Nejmoa1602489 PDF

new journal
The
england of
medicine
established in 1812
August 11, 2016

vol. 375 no. 6
Randomized Trial of Thymectomy in Myasthenia Gravis

G.I. Wolfe, H.J. Kaminski, I.B. Aban, G. Minisman, H.C. Kuo, A. Marx, P. Ströbel, C. Mazia, J. Oger, J.G. Cea,
J.M. Heckmann, A. Evoli, W. Nix, E. Ciafaloni, G. Antonini, R. Witoonpanich, J.O. King, S.R. Beydoun, C.H.
Chalk, A.C. Barboi, A.A. Amato, A.I. Shaibani, B. Katirji, B.R.F. Lecky, C. Buckley, A. Vincent, E. DiasTosta, H.
Yoshikawa, M. WaddingtonCruz, M.T. Pulley, M.H. Rivner, A. KosteraPruszczyk, R.M. Pascuzzi, C.E. Jackson,
G.S. Garcia Ramos, J.J.G.M. Verschuuren, J.M. Massey, J.T. Kissel, L.C. Werneck, M. Benatar, R.J. Barohn, R.
Tandan, T. Mozaffar, R. Conwit, J. Odenkirchen, J.R. Sonett, A. Jaretzki, III, J. NewsomDavis, and G.R. Cutter, for
the MGTX Study Group*
abstract
BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no
The authors’ full names,
academic de conclusive evidence of its benefit. We conducted a multicenter, ing thymectomy plus prednisone with
prednisone alone.
randomized trial compar-
grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Wolfe at the Department of Neurol
METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day
prednisone alone. Patients 18 to 65 years of age who had generalized nonthy-
ogy, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York, 100 High St.,
Buffalo, NY 14203, or at gilwolfe@ momatous myasthenia gravis with a disease duration of less than 5 years were included
buffalo . edu. if they had
Myasthenia Gravis Foundation of America clinical class II to IV disease (on a
* A complete list of the
members of the scale from I to V, with higher classes indicating more severe disease) and elevated circulat- ing
concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average
Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with
Thymectomy Trial in NonThymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) Study Group is
provided in the Supplementary higher scores indicating more severe disease) over a 3-year period, as assessed by means
Appendix, available at
NEJM.org. of blinded rating, and the time-weighted average required dose of prednisone over a 3-year
This article was updated on May
4, 2017, period.
at NEJM.org.
RESULTS
N Engl J Med
2016;375:511-22. A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who
underwent thymectomy had a lower time-weighted average Quantitative
DOI: 10.1056/NEJMoa1602489 Copyright © 2016 Massachusetts Medical Society.
Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001);
patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (32 mg vs. 54
mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required
immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%,
P<0.001). The number of patients with treatment-associated complications did not differ significantly between
groups (P = 0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to
immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P = 0.003).
CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous
myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX
ClinicalTrials.gov number, NCT00294658.)
n engl j med 375;6 nejm.org August 11, 2016
The New England Journal of Medicine Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses
without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.
511

512
new The
england journal
of
medicine T
he tomy myasthenia first in patients reported gravis with was use of thymec- nonthymomatous 75 years ago.1 Of six
patients who underwent surgery, three had a favorable response. Subsequent retrospective studies have shown
benefits of thymectomy in patients with nonthymomatous myasthenia gravis but with widely varying rates of
clinical improvement or remission. A compilation of retrospective studies comparing surgery with medical
management did not show a difference in remission rates.2 Two studies that showed clinical improvements after
thymectomy indicated that benefit occurred in the first few years after the procedure, but after 5 years, rates of
clinical improvement were similar among surgically treated patients and those who were treated medically.3,4
Observational studies have not shown benefits of thymectomy, perhaps because of the effectiveness of modern
immunotherapeutic approaches.5
Despite calls for a randomized, controlled study, data are lacking, and uncertainty persists regarding the benefit
of thymectomy and the clinical characteristics of the patients who should be offered the procedure.6,7 A systematic
review8 of articles describing outcomes in 21 cohorts of patients with myasthenia gravis pointed out numerous
methodologic flaws that prevented definite conclusions to be drawn regarding the benefits of thymectomy in
patients with nonthymomatous myasthenia gravis.
Glucocorticoids have been widely used for the treatment of myasthenia gravis either as the sole therapy or with
thymectomy.9 Although adverse effects are not common with thymectomy, the procedure can cost up to
$80,00010 and can be associated with operative complications that need to be weighed against benefits. Glucocorti-
coids and other immunosuppressive agents place patients at risk for adverse events, some of which are
life-threatening, and affect quality of life. Therefore, establishing the role of thymectomy in patients receiving
glucocorticoids to manage myasthenia gravis would guide decisions regarding treatment and the costs of health
care.
We conducted the Thymectomy Trial in Non- Thymomatous Myasthenia Gravis Patients Re- ceiving Prednisone
Therapy (MGTX), an international, randomized, single-blind (rater-blinded) trial, to determine whether extended
transsternal thymectomy combined with a standardized
prednisone protocol would be superior to prednisone alone after 3 years, with respect to less- ening myasthenic
weakness, lowering the total dose of prednisone, and enhancing quality of life. Extended transsternal thymectomy
was cho- sen because it provides reproducible resection of A Quick Take
the maximal amount of thymic tissue with low is
available at NEJM.org
morbidity and a limited risk of phrenic-nerve injury.11
Methods
Trial Oversight The trial was designed and overseen by an executive committee that included lead investigators
and biostatisticians (see the Supplementary Appendix, available with the full text of this article at NEJM.org).
During the proposal and trial- design phase, feedback was received from re- viewers and staff at the National
Institute of Neurological Disorders and Stroke (NINDS). There was no commercial support for this trial. The
NINDS funded the trial and assembled a data and safety monitoring board to monitor the trial activities
independently.
Each trial site received approval from a local institutional review board or ethics committee, and each patient
provided written informed con- sent before enrollment. Data were collected by investigative teams at each trial site.
Data analysis and regulatory enforcement were performed by staff at the Data Coordinating Center, De- partment
of Biostatistics, University of Alabama at Birmingham. Data were managed at the Uni- versity of Alabama at
Birmingham with the use of a Web-based system. Notification of serious adverse events and visit tracking were
performed electronically. The first author wrote the first draft of the manuscript, with assistance from the executive
committee. All the authors vouch for the accuracy of the data and analyses reported. The trial was conducted and
reported with fidelity to the protocol, available at NEJM.org.
Trial Design MGTX was a multicenter, international, rater- blinded, randomized trial.12 Training meetings for
investigators were held in 2006 in the United States and the United Kingdom, and all the investigators were
required to pass a certification test to ensure the best possible adherence to the protocol. Thoracic surgeons were
certified after

Thymectomy Trial in Myasthenia Gravis
viewing a video of the surgical approach and passing a test to show that they understood the required procedure for
excision. Centers were asked to complete a screening questionnaire for every patient with myasthenia gravis who
was encountered at their sites.
The original inclusion criteria were a duration of myasthenia gravis of less than 3 years, an age of 18 to 60 years,
a serum acetylcholine-receptor–antibody level of more than 1.00 nmol per liter (elevated levels of 0.50 to 0.99
nmol per liter were accepted if the diagnosis was confirmed by a positive edrophonium test, abnormal repetitive
nerve stimulation, or abnormal single-fiber elec- tromyography), and a Myasthenia Gravis Founda- tion of America
clinical classification11 of II to IV (class I indicates weakness only in ocular muscles, class II mild generalized
disease, class III moderate generalized disease, class IV severe generalized disease, and class V a crisis requiring
intubation). Participants could be taking ap- propriate anticholinesterase therapy with or without oral
glucocorticoids. Exclusion criteria were thymoma on computed tomography or magnetic resonance imaging of the
chest, previous thymectomy, immunotherapy other than prednisone, pregnancy or lactation, unwillingness to avoid
pregnancy, contraindications to glucocorticoids, and substantial medical illness that would pre- clude participation.
In October 2008, which was 2 years after enrollment began, the eligibility criterion regarding disease duration
was increased from less than 3 years to less than 5 years and the age ceiling was raised from 60 years to 65 years to
enhance recruitment. In October 2009, the sample size was reduced from 200 to 150 participants to reflect a
lower-than-expected recruitment rate and better-than-expected retention of participants.
Trial Procedures Participants were stratified according to trial site with the use of a Web-based randomization
system in which participants were assigned, in a 1:1 ratio, to undergo thymectomy plus receive the standardized
prednisone protocol or to receive the same prednisone protocol alone. The receipt of prednisone began
immediately, and surgery was performed within 30 days after randomization. The randomization date was set as
month 0 (Fig. S1 in the Supplementary Appen-
dix). To preserve rater blinding, participants were seen exclusively until month 4, as they recovered from surgery, by
a neurologist who was aware of the trial-group assignments. At all visits, participants wore black, high-collared,
obscuring pullover shirts to conceal transsternal incisions; participants were under strict instruc- tions not to reveal
their assigned trial group to the evaluators.
Thymectomy was performed by means of a median sternotomy with the goal of an en bloc resection of all
mediastinal tissue that could anatomically contain gross or microscopic thymus (or both).11 Photographs of the
specimens were transmitted to the data coordinating center and analyzed by the surgical coordinator to judge the
extent of resection and compare it with a detailed operative report. Operative details are summarized in the
Supplementary Appendix. Data from patients who crossed over to the other group and from patients who had
thymoma discovered at surgery were handled according to an intention-to-treat model.
Participants who were not already receiving prednisone at baseline received an alternate-day dose of oral
prednisone starting at 10 mg, which was increased in 10-mg steps to 100 mg on alternate days or to 1.5 mg per
kilogram of body weight, whichever was lower. For participants who were already taking prednisone, the dose could
be increased up to 120 mg in those who did not reach minimal-manifestation status by month 4.
Minimal-manifestation status was defined as having “no symptoms or functional limitations from myasthenia
gravis, but there may be some weakness on examination of some muscles” (see the Supplementary Appendix).11
The prednisone dose was maintained until minimal-manifestation status was reached and the Quantitative
Myasthenia Gravis score13 (on a scale from 0 to 39, with higher scores on each of 13 items indicating more severe
weakness; a reduction of 2.3 points correlates with improved clinical status) was less than 14 and had also fallen at
least 1 point below baseline, as deter- mined by an evaluator who was unaware of the trial-group assignment.
The alternate-day prednisone dose was then reduced by 10 mg every 2 weeks until a level of 40 mg was reached,
with subsequent slowing of the taper to 5 mg every month, as long as the minimal-manifestation status was
maintained.
513

514
new The
england journal
of
medicine
If minimal-manifestation status was lost, the alternate-day prednisone dose was increased by 10 mg every 2 weeks
until the status was re- stored. Tapering could resume 4 weeks later.
Once prednisone tapering commenced, the total dose of pyridostigmine could not exceed 240 mg per day.
Plasmapheresis or intravenous immune globulin was permitted at the discre- tion of the unblinded neurologist in
patients whose condition was unstable, but it was not permitted in order to maintain minimal-manifestation status.
Patients who did not have minimal-manifestation status at 12 months or who had an unacceptable level of side
effects with prednisone could receive azathioprine at a dose of 2.5 mg per kilogram per day or another
immunosuppressant such as cyclosporine if azathioprine caused unacceptable side effects.
Trial Outcomes The dual primary outcome was the time-weighted average Quantitative Myasthenia Gravis score
and the time-weighted average required dose of prednisone over a 3-year period; this dual outcome involved a
staged approach to incorporat- ing the potential effect of thymectomy on the clinical response to therapy and its
influence on long-term requirements for glucocorticoid use. The rationale for the dual outcome was that an
improved clinical status could correlate with a greater prednisone dose and a poorer clinical status with a lower dose.
The first stage of analysis compared the clinical outcomes between groups according to the time-weighted average
Quantitative Myasthenia Gravis score over a period of 3 years, which was roughly equivalent to the average score
over time.14 On the basis of the results of the between-group comparison of the clinical outcomes (clinical
improvement, worsening, or status unchanged), we analyzed the difference in the total required dose of
prednisone over the period of 3 years (see below).
Prednisone was administered in blister packs containing 10-mg tablets, with separate sheets provided for each
dose. Alternate-day dosing between visits was recorded by the patient in a diary. At each clinic visit, pill counts
were de- rived from returned blister packs to determine intake and were compared with the diaries. Pill cutters were
provided for 5-mg dosing, and un- used half pills were returned to the blister-pack sheets. Pill counts formed the
basis for deter-
mining the cumulative prednisone exposure, but for confirmation purposes, a secondary analysis that used the
prescribed dose was performed, which was independent of adherence by the patients.
To address safety and quality of life, secondary analyses focused on serious adverse events, including days of
hospitalization over the 3-year period, on the results of surveys of the patients that were adapted from the
cardiac-transplanta- tion literature15 to assess 36 treatment-associated complications and 29 symptoms associated
with glucocorticoids (see the Supplementary Appen- dix), and on results of the Medical Outcomes Study 36-Item
Short Form Health Survey (SF-36). An order of importance of secondary-outcome measures was not prespecified.
Measures per- taining to quality of life were to be used for further analysis if the tiered primary outcome was
inconclusive, such as if the time-weighted Quantitative Myasthenia Gravis score favored the thymectomy group but
at the cost of a higher prednisone exposure. Other secondary outcomes were the Myasthenia Gravis Activities of
Daily Living score (on a scale from 0 to 24, with higher scores indicating more severe disease; a reduction of 2
points correlates with improved clinical status),16,17 the proportion of participants who achieved
minimal-manifestation status, and the use of nonglucocorticoid immunosuppres- sants, plasma exchange, and
intravenous immune globulin.
Laboratory monitoring included a complete blood count and glucose, glycated hemoglobin, and potassium levels
measured at least month- ly from month 0 to month 3 and then every 3 months thereafter. Laboratory monitoring
that was performed in patients who were treated with azathioprine or cyclosporine is described in the Supplementary
Appendix.
Statistical Analysis The trial was powered to detect a 30% difference in the time-weighted prednisone dose between
the groups, which resulted in a proposed sample size of 150 participants on the basis of Student’s t-test for two
independent samples, at a 5% sig- nificance level, assuming a mean-to-standard- deviation ratio of 2.0. The
denominator that was used to compute the time-weighted average for the Quantitative Myasthenia Gravis score and
the prednisone dose was the number of days

from randomization to the last visit. Computa- tions used the trapezoidal method. The intention-to-treat method
was used for all outcome analyses.
For the first stage of the primary analysis, the protocol specified that first a 99.5% confidence interval for the
difference (prednisone-only group minus the thymectomy group) in the time- weighted average Quantitative
Myasthenia Gra- vis score would be assessed. If the confidence interval contained zero, the clinical outcome would
be considered as not being better in one group than the other. The second stage would determine superiority on the
basis of the exposure to prednisone with the use of a two-sided Student’s t-test of the time-weighted average
prednisone dose, at a type I error rate of 0.05, given the clinical outcome. Three imputation methods were used for
missing data (see the Supplementary Appendix).
The protocol prespecified the analysis of three subgroups (defined according to previous or no previous
glucocorticoid use, sex, and age at disease onset of <40 years vs. ≥40 years). We conducted a post hoc analysis of
subgroups defined according to an age at enrollment of less than 50 years versus 50 years or older. Details of the
analysis are provided in the Supplementary Appendix. There were no planned adjustments for multiple secondary
outcomes.
At the outset of the trial, investigators were asked to predict whether the trial would show a favorable effect for
thymectomy (Table S1 in the Supplementary Appendix). These responses re- mained sealed until the closure of the
trial.
Results
Participants Details regarding recruitment of the participants are provided in Figure S1 in the Supplementary
Appendix. A total of 67 centers in 18 countries on six continents (North America, South Amer- ica, Europe, Africa,
Asia, and Australia) participated, with 36 centers conducting recruitment; 32 participating centers were in the
United States. A total of 6958 persons underwent screening, 3003 of whom were in the United States. A total of
6727 patients did not meet the inclusion criteria. The main reasons for exclusion were duration of disease of 5 years
or more (3129 participants [47%]), an age that did not meet
specifications (2842 [42%]), use of nonglucocorticoid immunosuppressive drugs (1977 [29%]), and previous
thymectomy or chest surgery (1901 [28%]); multiple reasons for exclusion could have applied to individual patients.
Of the 231 eligible patients, 105 declined to participate, and 126 underwent randomization between Septem- ber
2006 and November 2012 (Fig. S1 in the Supplementary Appendix). There were no significant between-group
differences in the characteristics at baseline (Table 1).
Eight patients who were randomly assigned to the thymectomy group declined surgery. Eight patients who were
randomly assigned to the prednisone-only group underwent thymectomy outside the protocol (Fig. S1 in the
Supplemen- tary Appendix). Histologic findings are reported in Table S2 in the Supplementary Appendix. One
thymoma was discovered in a patient in the thymectomy group.
Analysis of Two-Stage Primary Outcome In the first stage of the analysis, the time- weighted average Quantitative
Myasthenia Gravis scores were significantly lower (indicating improved clinical status) in the thymectomy group
than in the prednisone-only group through month 36 (P<0.001) (Fig. 1A and Table 2). The estimated difference in
the mean score between the thymectomy group and the prednisone-only group was 2.85 points (99.5% confidence
interval [CI], 0.47 to 5.22).
Analyses in the second stage showed that over a period of 36 months, the time-weighted average prednisone dose
was significantly lower in the thymectomy group than in the prednisone- only group (Fig. 1B and Table 2). The
average alternate-day dose was 32 mg in the thymectomy group, as compared with 54 mg in the prednisone-only
group (estimated difference, 22 mg; 95% CI, 12 to 32; P<0.001). Less than 1% of the trial visits in the
prednisone-only group were missed, as compared with 1% of those in the thymectomy group. None of the
imputation methods for the missing data changed the un- derlying findings.
Subgroup Analysis The tests for interactions were not significant in any of the three subgroup analyses, and there-
fore, conclusions cannot be drawn about differ- ential benefits in the subgroups. A total of 26
515

new The
england journal
of
medicine
Table 1. Demographic and Clinical Characteristics of the Participants corticoids at Baseline.*
participants had not previously used glucocorticoids. Use of the drug was not clear in 4 patients, 3 of whom were
in the prednisone-only group. Among participants who had not taken gluco-
previously, there was a significant between-group difference in the prednisone dose but not in the
Quantitative Myasthenia Gravis
Characteristic Female sex — no. (%) Age — yr
Median Prednisone
Thymectomy Alone
plus Prednisone (N = 60)
(N = 66) 39 (65) 50 (76)
score; among patients with previous exposure to glucocorticoids, the between-group differences favored the
thymectomy group for both outcomes (Table 2). Among women, the between-group dif-
33 32
ferences in the two outcomes were significant; among men, the difference in prednisone dose was Range 18–64
18–63
significant. Thymectomy was associated with a
Race or ethnic group — no. (%)†
significantly lower time-weighted average predni-
Asian 4 (7) 6 (9)
sone requirement and Quantitative Myasthenia
Black 6 (10) 7 (11)
Gravis score (indicating clinical improvement)
Hispanic 17 (28) NonHispanic white 30 (50) Other 3 (5) Therapy at enrollment — no. (%)
17 (26)
31 (47)
5 (8)
than prednisone alone both in participants with disease onset at less than 40 years of age and in those with disease
onset at 40 years of age or older (Table 2).
Pyridostigmine 56 (93) 60 (91)
Secondary Outcome Measures Glucocorticoid 47 (78) 49
(74)
The survey regarding treatment-associated com-
Previous therapy — no. (%)
plications showed no significant difference be-
Intravenous immune globulin 13 (22) 12 (18)
tween the two treatment groups over a period
Plasma exchange MGFA class — no. (%)‡
IIa IIb 7 (12) 9 (14)
of 3 years (P = 0.73). The survey regarding treatment-associated symptoms favored the thymec-
25 (42) 14 (23) 25 (38) 18 (27)
tomy group over the prednisone-alone group in the number of participants with symptoms (P<0.001), in the total
number of symptoms III 20 (33) 21 (32)
(P<0.001), and in the distress level related to IV 1
(2) 2 (3)
symptoms (P = 0.003) over the 3-year period. No
Duration of disease — yr
significant between-group differences were seen
Median 1.14 1.08
in either the physical or the mental component
Range QMG score§ Prednisone use at baseline
No. of patients (%) 0.15–4.38 12.35±4.90 0.02–4.41 11.40±5.12
of the SF-36. Details regarding these outcomes are provided in Tables S5, S6, and S7 in the Supplementary
Appendix.
47 (78) 49 (74)
Table 3 lists data regarding adverse events. Fewer patients were hospitalized for exacerba- Dose — mg 42.49±23.52
43.43±28.92
tions of myasthenia gravis in the thymectomy
* Plus–minus values are means ±SD. There were no significant betweengroup
differences in the characteristics at baseline. Percentages may not sum to 100
group than in the prednisone-only group (9% vs. 37%, P<0.001). The mean (±SD) cumulative because of rounding. † Race and
ethnic group were selfreported. Other race included mixed race,
Native American, and Alaskan Native. ‡ Myasthenia Gravis Foundation of America (MGFA) class II indicates mild
number of hospital days was 8.4±8.6 in the thymectomy group, as compared with 19.2±24.5 in the prednisone-only group (P =
0.09). generalized weakness, class III moderate generalized weakness, and class IV severe generalized weakness. A notation of
“a” denotes predominantly limb or axial weakness, and “b” predominantly bulbar weakness. § Three participants in the group
that received prednisone alone and one in the
When we compared prednisone requirements on the basis of prescribed dose instead of pill counts, the pattern favoring
thymectomy over thymectomy group withdrew without completing the baseline Quantitative Myasthenia Gravis (QMG) test.
QMG scores range from 0 to 39, with higher scores indicating more severe disease.
prednisone alone persisted (34 mg vs. 56 mg, P < 0.001) (see the Supplementary Appendix). Similarly, other
findings favored thymectomy over prednisone alone, including the time- weighted average score on the Myasthenia
Gravis Activities of Daily Living scale (2.24 vs. 3.41, P = 0.008), azathioprine use (17% vs. 48% of
516

participants, P<0.001), and the percentage of patients who had minimal-manifestation status at month 36 (67% vs.
47%, P = 0.03) (Table S4 in the Supplementary Appendix). In an analysis that maintained the prednisone dose at the
time that azathioprine was added through month 36, we found that prednisone exposure was 42% lower in the
thymectomy group than in the prednisone-only group (average alternate-day requirement, 33 mg vs. 58 mg;
difference, 25 mg; 95% CI, 13 to 37; P<0.001). Other secondary outcomes (use of plasma exchange, use of intra-
venous immune globulin, Myasthenia Gravis Activities of Daily Living score, minimal-manifestation status, and
hospitalizations at time points before 3 years) are summarized in the Supplementary Appendix.
Unblinding Over the 9-year period of trial visits, six episodes of self-reported unblinding of the rater occurred. One
participant became pregnant, and trial personnel were informed of the treatment-group assignment for safety
reasons. In the other cases, two episodes of unblinding occurred when patients crossed over to the thymectomy
group and three when unblinded personnel performed assessments because the blinded evaluator was unavailable.
Discussion
This trial provides evidence supporting the use of thymectomy for improving clinical outcomes and reducing the
need for immunosuppressive therapy in patients with myasthenia gravis. Over a period of 3 years, thymectomy was
associated with a more favorable outcome than was prednisone alone, with a difference in Quantitative Myasthenia
Gravis scores that correlated with clinically significant improvement.13,14 In this trial, thymectomy was associated
with a score that was 2.85 points lower than that with medical therapy alone. The minimal clinically impor- tant
difference for this scale has not been deter- mined, but in a study assessing the validity of this scale, scores were 2.3
points lower in patients who were assessed by neurologists as having had clinical improvement over time.14 The
time-weighted average required alternate-day prednisone dose was significantly lower in the thymectomy group than
in the prednisone-only group.
A Quantitative Myasthenia Gravis Score
15
12
Prednisone alone 9
6
3
Thymectomy plus prednisone
0
0 63 4 9 12 15 18 21 24 27 30 33 36
Visit Month
B Prednisone Dose
100
80
60
40
20
0
0 421 63 9 12 15 18 21 24 27 30 33 36
Visit Month
Prednisone alone
Thymectomy plus prednisone
Figure 1. Quantitative Myasthenia Gravis Score and Prednisone Dose, According to Treatment Group. Quantitative Myasthenia
Gravis scores range from 0 to 39, with higher scores on each of 13 items indicating more severe disease; a reduction of 2.3 points
correlates with improved clinical status. I bars indicate standard errors.
The finding that prednisone doses at month 36 were higher in each group than might be predicted (according to
routine practice) could be related to the protocol requirement to maintain minimal manifestation of disease and
lower use of glucocorticoid-sparing agents. Patients in the prednisone-only group were more likely than those in the
thymectomy group to be treated with azathioprine. We do not believe that even greater use of glucocorticoid-sparing
immunosuppressive drugs in the prednisone-only group would have negated the improved clinical outcomes that
were associated with thymectomy. Randomized trials of mycophenolate mofetil did not show improved clinical
outcomes when the drug was added to prednisone in patients with myasthenia gravis.18,19 The inability of this trial
517

new The
england journal
of
medicine
Table 2. Primary and Subgroup Analyses of the Primary Outcomes.*
Thymectomy
Estimated Difference Outcome
Prednisone Alone
plus Prednisone
(95% CI)† P Value‡
no. of
no. of value
patients value
patients
Primary analyses
Timeweighted average QMG score over 3yr
8.99±4.93 56 6.15±4.09 62 2.85 (0.47 to 5.22) <0.001 period
Timeweighted average alternateday predni
54±29 56 32±23 61 22 (12 to 32) <0.001 sone dose over 3yr period (mg)
Subgroup analyses
Timeweighted average QMG score
Prednisone use at enrollment 0.86
Yes 9.10±5.06 46 6.30±3.89 47 2.80 (0.11 to 5.49) 0.004
No 8.84±4.60 9 5.66±4.79 15 3.18 (−3.03 to 9.39) 0.12
Sex 0.57
Female 9.73±5.16 38 6.47±4.13 46 3.26 (0.34 to 6.18) 0.002
Male 7.45±4.11 18 5.23±3.95 16 2.22 (−1.96 to 6.40) 0.12
Age at disease onset 0.74
<40 yr 9.60±5.32 34 6.50±4.41 42 3.10 (−0.13 to 6.33) 0.007
≥40 yr 7.85±3.50 18 5.33±2.79 18 2.52 (−0.65 to 5.69) 0.02
Timeweighted average alternateday predni
sone dose (mg)
Prednisone use at enrollment 0.91
Yes 56±31 46 35±25 46 22 (10 to 33) <0.001
No 45±22 9 25±17 15 20 (4 to 37) 0.02
Sex 0.79
Female 54±27 37 33±25 45 21 (9 to 32) <0.001
Male 55±34 19 31±18 16 24 (5 to 42) 0.01
Age at disease onset 0.81
<40 yr 55±30 33 35±25 41 20 (8 to 33) 0.002
≥40 yr 49±29 19 27±18 18 23 (7 to 39) 0.007
* CI denotes confidence interval. † We used 95% confidence intervals in all analyses except for analyses involving the QMG
score, for which we used 99.5% confidence inter
vals, per protocol. ‡ P values for betweengroup comparisons are based on two independent sample Student’s ttests. P values for
interaction with treatment
were based on fitting a general linear model separately for each variable.
to show significant between-group differences
present in 10% of patients with myasthenia gra- among men or
in the subgroup of patients who
vis, and thymectomy is considered to be manda- had not taken
prednisone previously with re-
tory to prevent further spread.21 Up to 70% of spect to the
Quantitative Myasthenia Gravis
the remaining patients with myasthenia gravis score may relate
to the small number of pa-
have hyperplastic thymic changes that are not tients but is worth
further exploration.
seen in healthy persons.20,22 However, the suc- Thymectomy for
the treatment of myasthenia
cess of immunotherapy has raised questions re- gravis is based
on several lines of evidence that
garding whether such an operation is necessary.2 support a
central role of the thymus in the
A U.S. database suggests that hospital admissions pathogenesis
of the disease.20,21 Thymomas are
for thymectomy in patients with myasthenia
518

Table 3. Adverse Events.*
Prednisone
Thymectomy Alone
plus Prednisone Variable
(N = 60)
(N = 66) P Value
No. of events 93 48 <0.001†
≥1 event — no. of patients (%) 33 (55) 25 (38) 0.05‡
Event
Lifethreatening event — no. of patients (%) 7 (12) 1 (2) 0.03§
Disability or incapacity — no. of patients (%)¶ 2 (3) 8 (12) 0.10
Event requiring medical or surgical intervention
5 (8) 9 (14) 0.40 — no. of patients (%)
Death — no. of patients (%) 1 (2) 0 0.48
Complication due to thymectomy — no. of patients (%) NA 1 (2) —
Hospitalization — no. of patients (%) 31 (52) 15 (23) <0.001‡
Hospitalization for exacerbation of myasthenia
22 (37) 6 (9) <0.001‡ gravis — no. of patients (%)
Cumulative no. of hospital days 19.2±24.5 8.4±8.6 0.09
Reason for hospitalization according to MedDRA term
— no. (%)
Gastrointestinal disorder 2 (3) 2 (3) 1.00
Hepatobiliary disorder 1 (2) 0 0.48
Infection or infestation 7 (12) 4 (6) 0.35
Injury, poisoning, or procedure complication 0 2 (3) 0.50
Metabolism or nutrition disorder 0 1 (2) 1.00
Nervous system disorder 22 (37) 8 (12) 0.001‡
Respiratory, thoracic, or mediastinal disorder 2 (3) 1 (2) 0.60
Surgical or medical procedure 7 (12) 0 0.005§
Vascular disorder 1 (2) 0 0.48
* Plus–minus values are means ±SD. MedDRA denotes Medical Dictionary for Regulatory Activities, and NA not applicable. †
The P value is based on Poisson regression that included all 126 patients. ‡ The P value is based on a chisquare test that included
all 126 patients. § The P value is based on Fisher’s exact test that included all 126 patients. ¶ Causes of disability or incapacity in
the group that received prednisone alone included worsening swallowing difficulties and myasthenia gravis; causes in the
thymectomy group included osteoporotic thoracic fracture, ocularmuscle involve ment due to relapsing myasthenia gravis,
postthymectomy diaphragmatic hemiparesis, rib fracture, impending myas thenic crisis, ankle fracture, tear of left knee meniscus,
and low back pain with possible stenosis.
gravis fell dramatically after 2000.23 Planned
pericardial fields.24 In some studies, ectopic thy- analysis of
trial data to assess for correlation
mus has had a negative effect on outcomes at a between
histologic findings and response to
follow-up of more than 7 years.30 Furthermore, thymectomy
have not yet been conducted.
numerous reports describe patients with myas- Extended
transsternal thymectomy requires
thenia gravis as not having clinical improvement median
sternotomy and is associated with a re-
after incomplete thymic resections.31-33 Random- section of 85
to 95% of thymic tissue.11,24 The
ized trials to compare resectional techniques are MGTX did not
test less-invasive thymectomy ap-
needed. proaches that have similar effectiveness and
Potential limitations of our trial include its shorter
postoperative recovery times and better
single-blind nature and the pill-count method. It cosmesis.25-29
One concern is that surgeons who
was deemed unethical to subject control patients use minimally
invasive techniques may leave
to a transsternal sham thymectomy. A clinical behind ectopic
thymic tissue in perithymic and
measure alone could not be used as the primary
519

520
new The
england journal
of
medicine
end point since it would not account for the prednisone use that would be required to achieve minimal-manifestation
status, which can occur with glucocorticoids alone.9 We used pill counts to measure prednisone intake, but pill
counts are not a precise measure of actual intake (for comparison with other methods, see the Supplemen- tary
Appendix).
In conclusion, this randomized, medication- controlled, rater-blinded trial showed a benefit of thymectomy in
patients with myasthenia gravis over a period of 3 years with respect to clinical outcomes, requirements for
prednisone and azathioprine therapy, the number of symptoms and the distress level related to immunosuppressive
agents, and the need for hospitalization to manage disease exacerbations.
Supported by a grant (U01 NS042685) from the National In- stitute of Neurological Disorders and Stroke (NINDS), National
Institutes of Health, and by the Muscular Dystrophy Association and the Myasthenia Gravis Foundation of America.
Dr. Wolfe reports receiving lecture fees and fees for serving on advisory boards from Grifols and Baxalta, consulting fees from
Alpha Cancer Technologies, argenx, and UCB, and grant support from CSL Behring and Alexion Pharmaceuticals; Dr.
Kaminski, receiving fees for serving on data and safety monitoring boards from Genentech and Novartis, consulting fees from
Alnylam Pharmaceuticals, UCB, Chugai Pharma, Rubius Thera- peutics, RA Pharmaceuticals, and Momenta Pharmaceuticals,
receiving serum samples from Rubius Therapeutics, receiving study medication from Genentech, and holding a patent related to
technology to focus a complement inhibitor on the neuromuscu- lar junction for the treatment of myasthenia gravis (U.S. patent
no. 8,961,981); Dr. Evoli, receiving fees for serving on an advisory board from CSL Behring and for serving as a scientific-award
jury member from Grifols; Dr. Beydoun, receiving consulting and lecture fees from Grifols and Baxalta and grant support from
GlaxoSmithKline, Alexion Pharmaceuticals, and CSL Behring; Dr. Vincent, receiving grant support from Glaxo SmithKline, and
royalties from patents related to MuSK antibodies for diagnosis of myasthenia gravis (U.K. patent no., PCT/GB01/02661;
licensed to Athena Diagnostics) and LGI1 and CASPR2 antibodies for autoimmune encephalitis (U.K. patent no.,
PCT/GB2009/051441; licensed to Euroimmun); Dr. Yoshikawa, receiving grant support from Astellas Pharma; Dr.
Waddington-Cruz, receiving consulting fees from Pfizer, Genzyme, and Ionis Pharmaceuticals (for- merly Isis), travel support
from Pfizer, and grant support from Pfizer, Ionis Pharmaceuticals, and Alnylam Pharmaceuticals; Dr. Pulley, receiving personal
fees from Grifols and Mallinckrodt Pharmaceuticals; Dr. Verschuuren, receiving consulting fees from Alexion Pharmaceuticals
and Argenx, paid to his institution, and holding a patent (U.S. patent no. 14/486,400; royalties are paid to his institution) related
to therapy for anti-MuSK myasthenia gravis; and Dr. Cutter, receiving fees for serving on data and safety monitoring boards
from Biogen Idec, Teva Neurosci- ence, Pfizer, Sanofi, Celgene, Gilead Sciences, Neuren Pharma- ceuticals, ModigeneTech,
Opko Biologics, Ono Pharmaceuticals, Merck Serono, GlaxoSmithKline, Horizon Pharma, Reata Phar- maceuticals, and PTC
Therapeutics, fees for serving on a steering committee from MedImmune, fees for serving on advisory boards from EMD Serono,
Novartis, Questcor Pharmaceuticals, Genentech, and Janssen Pharmaceutica, consulting fees from Teva Neuroscience, Genzyme,
Genentech, Transparency Life Sciences, Roche, Opexa Therapeutics, Somahlution, Savara Pharmaceuticals, and Nivalis
Therapeutics, fees from a law firm for providing a legal opinion regarding a patent infringement case on behalf of Galderma, and
grant support to his institution from Teva Neuroscience. No other potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the members of the data and safety monitoring board (Steven Keller, M.D. [chair], Alan Dyer, Ph.D., Donald
Schotland, M.D., John Winer, M.D., and Peter Gilbert, Sc.M. [ex officio]); Audrey Penn, M.D., of the NINDS, Johan Aarli,
M.D., Robert Griggs, M.D., Robert Lisak, M.D., and Lewis Rowland, M.D., for advocating for the trial in its early stages; and the
patients who participated in this trial and were willing to be randomly assigned to either a surgical group or a nonsurgical
group and to adhere to a trial protocol that lasted for years.
Appendix The authors’ full names and academic degrees are as follows: Gil I.
Wolfe, M.D., Henry J. Kaminski, M.D., Inmaculada B. Aban, Ph.D., Greg Minisman, M.A., Hui-Chien Kuo, M.S., Alexander
Marx, M.D., Philipp Ströbel, M.D., Claudio Mazia, M.D., Joel Oger, M.D., J. Gabriel Cea, M.D., Jeannine M. Heckmann, M.B.,
Ch.B., Ph.D., Amelia Evoli, M.D., Wilfred Nix, M.D., Emma Ciafaloni, M.D., Giovanni Antonini, M.D., Rawiphan
Witoonpanich, M.D., John O. King, M.D., Said R. Beydoun, M.D., Colin H. Chalk, M.D., Alexan- dru C. Barboi, M.D., Anthony
A. Amato, M.D., Aziz I. Shaibani, M.D., Bashar Katirji, M.D., Bryan R.F. Lecky, M.D., Camilla Buckley, M.D., Angela
Vincent, M.B., B.S., Elza Dias-Tosta, M.D., Ph.D., Hiroaki Yoshikawa, M.D., Ph.D., Márcia Waddington-Cruz, M.D., Ph.D.,
Michael T. Pulley, M.D., Ph.D., Michael H. Rivner, M.D., Anna Kostera-Pruszczyk, M.D., Robert M. Pascuzzi, M.D., Carlayne
E. Jackson, M.D., Guillermo S. Garcia Ramos, M.D., Jan J.G.M. Verschuuren, M.D., Janice M. Massey, M.D., John T. Kissel,
M.D., Lineu C. Werneck, M.D., Ph.D., Michael Benatar, M.D., Ph.D., Richard J. Barohn, M.D., Rup Tandan, M.D., Tahseen
Mozaffar, M.D., Robin Conwit, M.D., Joanne Odenkirchen, M.P.H., Joshua R. Sonett, M.D., Alfred Jaretzki, III, M.D., John
Newsom-Davis, M.D., and Gary R. Cutter, Ph.D.
The authors’ affiliations are as follows: the Department of Neurology, University at Buffalo Jacobs School of Medicine and
Biomedi- cal Sciences, Buffalo (G.I.W.), the Department of Neurology, University of Rochester Medical Center, Rochester
(E.C.), and the Section of General Thoracic Surgery, Columbia University Medical Center, New York (J.R.S., A.J.) — all in New
York; the Department of Neurol- ogy, George Washington University School of Medicine and Health Sciences, Washington, DC
(H.J.K.); the Department of Biostatistics, University of Alabama at Birmingham, Birmingham (I.B.A., G.M., H.-C.K., G.R.C.);
the Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim (A.M.), the Institute of
Pathology, University of Göttingen, Göttingen (P.S.), and the Department of Neurology, Johannes Gutenberg University, Mainz
(W.N.) — all in Germany; the Department of Neurology, University of Buenos Aires, Buenos Aires (C.M.); the Division of
Neurology, University of British Columbia, Vancouver (J. Oger), and the Department of Neurology, McGill University, Montreal
(C.H.C.) — both in Canada; the Department of Neurology, University of Chile, Santiago (J.G.C.); the Division of Neurology,
Department of Medicine, University of Cape Town, Cape Town, South Africa (J.M.H.); the Department of Neurology, Catholic
University (A.E.), and the Department of Neurosciences, Mental Health and Sensory

Organs, Sapienza University of Rome (G.A.) — both in Rome; the Division of Neurology, Ramathibodi Hospital, Mahidol
University, Bangkok, Thailand (R.W.); the Department of Neurology, University of Melbourne, Melbourne, VIC, Australia
(J.O.K.); the Department of Neurology, University of Southern California, Los Angeles (S.R.B.), and the Department of
Neurology, University of California Irvine Medical Center, Orange (T.M.) — both in California; the Department of Neurology,
Medical College of Wisconsin, Milwaukee (A.C.B.); the Department of Neurology, Harvard Medical School, Boston (A.A.A.);
Nerve and Muscle Center of Texas, Houston (A.I.S.), and the Department of Neurology, University of Texas Health Science
Center, San Antonio (C.E.J.) — both in Texas; the Department of Neurol- ogy, Case Western Reserve University, Cleveland
(B.K.), and the Department of Neurology, Ohio State University Wexner Medical Center, Columbus (J.T.K.) — both in Ohio;
Walton Centre for Neurology and Neurosurgery, Liverpool (B.R.F.L.), and Nuffield Depart- ment of Clinical Neurosciences,
Oxford University, Oxford (C.B., A.V., J.N.-D.) — both in the United Kingdom; Unit of Neurology, University of Brasilia,
Brasilia (E.D.-T.), the Department of Neurology, Federal University, Rio de Janeiro (M.W.-C.), and the Department of
Neurology, Universidade Federal do Parana, Curitiba (L.C.W.) — all in Brazil; the Department of Neurology, Kanazawa
University, Kanazawa, Japan (H.Y.); the Department of Neurology, University of Florida, Jacksonville (M.T.P.), and the
Department of Neurology, University of Miami, Miami (M.B.) — both in Florida; the Department of Neurology, Georgia
Regents University, Augusta (M.H.R.); the Department of Neurology, Medical University of Warsaw, Warsaw, Poland (A.K.-P.);
the Department of Neurology, Indiana School of Medicine, Indianapolis (R.M.P.); the Department of Neurology and Psychiatry,
Instituto Nacional de la Nutrición, Tlalpan, Mexico (G.S.G.R.); the Department of Neurology, Leiden University Medical Center,
Leiden, the Netherlands (J.J.G.M.V.); the Department of Neurology, Duke University Medical Center, Durham, NC (J.M.M.);
the Department of Neurology, University of Kansas Medical Center, Kansas City (R.J.B.); the Department of Neurological
Sciences, University of Vermont College of Medicine, Burlington (R.T.); and the Division of Extramural Research, National
Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C., J. Odenkirchen).
References 1. Blalock A, Harvey AM, Ford FR, Lilien- thal JL. The treatment of myasthenia gravis by removal of the thymus
gland. JAMA 1941; 117: 1529-33. 2. McQuillen MP, Leone MG. A treatment carol: thymectomy revisited. Neurol- ogy 1977;
27: 1103-6. 3. Oosterhuis HJ. Observations of the natural history of myasthenia gravis and the effect of thymectomy. Ann N Y
Acad Sci 1981; 377: 678-90. 4. Rodriguez M, Gomez MR, Howard FM Jr, Taylor WF. Myasthenia gravis in children: long-term
follow-up. Ann Neu- rol 1983; 13: 504-10. 5. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis.
Muscle Nerve 2008; 37: 141-9. 6. Lanska DJ. Indications for thymectomy in myasthenia gravis. Neurology 1990; 40: 1828-9. 7.
Cea G, Benatar M, Verdugo RJ, Sali- nas RA. Thymectomy for non-thymomatous myasthenia gravis. Cochrane Data- base Syst
Rev 2013; 10: CD008111. 8. Gronseth GS, Barohn RJ. Practice pa- rameter: thymectomy for autoimmune myasthenia gravis (an
evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology
2000; 55: 7-15. 9. Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116
patients. Ann Neurol 1984; 15: 291-8. 10. Healthcare Cost and Utilization Proj- ect: nationwide inpatient sample. Rock- ville,
MD: Agency for Healthcare Research and Quality (http://www .hcup-us .ahrq .gov/ ). 11. Jaretzki A III, Barohn RJ, Ernstoff RM,
et al. Myasthenia gravis: recommen- dations for clinical research standards. Neurology 2000; 55: 16-23. 12. Newsom-Davis J,
Cutter G, Wolfe GI, et al. Status of the thymectomy trial for
nonthymomatous myasthenia gravis patients receiving prednisone. Ann N Y Acad Sci 2008; 1132: 344-7. 13. Barohn RJ,
McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliabil- ity testing of the Quantitative Myasthenia Gravis score. Ann
N Y Acad Sci 1998; 841: 769-72. 14. Bedlack RS, Simel DL, Bosworth H, Samsa G, Tucker-Lipscomb B, Sanders DB.
Quantitative Myasthenia Gravis score: assessment of responsiveness and longi- tudinal validity. Neurology 2005; 64: 1968- 70.
15. Moons P, De Geest S, Abraham I, Cleemput JV, Van Vanhaecke J. Symptom experience associated with maintenance
immunosuppression after heart trans- plantation: patients’ appraisal of side effects. Heart Lung 1998; 27: 315-25. 16. Wolfe GI,
Herbelin L, Nations SP, Fos- ter B, Bryan WW, Barohn RJ. Myasthenia Gravis Activities of Daily Living profile. Neurology
1999; 52: 1487-9. 17. Muppidi S, Wolfe GI, Conaway M, Burns TM. MG-ADL: still a relevant outcome measure. Muscle
Nerve 2011; 44: 727-31. 18. Muscle Study Group. A trial of mycophenolate mofetil with prednisone as ini- tial immunotherapy
in myasthenia gravis. Neurology 2008; 71: 394-9. 19. Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III,
randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008; 71: 400-6. 20. Conti-Fine BM,
Diethelm-Okita B, Ostlie N, Wang W, Milani M. Immuno- pathogenesis of myasthenia gravis. In: Kaminski HJ, ed. Myasthenia
gravis and related disorders. New York: Humana Press, 2009: 43-70. 21. Drachman DB. Myasthenia gravis. N Engl J Med 1994;
330: 1797-810.
22. Berrih-Aknin S, Le Panse R. Myas- thenia gravis: a comprehensive review of immune dysregulation and etiological
mechanisms. J Autoimmun 2014; 52: 90- 100. 23. Alshekhlee A, Miles JD, Katirji B, Preston DC, Kaminski HJ. Incidence and
mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurol- ogy 2009; 72: 1548-54. 24. Jaretzki A III
Thymectomy for myasthenia gravis: analysis of the controver- sies regarding technique and results. Neurology 1997; 48: Suppl
5: S52-63. 25. Lee CY, Kim DJ, Lee JG, Park IK, Bae MK, Chung KY. Bilateral video-assisted thoracoscopic thymectomy has a
surgical extent similar to that of transsternal extended thymectomy with more favorable early surgical outcomes for myasthenia
gravis patients. Surg Endosc 2011; 25: 849- 54. 26. Mack MJ, Landreneau RJ, Yim AP, Ha- zelrigg SR, Scruggs GR. Results of
video- assisted thymectomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg 1996; 112: 1352-9. 27. Mantegazza
R, Baggi F, Bernasconi P, et al. Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy
(T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of follow-up. J Neurol Sci 2003; 212: 31-6. 28.
Rückert JC, Swierzy M, Ismail M. Com- parison of robotic and nonrobotic thoracoscopic thymectomy: a cohort study. J Tho-
rac Cardiovasc Surg 2011; 141:673-7. 29. Shrager JB, Deeb ME, Mick R, et al. Transcervical thymectomy for myasthenia gravis
achieves results comparable to thymectomy by sternotomy. Ann Thorac Surg 2002; 74: 320-6. 30. Ponseti JM, Gamez J,
Vilallonga R, et al. Influence of ectopic thymic tissue
521

522
on clinical outcome following extended thymectomy in generalized seropositive nonthymomatous myasthenia gravis. Eur J
Cardiothorac Surg 2008; 34: 1062-7. 31. Jaretzki A III, Penn AS, Younger DS, et al. “Maximal” thymectomy for myas-
thenia gravis: results. J Thorac Cardiovasc Surg 1988; 95: 747-57. 32. Masaoka A, Monden Y, Seike Y, Tanio- ka T, Kagotani K.
Reoperation after transcervical thymectomy for myasthenia gravis. Neurology 1982; 32: 83-5.
33. Miller RG, Filler-Katz A, Kiprov D, Roan R. Repeat thymectomy in chronic refractory myasthenia gravis. Neurology 1991;
41: 923-4. Copyright © 2016 Massachusetts Medical Society.

Nejmoa1602489 PDF

Uploaded by

Copyright:

Available Formats

Nejmoa1602489 PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Nejmoa1602489 PDF

Uploaded by

Copyright:

Available Formats

new journal

August 11, 2016

Randomized Trial of Thymectomy in Myasthenia Gravis

You might also like