The quantitative myasthenia gravis score (QMGS) is a 13-item scale developed by Tindall et al1 and later modified by Barohn et al2 used to quantify disease severity in myasthenia gravis (MG). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits). Its reliability and longitudinal validity have been demonstrated in several studies.3,4 A variability of 1.34 on repeat testing has been observed, and a 3.5 unit change in QMGS established as a clinically meaningful change, although Barohn et al2 suggest that a change of ≥2.6 units is clinically significant.1 A task force of the Myasthenia Gravis Foundation of America (MGFA) recommended that the QMGS should be used in prospective clinical trials,5 and subsequently, it has been used as the primary outcome measure in several randomized trials in MG.6–8
Drawbacks to the QMGS are that it requires special instrumentation (dynamometer for grip strength and spirometer for vital capacity) and is time consuming, requiring 25–30 minutes to perform. The QMGS has also been criticized as not being fully representative of MG disease activity due to the lack of weighting of different domains. In light of these considerations, simpler measures, such as the MG composite,9 have been proposed for use in clinical trials. The MGFA scale categorizes myasthenic severity from grade I–V, but this categorical scale, similar to the historical Osserman scale, was not designed to measure change through time5 and is likely to be insensitive to any but major changes in clinical state. The MG composite is a promising novel scale that has not been widely used as of yet.9
In this study, we compared the QMGS with established clinical, electrophysiological, and serological parameters in MG to determine if the results support the use of the QMGS in clinical trials in MG.
PATIENTS AND METHODS
Data from patients enrolled in 2 previous, randomized, controlled trials studying intravenous immunoglobulin (IVIG) compared with placebo (double blind)6 and IVIG compared with plasmapheresis (PLEX) (single blind, evaluator masked)7 were used for the present study. The University Health Network Research Ethics Board approved the studies. Details of the study methodologies have been published previously.6,7 In brief, patients were 18 years or older and had a diagnosis of MG and worsening weakness requiring a change in therapy. At the screening visit, the QMGS was obtained and patients were classified using the MGFA scale. In the IVIG compared with placebo study, the entry QMGS was unrestricted, but in the IVIG compared with PLEX study, the screening QMGS was required to be ≥11 points as patients below this level in the first study did not show a response to IVIG.6 A subset of patients in the IVIG compared with PLEX trial completed a 60-item myasthenia gravis–specific quality of life survey (QOL-60),10 and from this, we also derived the scores for the more recent 15-item quality of life scale (QOL-15).11 As part of their baseline assessment, most patients had single fiber electromyography (SFEMG) of the frontalis muscle and repetitive nerve stimulation (RNS) of the facial nerve with recording of the compound muscle action potential amplitudes over the frontalis muscle. At entry into both studies, patients had acetylcholine receptor antibody (AchRAb) titers tested.
Statistical analyses were performed using JMP 5 for MacIntosh (2002; Cary, NC). The QMGS scores and MGFA ratings were compared by analysis of variance. Spearman Rho correlation coefficient (rs) was calculated to assess the relationship between QMGS and jitter, percent abnormal pairs, percent blocking pairs, percent decrement on RNS, AchRAb titers, and quality of life scores because these variables were not normally distributed when analyzed by Q-Q plots. We also analyzed the univariate relationship of QMGS with age, sex, duration of disease, thymoma history, and current medication treatment. A P value of <0.05 was considered significant.
One hundred thirty-five patients with MG were included in the analysis. All patients had baseline QMGS and MGFA categorization. One hundred sixteen patients had baseline SFEMG, 121 had RNS studies, and 129 had AchRAb titers. Of the 84 patients in the IVIG versus PLEX study, 65 completed the QOL-60 survey at study entry. The mean age was 57.6 ± 17.4 years. There were 68 females and 67 males (50.4% female). Thirty-three patients (24.6%) had a history of thymoma, and 46 patients (34.3%) had prior thymectomy. Fifty-four patients (40%) were taking prednisone, 32 (24%) were taking Imuran, and 7 (5%) were taking other immunosuppressant medications. In addition, 17 (13%) had received IVIG and 15 (11%) PLEX in the past. Of the 129 patients tested, 89 (68.9%) patients were AchRAb positive. The mean disease duration was 65.4 ± 85.4 months. The baseline clinical, laboratory, and electrophysiological parameters are shown in Table 1.
The QMGS was unrelated to age, sex, disease duration, history of thymoma, or current medications. However, the QMGS correlated strongly with the MGFA clinical scale (r2 = 0.54, P < 0.0001, and the pooled 95% confidence interval: I 5.2–9.9; II 10.8–12.2; III 16.0–17.7; IV 14.8–27.1; V 23.8–36.2) as shown in Figure 1. Only a single patient was classified as IV or V on the MGFA. The QMGS had a moderate correlation with the QOL-60 score (rs = 0.30, P = 0.014) and a good correlation with the QOL-15 (rs = 0.41, P = 0.0007).
The QMGS showed a good correlation with jitter (rs = 0.40, P < 0.0001) (Fig. 2) and a moderate correlation with percent abnormal pairs (rs = 0.34, P = 0.0002) and percent blocking pairs (rs = 0.33, P = 0.0003) and a similar correlation with the decrement on RNS studies (rs = 0.29, P = 0.0012). The QMGS did not correlate with AchRAb titers (rs = 0.11, P = 0.27). The QMGS did differ depending on AchRAb status: AchRAb-positive patients had a mean QMGS of 14.2 ± 4.5 compared with 12.0 ± 3.7 in AchRAb-negative patients (P = 0.008).
The present study shows that the QMGS for disease severity is positively associated with the MGFA scale, the MG-QOL-15, the serological status of patients, and objective markers of neuromuscular function, namely, electrophysiological parameters from SFEMG and RNS tests. These results indicate that the QMGS is a valid way to measure disease severity in MG. It would be valuable to compare how these measures perform in a longitudinal fashion, but this was not the aim of the present study; rather, we planned to evaluate how QMGS relates to different measures of disease severity at a given instance. A prospective study of the ability of the QMGS to accurately measure progression or evolution of MG would be a valuable aim of future research in this area.
Previous studies have also shown a good correlation between the QMGS and other clinical scales, like the myasthenic muscle score3 and the manual muscle test.12 It would have been interesting to compare the QMGS with the new MG composite score,9 but information on the MG composite was not available in the present patient population, and the authors are unaware of other published comparisons of these scales. A limitation of this study was the few patients in MGFA class IV and V, so our results cannot really be extrapolated to those patients.
The QMGS showed a positive association with both MG quality of life scales, although the association is stronger for the 15-item scale (QOL-15). The lack of a stronger association of the QMGS with the QOL-60 might be explained by a larger number of items in this scale, mostly of a subjective nature, which despite being important for the patients, is not reflected in the QMGS. This suggests certain insensitivity of the QMGS to represent all the symptoms that patients find troublesome and that may not be present at the time of the physical examination, given the fluctuating nature of MG. However, the good association of the more focused QOL-15 instrument with the QMGS indicates that the QMGS is representative of some patient concerns at least in terms of function, which is the main focus of this abbreviated scale, but can miss some other “existential” domains.
Given the availability of multiple clinical scales, it is important to evaluate how the different scales compare with other parameters assessing the severity of the disease, in order to choose the most appropriate clinical method for measurement. To our knowledge, this is the first report of a positive correlation between the QMGS and electrophysiological markers in a large cohort of patients, and in our view, this relationship enhances the validity of the QMGS for disease severity because electrophysiological tests are an objective measure of neuromuscular function. In a previous study by Zinman et al,13 the authors found that electrophysiological markers could not replace clinical ones for outcome measurement in MG but the study cohort was much smaller. The results of the present cross-sectional study, showing a positive relationship of the QMGS with electrophysiological markers, support further studies on the responsiveness of electrophysiological parameters, in conjunction with clinical scales, as outcome measures in MG to provide objective support for clinical changes. The absence of a demonstrable association between the QMGS and AchRAb titers was expected and consistent with long-standing observations that AchR antibody titers do not correlate with the severity of MG.14 However, a high number of patients were receiving some kind of treatment before being enrolled in the studies, so it is possible that their titers did not accurately reflect their pretreatment state. The observations of more severe MG, that is, higher mean QMGS for disease severity in seropositive patients, do suggest that the high-affinity AChRAb has more pathophysiologic activity in patients with MG compared to low-affinity AChRAb that were not measured here.15
In conclusion, the present study confirms that the QMGS is a valid marker of the severity of MG in patients with MGFA scale I–III, as indicated by the MG-QOL-15, electrophysiological markers, and serological status. Our study supports the use of the QMGS as an efficacy parameter in clinical trials of MG, although the study does not address the validity of other clinical tools. Newer scales should show validity similar to the QMGS if they are to be used as efficacy parameters in clinical trials of MG.
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