Involvement of Ocular Muscles in Patients With Myasthenia Gravis With Nonocular Onset

Background: Myasthenia gravis (MG) is an autoimmune disorder involving neuromuscular junctions and more than half of MG patients manifested with extraocular muscle weakness initially. In the remained patients, ocular weakness may occur later in the course of the disease. However, little data are available about ocular involvement in such patients. Therefore, the study aims to investigate ocular weakness in MG patients with nonocular onset and evaluate the associated factors influencing it. Methods: In our monocentric retrospective study, 54 adult-onset patients with MG with nonocular onset were included and were followed up for at least 2 years from the onset. The primary outcome was the occurrence of ptosis, diplopia, or both. Kaplan-Meier analysis was performed to estimate the time to the ocular weakness, and log-rank tests were used to analyze the association between clinical characteristics and ocular weakness. Multivariate Cox proportional hazards regression models were used to identify factors associated with ocular involvement. Results: A total of 47 (87.0%) patients developed ocular weakness during the study period. The median time to ocular weakness was 6.0 months. Time to the ocular involvement was earlier in patients with bulbar onset (P = 0.007), whereas patients receiving pyridostigmine monotherapy and immunomodulatory therapy had a longer median time of ocular weakness (P < 0.0001). No significant difference was noted between ocular weakness and age of onset, gender, and thymoma. The Cox analysis showed that bulbar onset was a risk factor of ocular weakness (adjusted hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.41-4.99), whereas pyridostigmine monotherapy (adjusted HR 0.28, 95% CI 0.13-0.60) and immunotherapy (adjusted HR 0.09, 95% CI 0.04-0.22) were protective factors. Conclusions: Eighty-seven percent of patients with MG with nonocular onset developed ocular weakness. Bulbar onset was an independent risk factor for ocular involvement, whereas pyridostigmine and immunotherapy were protective factors.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Involvement of Ocular Muscles in Patients With Myasthenia Gravis With Nonocular Onset Lin Lei, MM, Zhirong Fan, MM, Shengyao Su, MM, Min Xu, MD, Hai Chen, MD, Wenjia Zhu, MD, Qinrong Luan, BS, Yuwei Da, MD Background: Myasthenia gravis (MG) is an autoimmune disorder involving neuromuscular junctions and more than half of MG patients manifested with extraocular muscle weakness initially. In the remained patients, ocular weakness may occur later in the course of the disease. However, little data are available about ocular involvement in such patients. Therefore, the study aims to investigate ocular weakness in MG patients with nonocular onset and evaluate the associated factors influencing it. Methods: In our monocentric retrospective study, 54 adultonset patients with MG with nonocular onset were included and were followed up for at least 2 years from the onset. The primary outcome was the occurrence of ptosis, diplopia, or both. Kaplan–Meier analysis was performed to estimate the time to the ocular weakness, and log-rank tests were used to analyze the association between clinical characteristics and ocular weakness. Multivariate Cox proportional hazards regression models were used to identify factors associated with ocular involvement. Results: A total of 47 (87.0%) patients developed ocular weakness during the study period. The median time to ocular weakness was 6.0 months. Time to the ocular involvement was earlier in patients with bulbar onset (P = 0.007), whereas patients receiving pyridostigmine monotherapy and immunomodulatory therapy had a longer median time of ocular weakness (P , 0.0001). No significant difference was noted between ocular weakness and age of onset, gender, and thymoma. The Cox analysis showed that bulbar onset was a risk factor of ocular weakness (adjusted hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.41–4.99), whereas pyridostigmine monotherapy (adjusted HR 0.28, 95% CI 0.13–0.60) and immunotherapy (adjusted HR 0.09, 95% CI 0.04–0.22) were protective factors. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China. Supported by the National Key R&D Program of China, Precision Medicine Program (No. 2017YFC0907700), Beijing Municipal Health Commission Fund (No. PXM2020_026283_000005), Capital Health Development Research Project (No. 2018-4-2015), and National Natural Science Foundation of China (No. 82001352). The authors report no conflicts of interest. Address correspondence to Yuwei Da, MD, Department of Neurology, Xuanwu Hospital, Capital, Medical University, Changchun Street, Beijing 100053, China; E-mail: [e-mail] e260 Conclusions: Eighty-seven percent of patients with MG with nonocular onset developed ocular weakness. Bulbar onset was an independent risk factor for ocular involvement, whereas pyridostigmine and immunotherapy were protective factors. Journal of Neuro-Ophthalmology 2022;42:e260–e266 doi: 10.1097/WNO.0000000000001325 © 2021 by North American Neuro-Ophthalmology Society BACKGROUND M yasthenia gravis (MG) is an autoimmune disorder mediated by autoantibodies targeting the postsynaptic membrane, leading to muscle weakness and fatigue (1). The disease may affect all skeletal muscles, but a striking preference exists for extraocular muscles (EOMs), resulting in ptosis, diplopia, or both. Ocular weakness is a cardinal feature of MG. It not only provides a key clue for the diagnosis of MG but also is an important component of a variety of MG scales for clinical management and research, including MG Activities of Daily Living, MG Composite, and Quantitative MG (2–4). Moreover, there may be a different response to therapy in ocular weakness as compared with other symptoms. Barnett found that prednisone was more effective for ocular symptoms than generalized weakness, whereas intravenous immunoglobulin (IVIg) and plasma exchange were on the contrary (5). Thus, it is of great value to investigate ocular weakness in MG both for clinical management and research. It is reported that approximately 50%–85% of patients have ptosis or double vision as initial symptoms (6–8). In the remaining patients with MG, weakness of EOMs may be secondary to other symptoms including bulbar, limb, neck, or respiratory weakness. However, little data are available about the occurrence of ocular weakness in such patients. Therefore, our study is to retrospectively investigate the involvement of Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution ocular muscles and factors influencing ocular weakness in patients with MG with nonocular onset. METHODS Data Source The retrospective cohort study was based on data from a single-center MG registry (MGR) in Xuanwu hospital established as a part of a nationwide MGR (NCT04101578), founded in 2017. It is a neurologistdriven registry that collects retrospective and prospective data from patients with MG. The information includes demographic, clinical, immunological, therapeutic, and follow-up data. Follow-up data were collected by telephone or face to face and updated at least every 3 months in the first year and every 6 months thereafter. The study has been approved by the Institutional Ethics Committee of Xuanwu Hospital, Capital Medical University, and all patients enrolled have signed informed consent forms. Patients In the retrospective study, we selected all patients with MG with nonocular onset who were enrolled in the MGR from February 8, 2017, to July 1, 2020, and had a disease duration of at least 2 years from onset to the end of followup (November 1, 2020). Nonocular onset was defined by the initial muscle weakness elsewhere than the EOMs within the first month of onset, which may include bulbar weakness (facial weakness, dysphagia, slurred speech, and difficulty chewing) and limb, neck, and respiratory weakness. The MG diagnosis was confirmed according to characteristic signs and symptoms and at least one of the following: (1) seropositivity for antiacetylcholine receptor antibody (AChR-Ab) or antimuscle-specific kinase antibody (MuSK-Ab), (2) positive repetitive nerve stimulation (RNS) tests, and (3) unequivocal response to neostigmine. The exclusion criteria were patients who (1) had an age of onset younger than 18 years, (2) had incomplete medical records, and (3) were unable to provide information about previous treatments before ocular involvement. Data Acquisition The primary outcome was the first occurrence of ocular weakness. Time to ocular weakness was defined by the time frame from onset to the occurrence of ocular signs at the end of follow-up or loss of follow-up. Ocular signs included ptosis, diplopia, or both, which were based on complaints (ptosis and double vision) and then confirmed by experienced neurologists or ophthalmologists. Besides, we included data on demographics (gender and age at onset), initial symptoms, thymoma, AChR-Ab status, results of RNS and neostigmine tests, and received treatments before the occurrence of ocular weakness, including thymectomy and medication (e.g., pyridostigmine, IVIg, corticosteroids, Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 and other immunosuppressive agents). Late-onset MG was defined by symptom onset after age 50 ($50). All thymoma was identified by thymus histopathology. Statistical Analysis Data analyses were performed using SPSS Statistics version 20.0 (IBM Corp, Armonk, NY) and GraphPad Prism version 5.0 (GraphPad Software Inc, San Diego, CA). Categorical variables were reported as counts and proportions and continuous variables as means ± SD or medians (interquartile ranges [IQRs]). The Mann–Whitney U test was used to evaluate the difference in age of onset, and differences of categorical variables between groups were evaluated by the Pearson x 2 test and continuity correction x2 test when necessary. The Kaplan–Meier (K–M) analysis was used to estimate the cumulative probability of occurrence of ocular weakness. A log-rank test was used for the comparison of time to ocular weakness with clinical characteristics, including gender, age of onset, initial muscle weakness, thymoma, AChR-Ab status, and treatments. Factors with a P value less than 0.1 from log-rank tests were included in multivariate Cox proportional hazard regression analyses to evaluate the association of these factors with the occurrence of ocular weakness. A P value of less than 0.05 was considered significant. RESULTS There were 480 patients with a disease course of at least 2 years in the MGR by the end of follow-up. Three patients with motor neuron disease, benign essential blepharospasm, and thyroid-associated ophthalmopathy were misdiagnosed with MG. Twenty-four patients had incomplete medical records or were lost to follow-up. Thirty-four patients with an age of onset ,18 years were not included. Therefore, a total of 419 patients with MG were included and 365 of them initially manifested ocular weakness (Fig. 1). Demographic and Clinical Features of Patients With MG With Nonocular Onset A total of 54 (12.9%) patients with MG had nonocular onset who had a median disease duration of 39.5 months (IQRs 32.0–56.0) from the onset to the end of follow-up. Table 1 summarized demographic and clinical data of 54 patients with MG with nonocular onset. Thirty-two (59.3%) patients were women, and the ratio of women to men was 1.5:1. The median age at onset was 47 years (IQRs 32.8–64.3) ranging from 21 to 84 years, and 25 (46.3%) patients were late-onset MG. On initial symptoms, 28 patients had limb onset, 25 had bulbar onset, and one presented neck flexion weakness. All patients with MG were tested for AChR-Ab and MuSK-Ab, and 47 of them (87.0%) had AChR-Ab. Only one (1.9%) patient was seropositive for Musk-Ab. Twenty-seven patients were available for the neostigmine test and 85.2% of them had a positive e261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Flowchart shows patients included in the study. MG, myasthenia gravis. response. Thirty-three (84.6%) of 39 patients presented abnormal RNS results. Fifteen patients underwent thymectomy, and the results of postoperative pathology revealed that thymoma was noted in 14 cases (25.9%). Before the occurrence of ocular involvement, 21 (38.9%) patients were misdiagnosed with other diseases including cerebrovascular disease, pharyngitis, cervical, or lumbar strain at local hospitals and were not given targeted treatments of MG. Among the 21 patients, the ratio of women to men was 1.3:1. The age of onset ranged from 21 to 81 years with a median age of 54 years. Twelve of them had bulbar weakness as the first symptom and 9 presented limb fatigue or weakness. The remaining 33 were diagnosed with MG, and all of them received treatments of MG. Thymectomies were performed in 3 patients, pyridostigmine was administrated in 29 patients, and immunomodulatory agents including corticosteroids, tacrolimus, methotrexate, and IVIg were administrated in 19 cases. According to whether or which treatment of MG was given, 54 patients were divided into 3 subgroups: treatment-naive, pyridostigmine monotherapy, and immunotherapy (Table 1). Given that the benefit of thymectomy is often delayed for several years (9–11), which may not influence the occurrence of ocular involvement in such a short time frame, we did not consider thymectomy. The subgroup of immunotherapy consisted of 14 cases with combined immunomodulatory agents with pyridostigmine and 4 cases with immunomodulatory agents. Ocular Involvement in Patients With MG With Nonocular Onset During the study period, a total of 47 (87.0%) patients presented ocular weakness with the course of disease ranging from 1.3 to 144 months while the remaining 7 patients did not develop ocular weakness who had a disease duration of 32 months–82.7 months. The frequency of immunomodulatory e262 therapy was significantly lower in the ocular group than in the nonocular group (P = 0.006). No significant differences were noted in gender, age of onset, initial symptoms, thymoma, and AChR-Ab status between the 2 groups (Table 2). Of the 47 patients with ocular involvement, 37 (78.8%) cases occurred within the first year, 4 (8.5%; cumulative, 87.2%) during the second year, and 4 (8.5%; cumulative, 95.7%) during the third year. Both ptosis and diplopia were noted in 17 patients, ptosis was observed in 20 patients, and diplopia in 10 patients. All of them were relieved by pyridostigmine or immunomodulatory agents. Among the 7 patients with MG without ocular phenotype, the mean age of onset was 42.0 ± 14.3 years and 5 were early-onset MG. Five patients were women, and 6 cases manifested with limb muscle fatigue. Five patients were seropositive for AChR-Ab and one had thymoma. All 7 patients received therapy for MG, and 6 of them were treated with corticosteroids or immunosuppressive drugs. Probability of Ocular Involvement in Patients With Nonocular Onset K–M curves were plotted to obtain cumulative probabilities for the occurrence of ocular signs from the onset. The median time of ocular weakness in 54 patients was 6.0 months (Fig. 2A). Bulbar onset was associated with a shorter median time of ocular weakness (Fig. 2B), whereas patients who received treatments including pyridostigmine and immunotherapy had a longer median time (Fig. 2C). No significant difference was noted between ocular weakness and age of onset (P = 0.09), gender (P = 0.94), and thymoma (P = 0.28). Risk Factors for Time to Occurrence of Ocular Weakness Clinical variables including the age of onset, symptoms at onset, and received treatments were selected for the Cox analysis (table 3). The model revealed bulbar onset was associated with a higher frequency of ocular weakness (adjusted hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.41–4.99). Receiving pyridostigmine monotherapy and immunotherapy were associated with a lower rate of ocular weakness. The adjusted HRs were 0.28 (95% CI 0.13–0.60) and 0.09 (95% CI 0.04–0.22) for pyridostigmine monotherapy and immunotherapy, respectively. DISCUSSION In the study, approximately 87.0% of patients with MG with nonocular onset developed ocular weakness, mainly in the first 2 years of onset. Bulbar onset was a risk factor for ocular weakness, whereas pyridostigmine monotherapy and immunotherapy could delay the time of ocular involvement. To the best of our knowledge, this is the first investigation of factors affecting the involvement of ocular muscles in patients with MG with nonocular onset. Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic and clinical features of 54 patients with MG with nonocular onset Characteristics Sex, female, n (%) Age at onset, years, median (IQRs) Late-onset MG ($50 years), n (%) Initial symptom, n (%) Limb onset Bulbar onset Neck onset AChR-Ab status, n (%) Positivity Negativity Thymoma, n (%) Treatment*, n (%) Treatment-naive Pyridostigmine monotherapy Immunotherapy† Total 32 (59.3) 47.0 (32.8–64.3) 25 (46.3) 28 (51.9) 25 (46.3) 1 (1.8) 47 (87.0) 7 (13.0) 14 (25.9) 21 (38.9) 15 (27.8) 18 (33.3) *Before the occurrence of ocular weakness. † Received immunomodulatory agents with or without pyridostigmine. AChR-Ab, antiacetylcholine receptor antibody; IQRs, interquartile ranges; MG, myasthenia gravis. In our single-center MG cohort study, nearly 12.9% (54/ 419) of patients manifested with nonocular weakness within the first month of disease, mostly limb weakness, followed by bulbar involvement, which was slightly lower than that in previous studies (6–8). Among these patients with nonocular onset, 87.0% (47/54) developed ocular weakness during the subsequent course of the disease. The high susceptibility of EOMs to MG may be related to several characteristics of EOMs. First, a minor loss of EOM force generation will produce more dramatic symptoms than limb muscles (12). Second, EOMs have fewer synaptic folds, fewer amount AChRs, and wider endplates compared with limb muscle, perhaps producing a lower safety factor for neuromuscular transmission (13). Third, genes associated with the immune response are expressed differently in EOMs, in particular complement-mediated immune response pathways (14). Besides, EOMs express the embryonic form of AChR, different from AChR in skeletal muscle (15), but there is no evidence for specific immunologic targeting of AChR in MG. Among 47 patients with ocular involvement, 87.2% (41/47) of patients manifested with ocular weakness in the first 2 years of onset. Previous studies on the conversion of ocular MG (OMG) to GMG have shown that it was within 2 years that most patients with OMG converted to GMG (7,16– 18). These findings suggest that there may be a robust abnormal immune response in the first 2 years of both GMG and OMG. Patients with MG with bulbar onset were predisposed to develop ocular weakness as compared with nonbulbar onset. The neuromuscular junction (NMJ) is a cellular synapse between motor neurons and muscle fibers, responsible for transmitting nerve impulses from motor neurons to muscle fibers and subjecting the muscle contraction. Studies have demonstrated that the formation and function of NMJ are regulated by motor neurons. On the one hand, the postsynaptic differentiation of NMJ requires motor neurons, which release agrin protein and thereby disperse ectopic postsynaptic apparatus (19,20). On the other hand, the “safety factor” of neuromuscular transmission is affected by the size of the motor nerve terminal. In addition, muscle fiber phenotypes are governed by motor neuron discharge properties to some extent (21). Both EOMs and bulbar muscles are muscles innervated by the cranial motor neurons, whereas limb muscles are controlled by spinal motor neurons. A study has revealed that stem cell–derived cranial neurons have a higher level of proteasome activity than spinal motor neurons, hinting that intrinsic characteristics vary between cranial and spinal motor neurons (22). Therefore, it is likely that a more similarity of NMJ and muscle fiber phenotypes may exist in between ocular and bulbar TABLE 2. Clinical characteristics of patients with MG with and without ocular weakness Clinical Characteristics Ocular Weakness (n = 47) Sex, female, n (%) Age at onset, years, mean (SD) Late-onset MG ($50 years), n (%) Symptoms at onset, n (%) Bulbar onset Nonbulbar onset Positive AChR-Ab, n (%) Thymoma, n (%) Treatment-naive, n (%) Pyridostigmine monotherapy, n (%) Immunotherapy*, n (%) No Ocular Weakness (n = 7) P value 27 (57.4) 50 (17.7) 23 (48.9) 5 (71.4) 42 (14.3) 2 (28.6) 0.772 0.310 0.547 0.157 24 23 42 13 21 14 12 1 6 5 1 0 1 6 (51.1) (48.9) (89.4) (27.7) (44.7) (29.8) (25.5) (14.3) (85.7) (71.4) (14.3) (9.1) (90.9) 0.475 0.772 0.065 0.688 0.006† *Received immunomodulatory agents with or without pyridostigmine. † P , 0.05. AChR-Ab, antiacetylcholine receptor antibody; MG, myasthenia gravis. Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 e263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A, Kaplan-Meier curve of ocular weakness in MG patients with nonocular onset; B and C, Kaplan-Meier curves of ocular weakness by symptoms at onset and received treatments. MG, myasthenia gravis. muscles than in between ocular and limb muscles, which in turn results in a higher frequency of ocular weakness in bulbar onset MG than in nonbulbar onset MG. The administration of pyridostigmine delayed the time to occurrence of ocular signs, which was similar to a recent study that revealed that pyridostigmine was associated with lower rates of conversion to GMG (23). Apinyawasisuk et al pointed out that the protective effect from conversion to GMG may be related to its cholinergic anti-inflammatory effects (23). As a widely used acetylcholinesterase inhibitor in MG (24,25), pyridostigmine may increase serum acetylcholine to promote the activation of circulating macrophages expressing a7 nicotinic acetylcholine receptor, e264 thereby suppressing the production of inflammatory cytokines including tumor necrosis factor a, high-mobility group box of proteins, and interleukin 6 (23,26). Therefore, we speculated that the protective effect of pyridostigmine on ocular weakness may be also associated with its immunomodulatory effects. Besides, it has been believed that pyridostigmine can relieve ocular symptoms, especially ptosis (25); thus, we cannot rule out the probability that ocular weakness was not delayed but relieved by pyridostigmine. Compared with patients with MG with pyridostigmine monotherapy, patients with immunomodulatory therapy presented significantly delayed occurrence of ocular weakness. Previous studies have shown that immunotherapy can not only relieve clinical symptoms of MG but also reduce the conversion rate of OMG to GMG (23,24,27–31). Thus, we speculate that immunotherapy may play a key role in the preventive effect of ocular weakness. Further studies on immunotherapy influencing ocular symptoms are needed. Seven patients with MG did not develop ocular weakness during their disease, accounting for only 1.7% (7/419) of the total population. These 7 patients were mainly women, and the average age was 42.0 years, which was similar to de Meel et al’s report (32). Ten of the 15 patients were women, and the mean age was 43.6 years. However, the rate of patients with MG without ocular involvement in our cohort was much lower than 7.0% (15/225) in the latter study (32). There may be several factors contributing to the discrepancy: First, the follow-up time for nonocular phenotype varied. Our patients with MG were required to be followed up for at least 2 years, whereas follow-up of 15 patients was less than 2 years in de Meel et al’s study. Second, the frequency of patients receiving treatments of MG at baseline in our study was lower than that in de Meel et al’s report. Third, environmental or genetic factors may play a role. Studies have revealed that it is environmental and genetic traits that not only may influence the frequency of MG but also may affect the clinical phenotype (33,34). The frequency of OMG has been reported to be higher in Chinese populations than in Caucasians (35). There were several limitations to the study. First, this was a retrospective study and there was a recall bias because patients were asked to report their initial symptoms from an early stage of the disease. Second, early recognition of ocular weakness was based on complaints in our study, which were subjective. The tolerability for EOM weakness may vary in patients, perhaps affecting the recognition of ocular weakness. Besides, ocular weakness caused by ophthalmological diseases may not be completely excluded, for that not all patients with MG with ocular weakness underwent comprehensive ophthalmic examinations. However, all included ocular weakness responded to pyridostigmine or immunomodulatory agents. Thus, we consider it reasonable that ocular signs were related to MG. Third, this was a singlecenter study in a tertiary referral center that may not fully reflect the total MG population and there may be a referral Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Hazard ratios of occurrence of ocular weakness in 54 patients with myasthenia gravis with nonocular onset Characteristic Crude HR (95% CI) Late onset Bulbar onset Pyridostigmine monotherapy Immunotherapy 1.63 2.17 0.30 0.11 (0.90–2.94) (1.20–3.95) (0.14–0.62) (0.05–0.25) Adjusted HR (95% CI) 1.15 2.65 0.28 0.09 (0.63–2.11) (1.41–4.99) (0.13–0.60) (0.04–0.22) CI, confidence interval; HR, Hazard ratios. bias in the study. Finally, the sample size was small because of the low rate of nonocular onset. Thus, prospective multicenter studies are needed to prove the result further. In conclusion, the current study showed that about 87.0% of patients with MG with nonocular onset developed ocular weakness during the disease course. Bulbar onset was a risk factor for ocular symptoms, whereas pyridostigmine and immunomodulatory agents were protective factors for the occurrence of ocular involvement. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: L. Lei and Y. Da; b. Acquisition of data: Z. Fan, S. Su, M. Xu, H. Chen, W. Zhu, Q. Luan, and Y. Da; c. Analysis and interpretation of data: L. Lei. Category 2: a. Drafting the manuscript: L. Lei; b. Revising it for intellectual content: Z. Fan, S. Su, and Y. Da. Category 3: a. Final approval of the completed manuscript: L. Lei, Z. Fan, S. Su, M. Xu, H. Chen, W. Zhu, Q. Luan, and Y. Da. 10. 11. 12. 13. 14. 15. 16. REFERENCES 1. Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers. 2019;5:30. 2. Muppidi S. The myasthenia gravis—specific activities of daily living profile. Ann N Y Acad Sci. 2012;1274:114–119. 3. Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998;841:769–772. 4. Burns TM, Conaway M, Sanders DB. The MG composite: a valid and reliable outcome measure for myasthenia gravis. Neurology. 2010;74:1434–1440. 5. Barnett C, Bril V, Kapral M, Kulkarni AV, Davis AM. Myasthenia gravis impairment index: responsiveness, meaningful change, and relative efficiency. Neurology. 2017;89:2357–2364. 6. Grob D, Arsura EL, Brunner NG, Namba T. The course of myasthenia gravis and therapies affecting outcome. Ann N Y Acad Sci. 1987;505:472–499. 7. Bever CT Jr, Aquino AV, Penn AS, Lovelace RE, Rowland LP. Prognosis of ocular myasthenia. Ann Neurol. 1983;14:516– 519. 8. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37:141–149. 9. Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, Ströbel P, Mazia C, Oger J, Cea JG, Heckmann JM, Evoli A, Nix W, Ciafaloni E, Antonini G, Witoonpanich R, King JO, Beydoun SR, Chalk CH, Barboi AC, Amato AA, Shaibani AI, Katirji B, Lecky BR, Buckley C, Vincent A, Dias-Tosta E, Yoshikawa H, Waddington-Cruz M, Pulley MT, Rivner MH, Kostera-Pruszczyk A, Pascuzzi RM, Jackson CE, Garcia Ramos GS, Verschuuren JJ, Massey JM, Kissel JT, Werneck LC, Benatar M, Barohn RJ, Tandan R, Mozaffar T, Conwit R, Odenkirchen J, Sonett JR, Jaretzki A, Newsom-Davis J, Cutter GR. Randomized trial of Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 17. 18. 19. 20. 21. 22. 23. 24. thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511–522. Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:7–15. Taioli E, Paschal PK, Liu B, Kaufman AJ, Flores RM. Comparison of conservative treatment and thymectomy on myasthenia gravis outcome. Ann Thorac Surg. 2016;102:1805–1813. Kaminski HJ, Li Z, Richmonds C, Ruff RL, Kusner L. Susceptibility of ocular tissues to autoimmune diseases. Ann N Y Acad Sci. 2003;998:362–374. Liu R, Xu H, Wang G, Li J, Gou L, Zhang L, Miao J, Li Z. Extraocular muscle characteristics related to myasthenia gravis susceptibility. PLoS One. 2013;8:e55611. Soltys J, Gong B, Kaminski HJ, Zhou Y, Kusner LL. Extraocular muscle susceptibility to myasthenia gravis: unique immunological environment? Ann N Y Acad Sci. 2008;1132:220–224. Kaminski HJ, Kusner LL, Block CH. Expression of acetylcholine receptor isoforms at extraocular muscle endplates. Invest Ophthalmol Vis Sci. 1996;37:345–351. Kupersmith MJ, Latkany R, Homel P. Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol. 2003;60:243–248. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018;36:253–260. Feng X, Huan X, Yan C, Song J, Lu J, Zhou L, Wu H, Qiao K, Lu J, Xi J, Luo S, Zhao C. Adult ocular myasthenia gravis conversion: a single-center retrospective analysis in China. Eur Neurol. 2020;83:182–188. Tintignac LA, Brenner HR, Rüegg MA. Mechanisms regulating neuromuscular junction development and function and causes of muscle wasting. Physiol Rev. 2015;95:809–852. Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature. 2001;410:1057–1064. Porter JD, Baker RS. Muscles of a different ’color’: the unusual properties of the extraocular muscles may predispose or protect them in neurogenic and myogenic disease. Neurology. 1996;46:30–37. An D, Fujiki R, Iannitelli DE, Smerdon JW, Maity S, Rose MF, Gelber A, Wanaselja EK, Yagudayeva I, Lee JY, Vogel C, Wichterle H, Engle EC, Mazzoni EO. Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons. Elife. 2019;8:8. Apinyawasisuk S, Chongpison Y, Thitisaksakul C, Jariyakosol S. Factors affecting generalization of ocular myasthenia gravis in patients with positive acetylcholine receptor antibody. Am J Ophthalmol. 2020;209:10–17. Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, Melms A, Murai H, Nicolle M, Palace J, Richman DP, Verschuuren J, Narayanaswami P. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87:419–425. e265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 25. Kerty E, Elsais A, Argov Z, Evoli A, Gilhus NE. EFNS/ENS guidelines for the treatment of ocular myasthenia. Eur J Neurol. 2014;21:687–693. 26. Pohanka M. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity. Int J Mol Sci. 2014;15:9809–9825. 27. Hong YH, Kwon SB, Kim BJ, Kim BJ, Kim SH, Kim JK, Park KS, Park KJ, Sung JJ, Sohn EH, Lee YB, Jeong D, Joo IS, Choi BO, Choi YC. Prognosis of ocular myasthenia in Korea: a retrospective multicenter analysis of 202 patients. J Neurol Sci. 2008;273:10–14. 28. Sussman J, Farrugia ME, Maddison P, Hill M, Leite MI, HiltonJones D. Myasthenia gravis: Association of British Neurologists’ management guidelines. Pract Neurol. 2015;15:199–206. 29. Kupersmith MJ. Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol. 2009;256:1314–1320. 30. Mee J, Paine M, Byrne E, King J, Reardon K, O’Day J. Immunotherapy of ocular myasthenia gravis reduces e266 31. 32. 33. 34. 35. conversion to generalized myasthenia gravis. J Neuroophthalmol. 2003;23:251–255. Monsul NT, Patwa HS, Knorr AM, Lesser RL, Goldstein JM. The effect of prednisone on the progression from ocular to generalized myasthenia gravis. J Neurol Sci. 2004;217:131– 133. de Meel RHP, Tannemaat MR, Verschuuren JJGM. Heterogeneity and shifts in distribution of muscle weakness in myasthenia gravis. Neuromuscul Disord. 2019;29:664–670. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol. 2010;10:46. Chiu HC, Vincent A, Newsom-Davis J, Hsieh KH, Hung T. Myasthenia gravis: population differences in disease expression and acetylcholine receptor antibody titers between Chinese and Caucasians. Neurology. 1987;37:1854–1857. Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W, Vincent A. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry. 2006;78:386– 390. Lei et al: J Neuro-Ophthalmol 2022; 42: e260-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.