Correlation Between Clinical Severity And Neuroelectrophysiological Characteristics In Myasthenia Gravis And Treating Experimental Autoimmune Myasthenia Gravis Using Rapamycin

Part oneCorrelation Between Clinical Severity andNeuroelectrophysiological Characteristics in Myasthenia GravisObjectiveAcquired myasthenia gravis（MG）is an antibody-mediated autoimmune disorderthat primarily involves the neuromuscular junction. Electrophysiological testing isessential for diagnosing MG, and the most commonly used electrophysiologicaltechnique is repetitive nerve stimulation（RNS）. Most studies only use RNS as adiagnostic tool. However, few studies have further explored the clinical significance ofthe decreased degrees of compound muscle action potential（CMAP）. Needle electrodeelectromyography（NEMG）tests are important for the differential diagnosis of MG. AndNEMG may show myopathic changes in some MG patients. But few researchesanalyzed and explained the clinical significance of this phenomenon. In this study, thecorrelation between disease severity and the degree of decreased CMAP in RNS testwas investigated. Also, the clinical characteristics between patients with differentNEMG test results were analyzed. We want to further explore the clinical significanceof electrophysiological tests results for MG.Materials and MethodsThis retrospective study examined77inpatients, diagnosed with MG at theDepartment of Neurology of Chinese PLA General Hospital between January2012andMay2013. Basic information was recorded in detail. The enrolled patients were classified according to the myasthenia gravis foundation of America（MGFA） clinicalclassification. Quantified myasthenia gravis scoring system（QMG） test and MGactivities of daily living（MG-ADL） profile was performed on all patients. Theseindexes were used to estimate disease severity. Low-frequency RNS testing wereperformed on facial, accessory, ulnar, and axillary nerves. And all patients underwentconventional NEMG testing. The correlations between the degree of CMAP in RNS testand disease severity were statistically analyzed. Besides,the differences of clinicalcharacteristics between patients with normal and myopathic changes in NEMG testwere analysed.ResultsAll the enrolled77patients were diagnosed as MG definitely, and all of themdemonstrated abnormal RNS results. The QMG and MG-ADL scores correlated wellwith the magnitude of the decremental response to RNS for multiple nerves. Whenstimulating facial nerve and recording on oculi muscles, correlation analysis showedstatistical results of CMAP amplitude decrement between QMG score and MG-ADLsocre were r=0.506, P <0.001and r=0.445, P <0.001respectively. When simulatingaccessory nerve and recording on trapezius muscles, the results were r=0.426, P=0.019and r=0.399, P=0.029respectively. When stimulating axillary nerve andrecording on deltoid muscles, the results were r=0.507, P <0.001and r=0.371, P=0.008respectively. When stimulating ulnar nerve and recording on abductor digitiminimi muscles, the results were r=0.340, P=0.018and r=0.364, P=0.011respectively. The results indicated that the relationship was apparent when recording onproximal muscles.NEMG demonstrated that22patients（28.6%） showed myopathic changes, andnone had abnormal spontaneous potentials. The NEMG results of these patientspresented shorter durations and lower amplitude MUPs. The data show that patientswith myopathic changes in NEMG test had higher QMG and MG-ADL score（sP<0.01）.Most patients with myopathic NEMG results were type Ⅲ and ⅣMGFA clinicalclassification, while patients with normal NEMG results were mainly type I and II. And MGFA classification differences between the two groups were statistically significant（P<0.01）. However, the differences were not statistically significant in gender, ages atonset, course of disease or thymus types（P>0.05）.ConclusionsOur study showed that the magnitude of the decrease in the CMAP amplitude inRNS correlates with MG severity, and that this relationship is more pronounced inproximal muscles than in distal muscles. The degree of decrement in CMAP amplitudemight reflect MG clinical severity. Patients with myopathic changes in the NEMG testalso tended to have more severe symptoms. Myopathic changes in NEMG might notcorrelated with age, gender, course of disease or thymus types. There was a correlationbetween the electrophysiological characteristics of MG and disease severity. Thus,electrophysiological tests are diagnostic tools for MG that might also reveal diseaseseverity.Part twoTreating Experimental AutoimmuneMyasthenia Gravis Using RapamycinObjectiveRapamycin（RAPA） is a new type macrolides immunosuppressant. RAPAproduce biological effect by binding to the target of rapamycin. MG is an autoimmunedisease and immunosuppressant has been widely used for the treatment of MG.However, we have not found systemic researches about treating MG with RAPA. In thisstudy, we attempted to treat experimental autoimmune myasthenia gravis（EAMG）animal models with RAPA for the first time. Also we tried to explored the possiblemechanisms preliminarily.Materials and MethodsEAMG animal models were established by immunizing97-116sequence of rat（R97-116）acetylcholine receptor（AChR）α-subunit in Lewis rats. Clinical symptoms of animal models were evaluated, the antibody level was tested and electrophysiologicaltest were performed to make sure that the animal models were established successfully.RAPA and cyclophosphamide（CTX）were used as pharmacological interventions forEAMG, and the treatment outcome were observed and recorded. Quantity of peripheralblood Treg cells and Th17cells were detected by flow cytometry technique.ResultsLewis rats exhibit weight loss and weakness gradually after immunized byR97-116. Antibody detection was positive and low-frequency RNS test was alsopositive. All evidence proved that the EAMG animal model were establishedsuccessfully, and the successful rate was74.28%. Clinical symptoms and focalinflammation were improved after intervention by both RAPR and CTX. But themortality rate of CTX group was higher than that of RAPA group. Also, rats in RAPAgroup gained more weight than CTX group. Comparing with EAMG group, Treg cellstatio increased and Th17cells decreased in RAPA group. But both Treg and Th17cellsdecreased in CTX group. There was no significant difference in quantity of CD4+Tlymphocytes in RAPA group and normal control group, but CD4+T lymphocytesdecreased significantly in CTX group. And the difference was statistically significant（P<0.01）.ConclusionsRAPA can treat EAMG animal models with anti-AChR antibodies effectively.Mortality rate and weight changes indicated that RAPA therapeutic effect was betterthan CTX. CD4+T lymphocytes were not suppressed obviously after intervented byRAPA. Comparing with case control the Treg cells increased while Th17cellsdecreased after treating with RAPA. Reversing the imbalance status of Treg/Th17mightbe the possible mechanism of effective treatment of RAPA for EAMG.