding and intubation with or without assisted ventilation. Classes II, III and IV have 2 subclasses: subclass (a) presents predominant affection of trunk and extremity muscles, with the possibility of mild oropharyngeal muscle weakness, while subclass (b) presents predominant affection of oropharyngeal and/or respiratory muscles with the possibility of mild affection of trunk and extremity muscles. Knowledge of this classification is necessary because of the different treatment procedures in the patients with different forms of MG, and also Acquired autoimmune myasthenia gravis Heterogenous entity 221 because it helps in analyzing the effects of the applied therapy during the follow up period. For example, in patients with purely ocular form of MG thymectomy should not be performed, but the treatment consists of anticholinesterase therapy alone or in combination with immunosuppressive drugs, in young patients with IIIb or IVa forms of the disease thymectomy is always recommended in combination with the dual immunosuppressive therapy with corticosteroids and azathioprin or cyclosporin A, while in patients with IVb or V forms of the disease treatment with plasma exchange or intravenous immunoglobulines is often necessary, usually as the preparation for the thymectomy or acceleration of the effects of the applied immunosuppressive therapy. Heterogeneity of MG regarding age at the disease onset In relation to the time at the symptom onset, MG can be classified as juvenile MG, early onset and late onset MG.