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Journal of Neuroimmunology xxx (2017) xxx–xxx

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Journal of Neuroimmunology

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Effect of thymectomy for thymic atrophy in myasthenia gravis: A


retrospective study on 93 patients
Keiichi Nakahara a, Shunya Nakane a,b,⁎, Makoto Nakajima a, Satoshi Yamashita a, Takeshi Mori c, Yukio Ando a
a
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
b
Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto, Japan
c
Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

a r t i c l e i n f o a b s t r a c t

Article history: To clarify the efficacy of thymectomy among myasthenia gravis (MG) patients with and without thymoma. We
Received 25 October 2016 classified MG patients who underwent thymectomy into 3 groups, such as thymic atrophy group, thymic follic-
Received in revised form 22 December 2016 ular hyperplasia (TFH) group and thymoma group. We compared the data of clinical features and postoperative
Accepted 11 January 2017
prognosis at very short-term, short-term, and medium-term. The clinical course of MG patients with atrophic
Available online xxxx
thymus after thymectomy was even better than those of TFH or thymoma, in this retrospective study. However,
Keywords:
we found no significant differences in the comparison of mean dose of prednisolone between the 3 groups at each
Myasthenia gravis time point.
Thymus pathology © 2017 Published by Elsevier B.V.
Thymectomy
Anti-acetylcholine receptor antibody
Prednisolone

1. Introduction 2. Materials and methods

Myasthenia gravis (MG) is an autoimmune disease of the neuromus- 2.1. Subjects


cular junction characterized by muscle weakness, production of anti-
bodies against skeletal muscle acetylcholine receptors (AChRAb), and We retrospectively reviewed the clinical records of 178 patients
frequent clinical response to therapeutic thymectomy (Gilhus and (male: 56, female: 122; average age: 53.9 ± 20.6) with confirmed MG,
Verschuuren, 2015). Thymomatous MG is the clinical setting in which who attended Kumamoto University Hospital, between April 2005 and
therapeutic thymectomy is routinely performed. However, it remains September 2015. Diagnosis of MG was based on clinical findings (fluctu-
unproven whether thymectomy is effective or not in non-thymomatous ating symptoms with easy fatigability and recovery after rest) with
MG, especially in cases of thymic atrophy. Although a randomized con- amelioration of symptoms after intravenous administration of anticho-
trolled trial (the MGTX study) reported the impact of thymectomy on linesterase, decremental muscle response to a train of low-frequency
myasthenic symptoms in patients with non-thymomatous MG (Wolfe repetitive nerve stimuli, or the presence of AChRAb. To avoid potential
et al., 2016), we should elucidate the relationship between the efficacy bias, we enrolled patients in various stages of illness in this single center
of thymectomy, thymus pathology, and the treatment requirements. cross-sectional study. Of these patients with MG, 96 patients with
To clarify the association with thymus pathology and the postoperative thymomatous MG or generalized non-thymomatous MG underwent
prognosis, we conducted a retrospective study on patients diagnosed thymectomy using the median sternotomy approach, until January
with MG in a decade. We classified MG patients into 3 groups, such as 2007, after when we adopted the video-assisted thoracoscopic surgery
thymic atrophy group, thymic follicular hyperplasia (TFH) group and approach, and identified thymic pathology (Mori et al., 2007;
thymoma group, based on the pathological findings. We evaluated clin- Yoshioka et al., 2006). As this study was based on detailed information
ical characteristics, as well as treatments and prognosis among the 3 for the entire course of treatment, 3 patients were excluded for insuffi-
groups. cient data. Finally, 93 MG patients were analyzed.
Serum AChRAb titers were determined by a radioimmunoassay
using 125I-a-bungarotoxin, and levels of 0.3 nmol/L were regarded as
⁎ Corresponding author at: 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan. positive. Muscle-specific tyrosine kinase antibodies positive MG and se-
E-mail addresses: 97056kn@gmail.com (K. Nakahara), nakaneshunya@gmail.com
(S. Nakane), nakazima04@gmail.com (M. Nakajima),
ronegative MG patients were excluded from this study.
yamashitasatosi@fc.kuh.kumamoto-u.ac.jp (S. Yamashita), The following basic patient information was collected: gender; age;
morimori@fc.kuh.kumamoto-u.ac.jp (T. Mori), andoy709@kumamoto-u.ac.jp (Y. Ando). age at onset; disease duration; MG Foundation of America (MGFA)

http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
0165-5728/© 2017 Published by Elsevier B.V.

Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
2 K. Nakahara et al. / Journal of Neuroimmunology xxx (2017) xxx–xxx

classification (Jaretzki et al., 2000); and AChRAb status. MGFA classifica- Table 1
tion was based on Chest CT scans were performed for diagnosis of MG to Clinical features of patients with MG at pre-thymectomy and operative procedure.

screen for thymomas. The degree of TFH of the thymus was classified Thymic
into 5 grades according to the classification of the MG study group of Thymic follicular
the Ministry of Health and Welfare of Japan in 1977: grade 0, involuted atrophy hyperplasia Thymoma
group group group p-Value
thymus; grade I, accumulation of lymphocytes in the distended medul-
la; grade II, 1 follicle in 1 section; grade III, 2 to 4 follicles in 1 section; Number of patients 25 29 39
Age (yr) 64.1 43.8 ± 18.0 59.9 b0.001
and grade IV, N 5 follicles in 1 section or N1 follicle in each lobule. We de-
± 13.6 ± 12.3
fined grade 0 or grade I as thymic atrophy, and grade II or above as TFH Age at onset (yr) 59.5 37.8 ± 17.2 54.6 b0.001
in non-thymomatous MG. Treatment-related information included: ± 13.4 ± 12.6
MGFA post-intervention (PI) status (Jaretzki et al., 2000); age at thy- Late onset MG (%) 20 (80) 6 (21) 29 (76) b0.001
mectomy; thymic histology; current prednisolone (PSL) dose; course Age at thymectomy (yr) 60.8 39.1 ± 17.0 55.3 b0.001
± 12.7 ± 12.3
of PSL dose; use of calcineurin inhibitors (CNIs); use of pyridostigmine; Sex, female (%) 14 (56) 24 (83) 28 (72) 0.163
steroid pulse therapy; plasmapheresis (PP); and intravenous immuno- MGFA I (%) 0 (0) 2 (7) 7 (18) 0.339
globulin (IVIg). Histological analyses of the thymus were performed classification II (%) 24 (96) 23 (80) 26 (67)
after thymectomy. In the present study, diagnoses of thymic atrophy, III (%) 0 (0) 3 (10) 3 (8)
IV (%) 0 (0) 0 (0) 0 (0)
TFH and thymoma were made by pathologists, certified by the Japanese
V (%) 1 (4) 1 (3) 1 (2)
Society of Pathology, in our institute (Kondo and Monden, 2005). Unclassified 0 (0) 0 (0) 2 (5)
We classified the MG patients who underwent thymectomy into 3 (%)
groups, such as thymic atrophy group, TFH group and thymoma Anti-AChR Ab (nmol/L) 27.9 354.3 ± 1084.6 51.2 0.015
group, based on pathological findings. We compared the data of clinical ± 28.7 ± 69.4
PSL (mg) 1.2 ± 6.0 3.7 ± 9.6 5.1 0.198
features and thymectomy outcomes among pre-thymectomy, 1 month,
± 11.7
1 year, and 3 years after thymectomy. Tacrolimus (mg) 0.0 ± 0.0 0.0 ± 0.0 0.1 ± 0.5 0.494
Cyclosporin A (mg) 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.000
2.2. Statistics VATS for thymectomy (%) 16 (64) 18 (62) 10 (26) 0.002

MG = myasthenia gravis; MGFA = MG foundation of America; anti-AChRAb = anti-ace-


Commercially available statistical software was used for data analy- tylcholine receptor antibodies; PSL = prednisolone; VATS = video-assisted thoracoscopic
sis (SigmaPlot®). Data that were normally distributed were analyzed by surgery.

one-way ANOVA. Pairwise comparisons were evaluated by Student-


Newman-Keuls methods. For data that was not normally distributed,
one-way ANOVA was used to provide ranking. Comparisons with TFH group, and thymoma group significantly improved over time
p b 0.05 were considered to be significantly different. We undertook sta- (p b 0.001, respectively, Fig. 1). And, significant differences were
tistical analysis of MGFA PI status at 1 year and 3 years only, because, for found among the 3 groups at the time points of 1 year and 3 years
example, “CSR” is defined as the status of the patients has had no symp- after thymectomy (p = 0.002, and b 0.001, respectively, Fig. 1). “Red”
toms or signs of MG for at least 1 year and has received no therapy for subgroup in each group, especially in the thymic atrophy group has in-
MG during that time. However, we consciously evaluated MGFA PI sta- creased yearly in the postoperative clinical course. In regard to serum
tus at 1 month to illustrate the trend of postoperative clinical course in a AChRAb, in the TFH group, mean titer was significantly higher than in
comprehensible way. the other 2 groups at the baseline, and it decreased with significant dif-
ference at the time point of first postoperative month, compared to the
3. Results thymic atrophy group and thymoma group (p = 0.022, 0.053, and
0.123, respectively, Fig. 2). In those days, we gradually increased oral
Of 93 MG patients (27 males and 66 females; 56 ± 17 years old) who PSL for patients with MG, but we found no significant differences in
underwent thymectomy, patients with thymic atrophy were 25 (27%), the comparison of mean dose of oral PSL among the 3 groups at each
patients with TFH were 29 (31%), and patients with thymoma were time point of postoperative state (p = 0.287, 0.576, and 0.705, respec-
39 (42%). Clinical features at the baseline of patients with MG and oper- tively, Fig. 3). No statistical significance was also detected in mean
ative procedure are summarized in Table 1. In the TFH group, age, age at dose of CNIs among the 3 groups at each time point.
onset and age at thymectomy are significantly lower, and serum
AChRAb titers were significantly higher than the other 2 groups. More- 4. Discussion
over, the number of late onset MG cases was significantly fewer in the
TFH group, compared to the thymic atrophy group and thymoma The MGTX trial could elucidate the efficacy of thymectomy in pa-
group (Uzawa et al., 2015). The results of the chest CT scan in each tients with non-thymomatous MG (Wolfe et al., 2016; Aban et al.,
group were as follows; in the group of thymic atrophy, thymic atrophy 2008; Newsom-Davis et al., 2008; Marx et al., 2012). In the present
was identified in 22 patients (88%) and residual thymus was identified study, we explored outcome of MG, changes of AChRAb titers, and med-
in 3 patients (12%). In the TFH group, thymic atrophy was identified in ication usage in depth, based on thymic histology. We demonstrated
9 patients (33%), residual thymus was identified in 14 patients (52%) that all 3 groups demonstrated an improved long-term outcome by thy-
and swelling of thymus was identified in 4 patients (15%) (we could mectomy, even thymic atrophy group. “Red” subgroup including CSR,
not confirm CT scans in 2 patients). Moreover, in the thymoma group, PR, and MM in MGFA PI status existed in each group, especially in the
thymoma was identified in 34 patients (97%) and nodule was identified thymic atrophy group. We found statistical differences in MGFA PI sta-
in 1 patient (3%), after excluding 5 patients that we could not confirm CT tus between the 3 groups at the time points of 1 year and 3 years. How-
scans. Administration of IVIg was more frequent in thymoma group, ever, no significant differences in mean dose of PSL and CNIs were
during the entire course, in the intervention for exacerbation of MG detected among the 3 groups at each time point. Administration of
(Table 2). IVIg was more frequent in the thymoma group, because patients with
We demonstrated MGFA PI status, at 1 year and 3 years after thy- thymomatous MG experienced more frequent episodes of exacerba-
mectomy, and divided each group into “red” subgroup (i.e. CSR, PR, tions than patients with non-thymomatous MG. Although thymectomy
and MM), “white” subgroup (i.e. I) and “blue” subgroup (i.e. U, and has been generally accepted as the most viable option of treatment for
W) according to MGFA PI status (Fig. 1). The thymic atrophy group, MG with thymoma or TFH, we concluded that the efficacy of the

Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
K. Nakahara et al. / Journal of Neuroimmunology xxx (2017) xxx–xxx 3

Table 2
Intervention for exacerbation of MG during entire course.

Thymic atrophy group Thymic follicular hyperplasia group Thymoma group p-Value

Number of patients 25 29 39
Intravenous methylprednisolone (%) 1 (4) 4 (14) 5 (13) 0.472
Intravenous immunoglobulin (%) 0 (0) 0 (0) 6 (15) 0.014
Plasmapheresis (%) 0 (0) 0 (0) 0 (0) 1.000

Fig. 1. Changes of MGFA PI status after thymectomy each group. Thymic atrophy group, thymic follicular hypertrophy (TFH) group, and thymoma group significantly improved over time
(p b 0.001, respectively). And, significant differences were found between the 3 groups at 1 year and 3 years (p = 0.002, and b0.001, respectively). The red end of the spectrum indicated
the combined percentage of improving (CSR, PR, and MM), white bar indicated the a substantial decrease in pretreatment clinical manifestations or a sustained substantial reduction in MG
medications (I), and the blue end of the spectrum indicated the combined percentage of worsening (U and W). (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)

thymectomy in the thymic atrophy group was consistent with the re- pure effect of thymectomy in the present study. A prospective, multi-
sults. The clinical outcome of the thymic atrophy group was even better center, and clinical observation is necessary to confirm the relationships
than that of the TFH or thymoma group. between the severities of MG symptoms (e.g. quantitative MG score),
Recent studies also reported MG patients with thymic atrophy that antibody levels, thymic pathology, and the treatments (e.g. dose of PSL
showed similar clinical improvement as those with TFH (Ishii et al., and CNIs, the frequency of PP, IVIg, and steroid pulse therapy). In sum-
2007). The typical microscopic appearance in patients with non- mary, on the basis of our results we conclude that the clinical course of
thymomatous MG is TFH characterized by the prominent germinal cen- MG patients with atrophic thymus after thymectomy was even better
ters in the medulla. The germinal center is where B cells differentiate than that of patients with TFH or thymoma.
into the cells producing antibodies with high affinity to the antigens.
The biological roles of thymectomy in MG patients with TFH were de-
pendent upon removing the germinal center B cells in the thymus
(Okumura et al., 2003). The results in this study also showed that
TFH-associated MG patients improved with marked reduction of the ti-
ters of AChRAb (Okumura et al., 2003; Nikolic et al., 2013). The patho-
physiology of MG with hyperplastic thymus is becoming clearer. The
intrathymic antibody production, increased number of activated den-
dritic cells, and enhanced production of autoreactive T cells can explain
why thymectomy has a therapeutic effect in early onset MG. The etiolo-
gy of MG associated with thymoma is likely different from that of MG
associated with TFH. Abnormal positive selection of naïve T cells is an
essential pathological mechanism of the thymoma-associated MG.
However, the roles of thymic atrophy in the mechanism of MG remain
to be clarified (Flores et al., 1999). In the recent report, the expressions
of B cell activation markers in thymic microenvironments elevated his-
tologically in the atrophic thymus tissue of MG patients, similar to its
distribution in hyperplastic thymuses of MG patients (Chen et al.,
2011). There is the possibility that immune abnormalities can play piv-
Fig. 2. The changes of mean serum AChRAb titer before and after thymectomy in each
otal roles in the progression of MG patients with thymic atrophy. group. Mean serum AChRAb titers at 1 month after thymectomy: Thymic atrophy group
The important limitations of the present study were the retrospec- (30.0 ± 45.0); TFH group (283.4 ± 971.2); thymoma group (55.2 ± 87.5). Mean serum
tive design and the small number of subjects. Additionally, therapeutic AChRAb titers at 1 year after thymectomy: Thymic atrophy group (18.9 ± 21.9); TFH
intervention was actually different in the 3 groups, and additional group (214.8 ± 784.9); thymoma group (18.3 ± 21.5). Mean serum AChRAb titers at
3 years after thymectomy: Thymic atrophy group (7.9 ± 16.5); TFH group (34.6 ±
immunomodulation therapy after thymectomy depended on the at- 52.1); thymoma group (17.8 ± 32.7). In TFH group, mean serum AChRAb titer was
tending physician. The clinical course of each group may not have significantly high, and it decreased significantly at the time points after thymectomy,
reflected the effect of only thymectomy and may have obfuscated the compared to the other two groups (p = 0.015, 0.022, 0.053, and 0.123, respectively).

Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
4 K. Nakahara et al. / Journal of Neuroimmunology xxx (2017) xxx–xxx

MG myasthenia gravis;
MGFA MG foundation of America
MGFA PI status MGFA post-intervention status
PR pharmacologic remissions
PP plasmapheresis
PSL prednisolone
TFH thymic follicular hyperplasia
U unchanged
W worse

Acknowledgements

We would like to thank all members of Department of Neurology at


Kumamoto University Hospital for helping with collection of clinical
data.

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I improved
IVIg intravenous immunoglobulin
MM minimal manifestation

Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005

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