Factors Affecting Generalization of Ocular Myasthenia Gravis in Patients With Positive Acetylcholine Receptor Antibody


To evaluate the associated factors of conversion of ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) among patients with seropositive acetylcholine receptor antibody (AchR Ab).


Retrospective cohort study.


Setting : Retrospective chart review. Patient : Seventy-one OMG patients with seropositive AchR Ab presented during July 2009 and December 2016. The exclusion criteria were patients who (1) first presented with GMG, (2) were unable to identify the time of onset of OMG or GMG, (3) were unable to provide information about previous treatments before the onset of GMG, and (4) had incomplete or lost medical records. Observation procedure : We collected demographic and clinical characteristics, including onset of OMG and GMG, presence of other autoimmune disorders, history of smoking, presence of thymic abnormalities, and medications received. Main outcome measures : Conversion to GMG and time to conversion.


Thirty-six patients experienced conversion to GMG. Overall incidence of GMG was 14 (95% confidence interval [CI] 10.09-19.4) per 100 patient-years. Probability of conversion at 2 years was .37 (95% CI .27-.49). Overall median conversion time was 4.97 years. Cox proportional hazard model showed that risk factors were female sex (HR 2.52, 95% CI 1.04-6.10), history of smoking (HR 3.42, 95% CI 1.40-8.45), and thymic abnormalities (HR 1.82, 95% CI 0.91-3.67). Protective factors against conversion to GMG were receiving immunosuppressive agents (HR 0.42, 95% CI 0.19-0.97) and pyridostigmine (HR 0.37, 95% CI 0.14-0.93).


OMG patients with seropositive AchR Ab should be informed that taking pyridostigmine and/or immunosuppressive agents as well as smoking cessation might prevent conversion to GMG.

Ocular myasthenia gravis (OMG) is an autoimmune disorder characterized by fatigable weakness of extraocular muscles, levator palpebrae, and orbicularis oculi, resulting in fatigable ptosis and binocular diplopia. Approximately 30% to 80% of patients with OMG experience a conversion to generalized myasthenia gravis (GMG) within 2 years. These patients not only have ptosis and diplopia but also limb weakness, bulbar symptoms, or even respiratory failure.

Previous studies reported that risk factors of conversion included being female, having older age of onset of OMG, seropositivity to acetylcholine receptor antibody (AchR Ab), , higher levels of seropositivity to AchR Ab, presence of autoimmune disorders, thymic hyperplasia, thymoma, and single ocular symptom (having either isolated ptosis or diplopia). Protective factors included longer duration of remaining OMG. However, previous studies included patients using diagnostic tests with low accuracy for OMG, resulting in possible contamination of the studied population by patients with a false positive test.

There has been a study reporting that prevalence of current smoking was higher in myasthenia patients compared with the general population. Moreover, current and former cigarette smoking was associated with both ocular and generalized symptoms severity. To our knowledge, no studies investigate whether smoking is associated with an increased risk of conversion to GMG.

The purpose of this study is to evaluate the risk and protective factors of having a conversion to GMG, determine time to conversion, and assess factors influencing the time to conversion in patients with AchR Ab–seropositive OMG. We hypothesized that patient’s characteristics and health-related behavior, OMG initial clinical presentation, and medications received might affect the conversion.


This is a retrospective cohort study of patients with OMG who had positive AchR Ab. We extracted the list of patients from the database of Neuroscience Laboratory, Thai Red Cross Emerging Infectious Disease Health Science Center, King Chulalongkorn Memorial Hospital. We retrospectively reviewed the charts of all patients who were aged 18 years or older and had positive AchR Ab test during July 2009 and December 2016. The exclusion criteria were patients who (1) first presented with GMG, (2) were unable to identify the time of onset of OMG or GMG, (3) were unable to provide the information about previous treatments before the onset of GMG, and (4) had incomplete or lost medical records. The study protocol was approved by the Faculty of Medicine, Chulalongkorn University’s institutional review board (certificate of approval number 936/2017). The informed consent process was waived for this study.

We reviewed a diagnosis of OMG, which was made by experienced neuro-ophthalmologists or neurologists at our institute based on the presence of fluctuating ptosis and/or diplopia and positive AchR Ab test. The AchR Ab serology test was performed using enzyme-linked immunosorbent assay.

Demographic and clinical characteristics were obtained from medical records. Demographic data included sex and date of birth. Clinical characteristics were onset and status of ocular symptoms (including ptosis and/or diplopia), presence of other autoimmune disorders, history of smoking, medication received prior to conversion to GMG (eg, pyridostigmine, systemic corticosteroids, and other immunosuppressive agents), date of first treatment (with pyridostigmine and/or immunosuppressive agents), presence of thymic abnormalities (ie, thymic hyperplasia or thymoma), diagnosis of GMG, and date of onset of GMG.

GMG diagnosis was determined by experienced neurologists based on the signs and symptoms of generalization (ie, swallowing difficulty, altered speaking, chewing problem, limited facial expression, proximal muscle weakness, fatigue, respiratory failure).

Statistical Analysis

Descriptive statistics, including mean and standard deviation (SD) and percentages, were conducted to describe demographic and clinical characteristics. Median and interquartile range (IQR) were used to report the duration of follow-up. Student t test and χ 2 statistics were used for continuous and categorical variables, respectively.

Univariate and multivariable logistic regression models were applied to assess the factors associated with a conversion to GMG. Factors with P value <.2 from univariate analysis were included for multivariate logistic regression.

Kaplan-Meier curves and log-rank tests were conducted to assess time from OMG diagnosis to conversion to GMG, and compare time to conversion between clinical characteristics, such as history of smoking and having autoimmune disease, respectively. The Cox proportional hazard model evaluated the association of the risk factors and time to GMG conversion. Subjects lost to follow-up were considered to be censored.

Risk factors, which were evaluated for both the logistic regression and Cox proportional hazard models, were sex, history of smoking, status of autoimmune disease, use of pyridostigmine or immunosuppressive agents (eg, systemic corticosteroids or other immunosuppressive agents) prior to GMG conversion, and status of thymic abnormality.


A total of 184 patients had positive AchR Ab test result during the study period. We excluded 56 patients who first presented with GMG, 18 patients with unknown time of onset of OMG and/or GMG, and 5 patients whose data about previous treatments could not be identified or who had incomplete medical records ( Figure 1 ). Among the remaining 105 patients, 71 patients had complete data of all risk factors and were included in analyses. Among the analysis set (N=71), 35 OMG patients remained without change toward the end of the study (Remained OMG group) and 36 patients experienced conversion to GMG (GMG group). The median duration of follow-up was 4.91 years (IQR 2.98, 6) in the Remained OMG group and 0.78 years (IQR 0.18, 2.47) in the GMG group. Three patients in the Remained OMG group were lost to follow-up.

Figure 1

Study flow chart. AchR Ab = acetylcholine receptor antibody; GMG = generalized myasthenia gravis; OMG = ocular myasthenia gravis.

Table 1 summarizes demographic data and characteristics for eligible participants (N=105) and participants with complete data who were included in analyses (N=71). There were 18 (51.4%) female patients in the Remained OMG group and 25 (69.4%) female patients in the GMG group. Mean age of onset of OMG of the whole group was 52.4 years (SD=16 years), whereas the mean ages of OMG onset for the Remained OMG group and the GMG group were 54.4 years (SD=17.9 years) and 50.5 years (SD=13.8 years), respectively.

Table 1

Characteristic of Patients With and Without Conversion to Generalized Myasthenia Gravis

Characteristic Total (N=105) Complete Cases a (N=71)
Remained OMG (n=47) GMG (n=58) Remained OMG (n=35) GMG (n=36)
Age at onset of OMG, mean (SD) 54.4 (17.6) 50.3 (14.3) 54.4 (17.9) 50.5 (13.8)
Duration of follow-up in years, median (IQR) NA 4.91 (2.98, 6) 0.78 (0.18, 2.47)
Female 28 (59.6) 42 (72.4) 18 (51.4) 25 (69.4)
Male 19 (40.4) 16 (27.6) 17 (48.6) 11 (30.6)
History of smoking 6 (14.6) 13 (33.3) 5 (14.3) 11 (30.6)
Presence of ptosis 45 (95.7) 57 (98.3) 33 (94.3) 36 (50.7)
Presence of diplopia 29 (61.7) 44 (75.9) 24 (68.6) 28 (77.8)
Positive RNS 14 (46.7) 23 (69.7) 11 (47.8) 17 (73.9)
Received pyridostigmine 44 (93.6) 43 (74.1) 33 (94.3) 26 (72.2) b
Received immunosuppressive agents c 27 (57.5) 22 (37.9) 23 (65.7) 13 (36.1) b
Presence of thymic abnormalities 6 (15.8) 23 (42.6) 5 (14.3) 14 (38.9) b
Presence of other autoimmune disorders 13 (27.7) 12 (55.2) 11 (31.4) 6 (16.7)

GMG = generalized myasthenia gravis; IQR = interquartile range; NA = not available; OMG = ocular myasthenia gravis; RNS = repetitive nerve stimulation test; SD = standard deviation.

Unless otherwise noted, values are n (%).

a Number of patients who had complete information of all factors of interest.

b P < .05.

c Including systemic corticosteroid.

Associations Between Demographic and Clinical Factors and GMG

Table 2 shows the odds of conversion to GMG for each risk factor. Females (odds ratio [OR] 2.15, 95% CI 0.81-5.67), history of smoking (OR 2.64, 95% CI 0.81-8.62), and presence of thymic abnormality (OR 3.82, 95% CI 1.20-12.18) were associated with a conversion to GMG. Receiving immunosuppressive agents and pyridostigmine prior to conversion to GMG had a lower rate of conversion. Crude OR for receiving immunosuppressive agents was 0.29 (95% CI 0.11-0.78) and 0.16 (95% CI 0.032-0.78) for pyridostigmine. Age of OMG onset and presence of other autoimmune disorders were not significantly associated with rate of conversion to GMG.

Table 2

Risk and Protective Factors for Conversion to Generalized Myasthenia Gravis (N = 71)

Characteristic Crude Odds Ratio (95% CI) Adjusted a Odds Ratio (95% CI)
Female 2.15 (0.81, 5.67) 4.02 (0.62, 18.72) b
Diplopia (having diplopia) 1.60 (0.55, 4.64)
Age of onset of ocular myasthenia 0.98 (0.96, 1.01)
Smoking status 2.64 (0.81, 8.62) 6.13 (1.13, 33.23) c
Thymic abnormality 3.82 (1.20, 12.18) 4.13 (1.09, 15.67) c
Received immunosuppressive agents 0.29 (0.11, 0.78) 0.47 (0.14, 1.59)
Received pyridostigmine 0.16 (0.032, 0.78) 0.23 (0.04, 1.53)

CI = confidence interval.

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Mar 14, 2020 | Posted by in OPHTHALMOLOGY | Comments Off on Factors Affecting Generalization of Ocular Myasthenia Gravis in Patients With Positive Acetylcholine Receptor Antibody

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