Neurol Sci (2017) 38:1753–1760
DOI 10.1007/s10072-017-3058-7
ORIGINAL ARTICLE
Thymectomy is a beneficial therapy for patients
with non-thymomatous ocular myasthenia gravis: a systematic
review and meta-analysis
Kai Zhu 1,2 & Jiaoxing Li 1,2 & Xin Huang 1,2 & Wei Xu 1,2 & Weibin Liu 1,2 & Jiaxin Chen 1,2 &
Pei Chen 1,2 & Huiyu Feng 1,2
Received: 17 March 2017 / Accepted: 1 July 2017 / Published online: 13 July 2017
# Springer-Verlag Italia S.r.l. 2017
Abstract Ocular myasthenia gravis, an autoimmune dis-
ease, is characterized by extraocular muscle weakness.
Myasthenia gravis is closely associated with the functional
status of the thymus gland. The efficacy of thymectomy for
non-thymomatous ocular myasthenia gravis remains con-
troversial. Here, we present the first systematic review and
meta-analysis of studies assessing the outcome of thymec-
tomy in patients with non-thymomatous ocular myasthenia
gravis and found that the pooled rate of complete stable
remission was 0.5074 with considerable heterogeneity.
Furthermore, subgroup analysis showed that the efficacy
of thymectomy differed according to geographical loca-
tion. Furthermore, thymectomy outcomes are better in chil-
dren than they are in adults. Thymectomy clearly repre-
sents an effective treatment for patients with non-
thymomatous ocular myasthenia gravis. However, more
multicenter, randomized, controlled clinical trials are now
required to confirm these conclusions.
Keywords Ocular . Myasthenia gravis . Thymectomy .
Non-thymomatous . Meta-analysis
Kai Zhu and Jiaoxing Li contributed equally to this work.
* Huiyu Feng
mgsysu@163.com
1
Department of Neurology, the First Affiliated Hospital, Sun Yat-sen
University, 58 Zhongshan 2nd Road, Guangzhou 510080, China
2
Guangdong Provincial Key Laboratory for Diagnosis and Treatment
of Major Neurological Disease, Guangdong, China
Introduction
Myasthenia gravis (MG) is an autoimmune disease that in-
volves neuromuscular junction acetylcholine receptors
(AChRs) on the postsynaptic membrane and is both
antibody- and complement-mediated [1]. The clinical man-
ifestations of this condition include extraocular muscle
weakness manifesting as eyelid ptosis and diplopia. The
diagnosis is ocular myasthenia gravis (OMG) in patients
without other muscle weakness [2]. Approximately 50%
of patients with OMG develop generalized myasthenia
gravis (GMG), which involves other muscles and manifests
as limb weakness and bulbar symptoms, within a 2-year
period [3]. The incidence of OMG is high in China, espe-
cially in children [4], and the pathogenesis of OMG and
GMG may differ. OMG is not a life-threatening disease.
The aims of treatment for OMG are currently to improve
vision and to prevent progression to GMG. Currently avail-
able pharmacotherapies include acetylcholinesterase inhib-
itor drugs, corticosteroids, and immunosuppressants. MG is
by far the most widely reported autoimmune disease asso-
ciated with the functional status of the thymus gland.
Approximately 70% of MG patients have hyperplasia of
the thymus and around 10% have a thymoma [5].
Thymectomy is considered the mainstay therapy for pa-
tients with OMG and thymomas. However, it remains con-
troversial as to whether thymectomy is essential for patients
with OMG without thymomas. Some researchers believe
that early surgery not only improves symptoms but also
prevents progression to GMG [6–9]. However, two studies
have failed to show any significant improvement in ocular
symptoms or a reduction in the risk of developing GMG
after thymectomy [10, 11]. In this systematic review and
meta-analysis, we assessed the efficacy of thymectomy in
patients with non-thymomatous OMG.
1754 Neurol Sci (2017) 38:1753–1760

Methods Statistical analysis

We performed this review in accordance with the Preferred
Reporting Items for Systematic reviews and Meta-Analyses
(PRISMA) statement [12]. We systematically searched the
following databases: Pubmed, the Cochrane Library, Web of
Science, EMBASE, the Chinese National Knowledge
Infrastructure database, and the WANFANG DATA database,
for all relevant publications between 1 January 1996 and 31
December 2016. The search terms included myasthenia
gravis, ocular or eye or visual, surgery or thymectomy or
therapy, and non-thymomatous.
Selection criteria
We used the Metaprop module of R-3.3.1 statistical software
(Free Software Foundation, Boston, MA, USA) to carry out
our meta-analysis. We converted the reported CSR rates from
logit to pooled data [18]. To assess for heterogeneity between
studies, we calculated I2 statistics. When the I2 statistic was
<50% and the p value for heterogeneity was >0.10, we chose a
fixed-effect model to pool CSR rates. In studies where I2 was
>50% and the p value was <0.10, we used a random-effect
model to pool CSR rates. We also performed Begg’s rank
correlation and Egger’s Test to evaluate potential publication
bias [19].

The selection criteria were as follows: (1) symptoms associat-

Results
ed with ocular muscle fatigue, including ptosis and diplopia,
in accordance with the criteria of the Myasthenia Gravis
Study selection
Foundation of America (MGFA) [13] and Osserman diagnos-
tic criteria [14]; (2) pathologically confirmed non-
Electronic searches of the selected databases yielded 4870
thymomatous disease; (3) all thymectomy procedures, includ-
papers, including 2919 published in English and 1951 in
ing video-assisted thoracoscopic surgery (VATS) and trans-
Chinese. By screening titles and abstracts, we firstly excluded
sternal thymectomy (TS); (4) randomized controlled trials
case reports, reviews, and duplicates, leaving 1308 papers for
(RCTs), cohort studies, or observational studies; and (5) the
full-text review. Secondly, we excluded papers in which
rate of complete stable remission (CSR).
thymomas were not pathologically confirmed, or where we
were unable to separately access data for patients with non-
Exclusion criteria thymomatous OMG. Finally, 26 papers reporting 640 patients
met the selection criteria and were subjected to systematic
The exclusion criteria were as follows: (1) comorbidities in-
cluding infections; (2) absence of other autoimmune diseases
(excluding hyperthyroidism); (3) inability to extract data of
patients with non-thymomatous OMG from all cases of
OMG; and (4) inability to extract data of patients with OMG
from all cases of non-thymomatous myasthenia gravis.

Data extraction

Two researchers independently filtered published reports by

screening titles and abstracts and subsequently reviewed the
full texts of papers that met the selection criteria. Articles that
unequivocally conformed to the inclusion criteria were includ-
ed. The researchers assessed the quality of the studies on the
basis of guidelines provided by Meta-analysis of
Observational Studies in Epidemiology (MOOSE) [15] and
Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) [16, 17]. The two researchers re-
solved disagreements between them by repeated discussion.
Data extracted from the articles included the first author’s
name, publication year, country or district, mean patient age,
diagnostic criteria, sample size, and CSR rate. When neces-
sary, simple calculations were performed to determine CSR
rate. Fig. 1 Meta-analysis flow chart of search strategy
Neurol Sci (2017) 38:1753–1760 1755

review and meta-analysis (Fig. 1). All eligible papers were
single-center, retrospective, observational studies. The charac-
teristics of the included papers are presented in Table 1.
CSR rate pooled in thymectomy in non-thymomatous
ocular myasthenia gravis
0.4954 (95% CI 0.3782–0.6131), as shown in Fig. 3a.
The pooled CSR of the 12 papers [9, 20, 21, 24–27, 31,
34, 35, 43, 44] reporting patients in other countries was
0.5876 (95% CI 0.5142–0.6573), as shown in Fig. 3b;
these results were less heterogeneous (I2 = 46.6%, 95%
CI 0.0–72.6%).

The 26 eligible studies reported the outcomes of thymectomy

in patients with non-thymomatous OMG [9, 20–44]. The
pooled CSR rate was 0.5074 (95% confidence interval [CI]
0.4196–0.5947), as shown in Fig. 2. To explore the source of
heterogeneity, we performed subgroup analysis as follows.
Chinese patients vs. patients from other countries
Fourteen studies [22, 23, 28–30, 32, 33, 36–42] provid-
ed CSRs for Chinese patients. Their pooled CSR was
Juvenile vs. adult patients
Age is an important epidemiological indicator of myas-
thenia gravis. Data for pediatric patients were provided
in 10 papers [22, 23, 29, 30, 32, 33, 38, 40, 42, 44].
Their pooled CSR rate was 0.5749 (95% CI 0.3953–
0.7367) with statistically significant heterogeneity
(I2 = 82.7%, 95% CI 69.5–90.2%), as shown in Fig.
4a. In contrast, the CSR rate in adults [9, 20, 24, 27,
31, 34, 36, 41, 43] was 0.4561 (95% CI 0.3041–0.6167)

Table 1 Characteristics of studies included in meta-analysis

Author Countries and Study Interventions Patients Total Patients Patients Classification Mean
regions period AChR-Ab number included CSR age
positive of patients

Tommaso Italy 2005–2012 TS NA 68 6 1 MGFA 41.1

Huang China Taiwan 1995–2010 TS 1 151 3 1 Osserman 47.7
Cheng China Guangdong 1990–2010 TS 69 141 96 24 MGFA 12
Tommaso Italy 1980–2007 TS NA 47 47 30 MGFA 19
Li China Guangdong 2003–2009 TS 36 59 36 25 Osserman 9.7
Tyson.L Australia 1997–2010 TS/VATS 3 12 4 3 MGFA 10.5
Liu China Guangdong 2006–2008 TS 61 115 105 49 MGFA NA
Xie China Hubei 1998–2007 TS NA 31 24 19 Osserman 8.4
Eugenio Italy 1995–2008 VATs NA 32 7 2 MGFA NA
Christos Greece 1990–2007 TS NA 78 9 5 Osserman 34.92
Lin China Taiwan 1995–2004 TS/VATS NA 60 22 7 MGFA NA
Deng China Zhejiang 1998–2009 TS NA 135 39 11 Osserman 8.67
Luo China Hainan 1998–2006 TS NA 52 24 14 Osserman 10.9
Wang China Hebei NA TS 10 10 10 3 Osserman 8.1
Federico Italy 2002–2004 VATS 15 33 5 1 Osserman 38
Marcin Poland 1967–2003 TS NA 118 5 3 Osserman 29
Lu China Guangdong 1997–2002 TS NA 18 18 4 Osserman 8.67
Tan China Guangdong 1978–2002 TS NA 43 24 17 Osserman 8.2
Zhang China 1982–2000 TS NA 20 12 6 Osserman NA
Henan/Jiangsu
Turkan Turkey 1980–2001 TS NA 204 13 9 Osserman NA
Rana India 1990–2002 TS NA 56 4 1 Osserman NA
Peter.F America/Italy 1970–1998 TS NA 61 49 35 Osserman 37
Chen China Chongqing 1979–1996 TS NA 19 11 7 Osserman 7.7
Hiroshige Japan 1971–1993 TS 8 22 22 7 NA 34.3
Akira Japan 1973–1993 TS NA 375 31 20 NA NA
Tong China Jilin 1983–1994 TS NA 24 14 12 Osserman 7.6

AChR-Ab acetylcholine receptor antibody, CSR complete stable remission, TS trans-sternal thymectomy, VATS video-assisted thoracoscopic surgery,
MGFA Myasthenia Gravis Foundation of America, NA not available
1756
Fig. 2 Forest plots for CSR of
overall patients
with less heterogeneity (I2 = 68.9%, 95% CI 37.8%–
84.5%), as shown in Fig. 4b.
Western vs. Asian countries
We also compared geographical location and race or ethnicity
and found that the CSR rate in Asian patients was 0.4871
(95% CI 0.3828–0.5925) with clear heterogeneity
(I2 = 75.3%, 95% CI 60.4–84.6%), as shown in Fig. 5a
[20–23, 25, 28–30, 32, 33, 36–42]. The pooled CSR of report-
ed patients from Europe, America, and Oceania [9, 24, 26, 27,
31, 34, 35, 43, 44] was 0.6239 (95% CI 0.5383–0.7025) with
medium heterogeneity (I2 = 32.9%, 95% CI 0.0%; 69.1%), as
shown in Fig. 5b.
Fig. 3 Forest plots for subgroup analysis of Chinese patients vs. patients from other countries
Neurol Sci (2017) 38:1753–1760
Publication bias
We constructed a Begg funnel plot (Fig. 6a) using R-3.3.1
statistical software. We also quantified publication bias
using Egger’s test (t = 0.29912, df = 24, p = 0.7674), as
shown in Fig. 6b. The regression curve produced did not
pass the original point, suggesting that our research was
associated with at least some publication bias.
Discussion
Our analysis of 26 papers revealed a pooled CSR rate for 640
patients with non-thymomatous OMG of 0.5074; however,
Neurol Sci (2017) 38:1753–1760
Fig. 4 Forest plots for subgroup analysis of juvenile vs. adult patients
there was obvious heterogeneity. The thymus may trigger au-
toimmunity against AChRs; thus, its removal may eliminate
the main source of antibody production against AChRs.
However, 50% of patients with OMG remain AChR anti-
body-negative, indicating that the thymus is not the cause of
OMG in such patients. Thymectomy in patients with non-
thymomatous OMG has not conclusively been shown to be
of benefit.
Our subgroup analysis showed that the CSR rate after thy-
mectomy was slightly lower in Chinese patients with OMG
than in patients from other countries. Additionally, the CSR
rate was higher in children than in adults, and higher in pa-
tients with OMG in Europe and America than in Asian pa-
tients, in whom findings were more homogeneous. Our anal-
ysis showed that thymectomy is an effective treatment for
patients with non-thymomatous OMG. Furthermore, we
found that thymectomy is more effective in Europe and the
USA than in Asia, which may be attributable to the higher
levels of medical care in these regions. Thymectomy out-
comes were also better in pediatric than adult patients, the
former having fewer complications and shorter courses after
thymectomy.
To our knowledge, this is the first systematic review and
meta-analysis of non-thymomatous OMG and thymectomy. A
Fig. 5 Forest plots for subgroup analysis of Western vs. Asian countries
1757
recently completed multi-center randomized trial of thymec-
tomy for MG showed that thymectomy improved prognosis
[45]. Thymectomy achieves long-term CSR in 47.3% of pa-
tients with long-term follow-up [46]. Other, more analytical,
observational studies are somewhat flawed in that they merge
patients with GMG and thymoma rather than providing data
for non-thymomatous OMG alone. Another confounding fac-
tor is differences in baseline patient characteristics between
different studies. There is also a lack of predictors for the
likelihood of patients with OMG developing GMG.
Thymectomy is often used in conjunction with immunosup-
pressive therapy, making assessment of the efficacy of thy-
mectomy difficult.
Serological features, especially the AChR antibody, repre-
sent critical data for MG patients [47]. Due to the lack of
antibody detection technology in the early years, only 6 arti-
cles reported data relating to AChR antibodies: 36 patients
which were antibody positive in Li’s study [42], 61 patients
in Liu’s study [39], 69 patients in Cheng’s study [40], and 15
patients in Federico’s study [31]. These studies involved large
sample sizes and are therefore consistent with our previous
research [48]. This data therefore representative and can serve
as a reference for positive antibody rates. Our previous study
[48] indicated that OMG patients have a lower AChR-Ab
1758
Fig. 6 Publication bias
positive rate. Therefore, there is no certain correlation between
AChR antibody titer and disease severity, although we should
never neglect cases of seropositive OMG.
We believe that it is necessary to discuss thymectomy
with patients with non-thymomatous OMG for the fol-
lowing reasons. Firstly, most patients with OMG are
children in China [49, 50]. Both surgery and medical
intervention inevitably influence growth and develop-
ment. Because surgery carries higher risks than medical
treatment, treatment decisions should be made cautious-
ly. Secondly, because of the higher cost of the surgery,
we do not recommend this approach over other types of
medical treatment if their efficacy is similar. Thirdly, it
remains uncertain as to whether surgery or drug therapy
can prevent the progression of OMG to GMG because
the course of OMG is so variable.
The limitations of this study include the following. The
poor quality of the evidence included in the review ham-
pers any meaningful conclusion relating to the efficacy of
thymectomy for non-thymomatous OMG. Furthermore, the
EPITOME trial of OMG had to close recently because of a
failure to recruit sufficient patients [51]. Moreover, there are
still no publications describing high-quality clinical research
on OMG. A recently completed MG multi-center clinical
trial has, however, highlighted new developments in OMG
treatment.
With the development of thoracoscopy, thymectomy is saf-
er and involves less trauma than previously. Federico et al.
[31], and Eugenio et al. [35], reported 12 patients in which
thymectomy was performed by thoracoscopy: of these, 3 pa-
tients achieved CSR. However, due to the small sample size,
we were not able to perform subgroup analysis. Federico et al.
[31] and Lin et al. [37] also reported that thymectomy by
thoracoscopy provides minimally invasive trauma with a bet-
ter probability of attaining CSR. Several systematic reviews of
thoracic surgery have highlighted that thoracoscopy thymec-
tomy increases surgical safety and achieves an equal surgical
Neurol Sci (2017) 38:1753–1760
efficacy in thymoma patients [52–54]. The difference in risk
between surgical and medical treatment has therefore decreased.
Unfortunately, drawing any conclusions about non-
thymomatous patients is currently limited by the lack of appro-
priate research.
For neurologists, taking account of time latency between
MG and thymectomy is both meaningful and valuable. Four
studies [26, 33, 38, 39] reported significantly better remission
rates when thymectomy was performed within the first
12 months of symptom onset, although one study [30] ob-
served that the duration of illness before operation had no
relevance to the CSR. Further clinical studies are now needed
to evaluate the precise time course of thymectomy. Nevertheless,
performing thymectomy early in the disease process is very worthy
of consideration [55].
Finally, further multicenter, randomized, controlled clinical
trials are now required to fully determine the efficacy of thy-
mectomy and medicinal therapy for patients with non-
thymomatous OMG. We believe that our current findings will
draw attention to the management of non-thymomatous OMG
and stimulate more clinical trials.
Acknowledgments This work was supported by the Project of
Guangzhou Science Technology and Innovation Commission (grant
number 201605122112149), the Undergraduate teaching reform project
of Sun-Yat Sen university (grant number 8000031911105), and
Guangdong graduate education innovation program (grant number
2015QTLXXM05).
Compliance with ethical standards
Conflicts of interest The authors declare that they have no con-
flict of interest.
Neurol Sci (2017) 38:1753–1760
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