Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by fluctuating muscle weakness and fatigability, often leading to disability and decreased quality of life. Two forms of the disease exist: (1) ocular myasthenia gravis (OMG) in which only the extraocular muscles and levator palpebrae are affected and (2) generalized myasthenia gravis (GMG) in which nonocular skeletal muscles become affected. Many studies have estimated the incidence and prevalence of MG, and meta-analyses have shown an increasing prevalence and incidence of MG (1–3). It has been reported that more women than men present with the disease at an early age (4). However, the prevalence and incidence of MG has become more frequent, particularly in older populations, likely due to improved prognosis and knowledge of the disease (2). OMG may progress to GMG in 53% of patients with 44% of OMG patients progressing within 2 years and with the majority of those patients progressing within 1 year (5–8). A recent study of 87 patients with OMG found that those who were untreated developed GMG within 1 year (mean = 0.22 y), whereas those who were treated with prednisone developed GMG less frequently (odds ratio = 0.41) and with a delayed onset (mean = 5.8 y) (9).
Estimates of the incidence of MG vary widely in the literature likely because of differences in case acquisition and population studied, but values range from 1.7 to 30.0 cases per million person-years, with one recent international meta-analysis estimating an incidence rate of 5.3 cases per million person-years (1,2). The same study then estimated prevalence of MG to be approximately 77.7 cases per million persons (1). In general, MG has been described as having a bimodal age distribution for women vs a unimodal distribution for men (1,10). The age distribution of OMG is less well studied, but one report described a younger age in women, similar to GMG (11). Published literature regarding the age of onset with respect to race is scant. One exception is a comparison of Asian populations with Caucasian populations, where OMG occurs more frequently among children in Asian populations (12). Another study compared black populations with Caucasian populations with MG overall (combined GMG and OMG). Black individuals had a higher incidence under the age of 50 years than Caucasians, and a higher prevalence, but these did not reach significance (13). In light of limited data regarding demographics and OMG, our goal was to evaluate the associations of age, gender, and race among patients presenting with OMG.
The Institutional Review Boards of Emory University, the New York Eye and Ear Infirmary, the University of Minnesota, the Vienna Medical Center, and the Kansas Medical Center approved this study. An a priori sample size calculation determined that 140 patients in total were required to establish a mean age equivalence of 10 years or less with a of power 90% and α = 0.05.
For the purposes of this study, OMG was defined as an autoimmune disorder causing ptosis, binocular diplopia, or extraocular motility limitation confirmed by ice test, acetylcholine receptor antibodies, or electromyography (14–16). Patients who exhibited any symptoms or signs of GMG, such as limb or oropharyngeal weakness, at time of initial diagnosis were excluded. All patients underwent careful clinical examination for signs of GMG.
Patients were identified through chart review with diagnoses made between 1980 and 2014. Age at diagnosis, race, and gender were retrospectively collected from consecutive patients with MG with only ocular manifestations at each site. Data were collected by Emory University and from other sites in a deidentified fashion. Statistical analysis was performed by one of the authors (B.B.B.) with R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, http://www.R-project.org) and JAGS (Martyn Plummer, http://mcmc-jags.sourceforge.net/). Robust Bayesian analysis (to provide equivalence testing) capabilities and linear regression were applied to evaluate whether age differed by gender or race (17).
A total of 433 patients with OMG were identified from the 5 centers (266 New York Eye and Ear Infirmary/INN, 57 University of Minnesota, 44 Medical University of Vienna, 41 Emory University, and 25 University of Kansas Medical Center). Men represented 258 (60%) of cases. Mean age at diagnosis (±SD) among men was 57 ± 19 years and 52 ± 21 years among women. The age and gender distribution was similar in the 5 participating centers showing a later age of presentation of OMG for men (Fig. 1). The mean age difference between men and women was 4.7 years with a 95% credible interval (CI) (Bayesian equivalent of confidence interval) of 0.8–8.7 years for mean age, with 99.6% of the highest density interval between 0 and 10 years.
Race was documented in 376 patients (87%). Of these patients, 308 of 376 (82%) were Caucasian, 31 of 376 (8%) were black, 13 of 376 (3%) were Asian, and 24 of 376 (6%) were other or multiracial. Caucasians were 17.3 years older than non-Caucasians at diagnosis (95% CI, 12.2–22.3 y; P < 0.001) controlling for gender. Excluding Asians, Caucasians were 18.9 years older than other non-Caucasians at diagnosis (95% CI, 13.1–24.6 y; P < 0.001). Comparing Caucasians with blacks only, Caucasians were 23.0 years older (95% CI, 16.2–29.8 y; P < 0.001). There was no additive interaction of gender and race (P = 0.74). Density plots showed a bimodal distribution for age at diagnosis for women peaking at approximately 30 and 60 years. Men had a left skewed unimodal age distribution peaking at age 70 (Fig. 2).
In OMG, we found that men were older than women at the time of diagnosis by about 5 years with high confidence that the difference is less than 10 years. The age and gender distribution pattern of OMG is similar to the one found in GMG with a bimodal distribution in women peaking at about age 30 and 60 years and a unimodal distribution in men peaking at about 70 years. Of particular note, we found that non-Caucasian patients diagnosed with OMG tended to be significantly younger when compared with Caucasian patients, on the order of nearly 2 decades.
Our study examined the influence of race and gender on the distribution of OMG by age. GMG has been described as occurring with higher frequency at a younger age among women vs men (4,11). This has been described as a bimodal distribution of incidence of GMG, with a peak incidence at a younger age among women, and a second peak among older men and women (1,13). Phillips et al (13) found a bimodal distribution among both women and men, although men were more likely to be diagnosed at a later age (41.7 vs 60.3 y). In OMG alone, Grob et al (11) described that women presented at a significantly earlier age when compared with men (36.3 ± 21.5 vs 44.4 ± 18.6, P < 0.001) (11). Overall, men had a higher incidence of purely OMG, but the incidence of OMG below the age of 20 was higher in women than men, whereas above the age of 40, the incidence was higher in men than women. Our study found a bimodal distribution among women, with men diagnosed with OMG at a later age, which was in concordance with previous studies on GMG.
A previous analysis found that there was a higher incidence of OMG among black men than black women, whereas there was a preponderance of Caucasian women with GMG (18). Phillips et al (13) found a higher incidence and prevalence of MG among blacks in comparison with Caucasians overall (incidence: 10.3 vs 8.9/million person-y; prevalence: 21.1/100,000 vs 13.3/100,000 persons). Asian populations have been described as having an earlier onset of MG, which is more frequently OMG rather than GMG (12). Our findings indicate that non-Caucasian patients with OMG tend to be younger at onset of disease. This may be due, in part, to a predisposing etiologic factor in the black population for the development of autoimmune diseases (13).
We acknowledge the inherent limitations of this study including the retrospective data collection and referral bias to tertiary care centers. However, the wide geographic range and similarity of age and gender data across institutions argue that our findings are likely generalizable. We recognize that our data are based on patients with OMG at diagnosis who may have later converted to GMG. Furthermore, we acknowledge that even the most rigorous clinical examination may miss subtle GMG. Although these limitations are relevant with respect to the pathophysiology of OMG and deserve future study, our data are relevant to the initial presentation of patients who do not have GMG at presentation. Although some patients may convert to GMG, the demographics of patients who demonstrate only ocular manifestations have relevance to the diagnosis of MG and may have pathophysiologic or prognostic implications. Patients may have been diagnosed with MG before their presentation to our clinics. Although this may have affected the absolute age of patients with the diagnosis of MG, we do not expect there would have been differential referral patterns with respect to age, gender, and race that would have biased our results.
In summary, patients with OMG have a bimodal distribution similar to GMG with women receiving a diagnosis at an earlier age than men, with non-Caucasian patients receiving a diagnosis earlier than Caucasian patients. It is unknown whether these differences affect prognosis, disease course, conversion to GMG, or responses to treatment.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: Michael S. Lee and Beau B. Bruce; b. Acquisition of data: Jason H. Peragallo, Elena Bitrian, Mark J. Kupersmith, Fritz Zimprich, Thomas J. Whittaker, Michael S. Lee, and Beau B. Bruce; c. Analysis and interpretation of data: Beau B. Bruce. Category 2: a. Drafting the manuscript: Jason H. Peragallo, Elena Bitrian, Mark J. Kupersmith, Fritz Zimprich, Thomas J. Whittaker, Michael S. Lee, and Beau B. Bruce; b. Revising it for intellectual content: Jason H. Peragallo, Elena Bitrian, Mark J. Kupersmith, Fritz Zimprich, Thomas J. Whittaker, Michael S. Lee, and Beau B. Bruce. Category 3: a. Final approval of the completed manuscript: Jason H. Peragallo, Elena Bitrian, Mark J. Kupersmith, Fritz Zimprich, Thomas J. Whittaker, Michael S. Lee, and Beau B. Bruce.
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