Introduction

Myasthenia gravis, an autoimmune disorder, mainly presents as diplopia, ptosis, fluctuating muscle weakness, and even respiratory failure [1]. Global estimates note its incidence and prevalence between 1950 and 2007 were about 5 and 77.7 per 100,000 persons, and mortality was 0.1–0.9 per 100,000 persons [2]. Annual medical costs for myasthenia gravis in the United States were found to be as high as $15,675 per patient [3]. Mental disorders, limited physical activity, and poor quality of life are significant problems for this socially vulnerable population [4,5]. Thymectomy was considered as an invasive but definite treatment procedure for patients with myasthenia gravis [6–11]. With the increasing incidence of myasthenia gravis in elderly people due to longer life expectancy and improved diagnostic methods, myasthenia gravis patients may be receiving increasing numbers of surgeries other than thymectomy [12].

Previous studies found that patients with myasthenia gravis were more likely to have perioperative complications such as exacerbated muscle weakness, residual muscle paralysis, and cholinergic and myasthenia crises [7–13]. However, these studies were limited to single medical institutes [7–11], or focused on a specific surgical procedure [7–11], lacked a control group [8–10], had a small sample size [7,8] or inadequate adjustment for potential confounding effects [8–10]. Most available information from previous studies are focused on long-term prognosis of thymectomy or different thymectomy technique comparisons [9–11], while general features in this population undergoing regular surgical procedures were ignored [7–11].

Using Taiwan’s National Health Insurance Research Database, we conducted a population-based study to investigate adverse events after major surgeries in patients with myasthenia gravis compared with the general population.

Methods

Results

After matching procedure by propensity score (Table 1), the baseline characteristics showed no significant differences between surgical patients with and without myasthenia gravis in terms of age, sex, low income, operation in teaching hospital or not, type of surgery or of anesthesia, or preoperative coexisting mental disorders, hypertension, diabetes, chronic obstructive pulmonary diseases, hyperlipidemia, liver cirrhosis, congestive heart failure, and renal dialysis.

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Table 1. Characteristics of surgical patients with and without myasthenia gravis.

https://doi.org/10.1371/journal.pone.0180433.t001

Compared with non-myasthenia gravis surgical patients (Table 2), patients with myasthenia gravis showed higher risks of postoperative complications, including pneumonia (OR = 2.09; 95% CI: 1.65–2.65), septicemia (OR = 1.31; 95% CI: 1.05–1.64), postoperative bleeding (OR = 1.71; 95% CI: 1.07–2.72), and overall complications (OR = 1.70; 95% CI: 1.44–2.00). Postoperative stay in intensive care unit (OR = 5.86; 95% CI: 5.23–6.57), prolonged stay, and increased medical expenditure were all significantly associated with preoperative myasthenia gravis.

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Table 2. Risk of postoperative adverse events in association with myasthenia gravis in the multiple logistic regression models.

https://doi.org/10.1371/journal.pone.0180433.t002

Table 3 shows that the specific associations between myasthenia gravis and postoperative adverse events were significant in males (OR = 1.53; 95% CI: 1.18–1.97), females (OR = 1.86; 95% CI: 1.50–2.31), and every age group. These included 20–39 years (OR = 2.19; 95% CI: 1.48–3.25), 40–49 years (OR = 1.95; 95% CI: 1.29–2.97), 50–59 years (OR = 2.07; 95% CI: 1.47–2.92), and ≥60 years (OR = 1.36; 95% CI: 1.06–1.74). Myasthenia gravis was also associated with postoperative adverse events in people with no medical conditions (OR = 2.15; 95% CI: 1.67–2.78), 1 (OR = 1.38; 95% CI: 1.03–1.85) or more than two (OR = 1.56; 95% CI: 1.13–2.16). Compared with surgical patients without myasthenia gravis (Table 4), those with significant increased risk of postoperative adverse events included those with preoperative emergency care visits (OR = 2.89; 95% CI: 1.99–4.21), hospitalization (OR = 2.79; 95% CI: 2.20–3.52), thymectomy (OR = 3.71; 95% CI: 1.23–11.2), and high medical expenditure (OR = 2.77; 95% CI: 2.08–3.67). The highest risk of postoperative adverse events was found in low-income patients with myasthenia gravis (OR = 5.98; 95% CI: 3.12–11.5). Compared with patients without myasthenia gravis, the ORs of postoperative adverse events for patients with myasthenia gravis who had symptomatic therapy, chronic immunotherapy, and short-term immunotherapy were 1.76 (95% CI 1.50–2.08), 1.70 (95% CI 1.36–2.11), and 4.36 (95% CI 2.11–9.04), respectively.

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Table 3. Stratification analysis of postoperative adverse events between myasthenia gravis patients and control by age, sex, and coexisting medical conditions.

https://doi.org/10.1371/journal.pone.0180433.t003

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Table 4. Risks of postoperative adverse events associated with preoperative characteristics of myasthenia gravis.

https://doi.org/10.1371/journal.pone.0180433.t004

Discussion

This nationwide retrospective population-based study shows myasthenia gravis as an independent risk factor increasing postoperative adverse outcomes after major surgery. Risks of pneumonia, septicemia, postoperative bleeding, and intensive care unit admission were found higher in those with myasthenia gravis, although 30-day in-hospital mortality did not increase. Prolonged length of stay and increased medical expenditure after surgery were also noted in patients with myasthenia gravis. Women, patients under age 60, and those without other medical conditions had higher incidences of postoperative adverse events. We also provided some parameters which could be easily obtained from personal history that could be helpful in predicting risks of postoperative adverse events. Unlike other investigations [7–11], this study is unique in its large sample size, selection of control group by matching procedure with propensity score and multivariate adjustment for potential confounding factors.

As with other systemic autoimmune diseases, myasthenia gravis often appears with other autoimmune diseases such as thyroid disease, polymyositis/dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, cardiomyositis, subclinical heart dysfunction, and cancer [20,21,22]. Although these comorbidities increase the complexity of medical treatment, advances in medical science have reduced mortality from myasthenia gravis [20,23].

Some previous studies suggested that surgical patients’ postoperative adverse events could be influenced by age, sex, low income, hospital type, types of surgery and of anesthesia, and coexisting medical conditions (mental disorders, diabetes, chronic obstructive pulmonary disease, liver cirrhosis, congestive heart failure, and renal dialysis) [14–17]. These sociodemographics, coexisting medical conditions, and operational characteristics were considered as potential confounding factors when investigating associations between myasthenia gravis and postoperative adverse events. In order to reduce such confounding effects, we used propensity score-matching procedure to adjust the preoperative difference between patients with and without myasthenia gravis. The further multiple logistic regressions were used to adjust residual confounding bias. The increased risk of postoperative adverse events in patients with myasthenia gravis was significant in males, females, every age group, and people with and without medical conditions. From an epidemiological viewpoint, this strengthens the association between myasthenia gravis and postoperative adverse events.

The findings of increased postoperative pneumonia, bleeding, and infection in patients with myasthenia gravis may have several possible reasons. First, the pharmacologic effects of immunosuppressant medications such as steroids, azathioprine, cyclophosphamide and mycophenolate mofetil put myasthenia gravis patients into immunocompromised status so they suffer from more opportunistic infections [24]. Steroids have been linked to increased reintervention rates for post-tonsillectomy bleeding [25]. Azathioprine and cyclophosphamide may also play a role in bleeding episodes due to myelotoxicity [26,27]. Second, empirical delay in extubation after surgery may cause unavoidable atelectasis [28,29], delay ambulation, and prolong intensive care unit stay, which might increase the risk of ventilator-associated pneumonia and embolism [30]. Third, the systemic inflammatory course of myasthenia gravis with other autoimmune comorbidities might directly contribute to systemic adverse events [21,22]. Fourth, poor communication between intubated patients and staff as well as mental illness-related communication issues might slow detection of adverse events.

Age and gender impacts on myasthenia gravis mortality have been controversial [22,23,31,32]. In our study, we found the incidence of postoperative complications lower in male and elderly patients than in females and other age groups. Similarly, a 2015 nationwide population-based study in Denmark enrolled 702 AChR-Ab-seropositive myasthenia gravis patients and found myasthenia gravis mortality rates were higher in women and early-onset myasthenia gravis, perhaps due to increased frequency of combined autoimmune disorders and thymoma in these patients [22,31,32]. Although mortality and postoperative complications differ, these groups of patients could be followed with greater care after surgery. Interestingly, the incidence of postoperative adverse events was higher in patients without medical conditions than in the other two groups. This could be because fewer comorbidities in early-onset myasthenia gravis patients still yield higher mortality [31], or other coexisting medical conditions’ impacts being eliminated by propensity score-matching procedure.

Another striking finding of our study is that myasthenia gravis patients had positive correlation with postoperative adverse events after most coexisting medical conditions were adjusted in the areas of low income, preoperative emergency care visit, hospitalization, and thymectomy. The myasthenia crisis could be provoked by other systemic issues that require emergency medical assistance [33]. Although patients with MG have a greater morbidity then general population, thymectomy was found to be a safe procedure [7]. As the condition worsens toward acute exacerbation, a treatment course with immunoglobulin G or plasmaphoresis and other intensive supportive care usually takes 2 to 5 days in hospital [32]. Based on this sequence, the severity of patient disease could be deduced from patient receiving emergency care or being hospitalized. Two recent studies found that unstable myasthenia gravis before surgery, preoperative plasmapheresis, and patients with a history of myasthenic crisis have increased incidence of myasthenic crisis after surgery [34,35]. Patients with these histories might be considered more vulnerable, and this might explain the significant increase in postoperative adverse events. Thymoma has been found in 10–15% of myasthenia gravis patients, mostly in early-onset and generalized forms of the disease [36,37]. Thymoma-associated myasthenia gravis has been associated with haematological autoimmune disorder, severe cardiomyositis, heart conduction abnormalities, and cancers [32]; it should be considered a paraneoplastic disease whose complex comorbidity interactions can contribute to postoperative adverse effects.

Our study has several limitations, starting with the lack of detailed patient lifestyle information (smoking, alcohol drinking, and physical activity) as well as lack of physical, medical, and laboratory examinations in the retrospective medical claims data we used. Second, we used ICD-9-CM codes claimed by physicians for myasthenia gravis without clarifying the severity of disease. Future researchers can use means such as Myasthenia Gravis Foundation of America Clinical Classification to assure comparability of investigations [38]. The influence of disease severity on postoperative complications can be only evaluated by indirect parameters such as history of emergency care and hospital admission. In addition, the coexisting medical conditions and postoperative complications identified using insurance claims data might represent an underestimate, because some patients with very minor illness might not seek medical treatment. However, this condition may distribute equally between surgical patients with and without myasthenia gravis. Finally, although we used propensity score matching procedure and multivariate logistic regressions to eliminate bias from confounders, residual confounding is always possible.

Conclusion

Our study found increased postoperative pneumonia, septicemia, bleeding, stay in intensive care unit, prolonged stay, and increased medical expenditure for patients with myasthenia gravis receiving major surgery compared with control. In particular, postoperative adverse events significantly increased in myasthenia gravis patients with preoperative history of hospitalization, emergency visit, thymectomy, low income and high medical expenditure. These findings have important clinical implications, both for their predictive value and for showing the urgent need to improve management of surgical patients with myasthenia gravis.

We suggest comprehensive perioperative assessment and greater understanding of the complex issues of care for patients with myasthenia gravis who undergo major surgery.

Acknowledgments

This study is based on data provided by the Bureau of National Health Insurance of Taiwan’s Ministry of Health and Welfare and managed by the National Health Research Institutes. The authors’ interpretations and conclusions do not represent those of the Bureau of National Health Insurance, the Ministry of Health and Welfare, or the National Health Research Institutes.