This study identified use of plasmapheresis, intubation status, and male sex as factors associated with increased LOS in acute MG exacerbation. Thymectomy was associated with shorter LOS. This may relate to the role of the thymus in MG pathogenesis [14]. Intubation was the strongest predictor of hospital LOS. Male sex and thymectomy status still had significant associations with change in LOS when intubation status was accounted for. Plasmapheresis did not.
Plasmapheresis as a contributor to longer hospital stays in non-intubated patients was unsurprising because this hospital’s protocol for treating MG exacerbation with plasmapheresis is one session every other day for a total of five sessions. Therefore, a course of plasmapheresis necessitates a minimum of 10 days in the hospital. The 7.09% of exacerbations treated with both plasmapheresis and IVIg likely represent those with severe refractory exacerbations, which would explain the longer average stay in these patients.
Perhaps the most interesting finding from this data is that patients with a thymectomy spent less time in the hospital for MG exacerbation. Thymectomy has already been shown to be helpful in reducing disease exacerbation and required use of prednisone/immunosuppressants [15]. This could demonstrate another way in which thymectomy helps ameliorate disease burden.
Thymectomy guidelines for MG patients (discussed in further detail below) are largely based on a meta-analysis which examined the benefits of thymectomy as they accrue over time (12 months or longer) [16,17,18]. Considering that most hospitalizations occurred within the first year of diagnosis, there are at least four possible explanations for why the rate of thymectomies increased with time from diagnosis to hospitalization. It could reflect that MG exacerbations become less frequent over time or that the longer one has had the diagnosis, the more likely they are to have undergone a disease modifying surgery. It could also support prior studies that purport thymectomy reduces frequency of exacerbation [19]. Finally, it may be considered that surgery has the potential to reduce hospital burden even within 12 months. As the hospital burden of MG and its natural history continue to be defined, it would be interesting to see in future studies if there is a relationship between time since surgery and hospital LOS for myasthenia exacerbation, which could indicate that the benefits of thymectomy in MG patients begin sooner than 12 months.
Current guidelines recommend thymectomy in the 10% of MG patients with thymoma [20]. For non-thymomatous patients, thymectomy is recommended in those < 50 years of age without MuSK or LRP4 antibodies but with either generalized MG or refractory disabling ocular MG [15]. Thymectomy may be considered in those 51 to 65 years of age depending on operative risks [16]. For patients 18 to 50 years of age with non-thymomatous generalized AChR antibody-associated MG, thymectomy is based on Grade 1B recommendations [17]. Otherwise, these are Grade 2C recommendations [5]. Beyond these patient populations, decision to proceed with thymectomy is made on an individual basis due to low-quality evidence supporting any benefits. This study includes the populations with weak evidence-based guidelines. Therefore, this finding that patients with thymectomy had shorter hospital stays may serve to help further guide individualized disease management decisions in patient groups where the role of thymectomy, such as those without AChR-Abs and older patients, remains under investigation.
Of these patient groups that remain under investigation, there has recently been more interest in exploring non-AChR serotypes and our findings may be taken in this context. For example, Koing et al. in Journal of Neurology (December 2021) concludes that MuSK-Ab status is associated with a longer need of mechanical ventilation, ICU LOS, and overall hospital-LOS in myasthenic exacerbation compared to AchR-Ab [21]. In contrast, our study did not find an association between seropositivity (including both MuSK and AchR-Ab) and hospital LOS. This could represent a lack of clinical significance in Koing et al.’s findings. Further analysis is still needed to clarify the nuances amongst the different stereotypes.
The study was limited by its retrospective nature. Such studies are prone to misclassification bias. For example, lack of appropriate ICD coding likely excluded potential exacerbations from this dataset. Inadequate documentation likely contributed to the large number of exacerbations with unknown causes and unknown MGFA classes. It is also likely that not all ICU admissions were captured. This is because in the EMR, the location within the hospital reflects the last location before discharge. It is reasonable to predict that if intubation significantly correlated with LOS, so would ICU admission. Given that the rate of intubation was much greater than 5%, there were likely more than 7 ICU admissions which if captured may or may not have changed these results.
In addition to the above limitations inherent to retrospective analyses, these findings may not be generalizable as they were limited to a single academic center and racially homogenous. This may reflect racial demographics of the city of the institution and/or consistency with findings of a retrospective study from 2007 in which Whites were more likely to develop treatment refractory generalized MG [22].
Finally, we did not consider comorbidities as it was beyond the scope of this study primarily assessing the effect of treatment on LOS. Comorbidities are potential confounding variables which may impact LOS as underlying conditions could independently contribute to poor disease control. This is illustrated in a recent retrospective cohort study examining independent risk factors for myasthenic crisis published in Journal of Neuroinflammation (April 2022) concluded that the number of comorbidities, intubation, prolonged mechanical ventilation, and myasthenic crisis triggered by infection were associated with worse outcomes [23]. Similarly, Neumann et al. in a multicenter analysis of myasthenic crisis demanding mechanical ventilation concluded that prolonged ventilation (> 15 days) depended on age, late-onset MG, a high MGFA Class before crisis, pneumonia, resuscitation, and number of comorbidities (> 3 comorbidities) [24]. Of note, it is interesting to contrast this with our results which showed similar average ages at time of initial diagnosis and the same most common MGFA class at time of initial diagnosis in intubated compared to non-intubated patients. Furthermore, our study found no association between age at diagnosis and LOS. This underscores the need for further study of MG disease progression.
Strengths of this paper include its longitudinal nature which spans a decade. It also includes demographics which have generally been excluded from previous MG studies (eg, seronegative, those older than 65 years) and therefore may be generalized to these understudied MG patients as discussed above [19].
Another strength of this study is the statistical model. The conclusions drawn from multivariate analysis are more likely to be accurate than a univariate analysis as it more closely resembles reality where independent and dependent variables rarely occur in isolation from other situational factors.
With a number of novel immunosuppressive drugs under current investigation for generalized MG therapy, this study may help clarify where the gaps are in acute MG treatment. It will be of interest to see if novel therapies have an impact on hospital length of stay for MG exacerbation patients. Continued evaluation of the effect of resources employed during exacerbation management on disease outcomes will be important to establish a basis of comparison as novel treatments advance through clinical trials.
