Journal of Neurology

, Volume 262, Issue 4, pp 823–830 | Cite as

Long-term outcome of 424 childhood-onset myasthenia gravis patients

  • Mengcui Gui
  • Xuan Luo
  • Jing Lin
  • Yue Li
  • Min Zhang
  • Xiaofan Zhang
  • Mingshan Yang
  • Wei Wang
  • Bitao Bu
Original Communication

Abstract

The objective of this study was to describe the clinical characteristics, outcome and factors that may affect the outcome of childhood-onset myasthenia gravis (CMG) patients in China. We have followed up 424 patients with CMG for at least 5 years at Tongji Hospital. At the end of follow-up, the outcome of all the patients was measured according to MGFA Post-intervention Status. In this study, the patients have been followed up for 9.8 ± 5.4 years. The mean onset age was 5.4 ± 3.6 years. Ocular myasthenia gravis (OMG) was the major type of CMG within 2 years after onset (95 %). Thymic hyperplasia was found in 116 patients, and thymoma was confirmed in 6 patients. Acetylcholine receptor antibodies were elevated in 69.5 % of the patients. All the patients were routinely treated. Thymectomy was performed in 34 patients (8.0 %). At the end of follow-up, seventy-one patients (16.7 %) were significantly improved, 66 patients (15.6 %) remained unchanged, 53 patients (12.5 %) were worsened, and 234 patients (55.2 %) were exacerbated. Importantly, fifty OMG patients (12.4 %) had transformed into generalized myasthenia gravis (GMG) over 2 years after onset. Thymectomy did not effectively reduce the transformation from OMG to GMG. However, GMG cases significantly benefited from the surgery. This study indicated that the cases with autoimmune CMG account for over 50 % in Chinese MG population. The long-term follow-up discloses that CMG patients have a low percentage of improvement, and a high percentage of worsening and exacerbation. The treatment should not be withdrawn too early after the patients obtain complete stable remission. More studies are needed to gain better control of CMG symptoms.

Keywords

Childhood-onset myasthenia gravis Ocular myasthenia gravis Transformed generalized myasthenia gravis Thymus Long-term outcome 

Introduction

Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by varying degrees of fluctuating muscle weakness and fatigability in which autoantibodies against nicotinic acetylcholine receptor (AChR) on endplates play an important role. In the Western countries, the disease mainly affects adults, and just 10–15 % of all the MG cases were childhood-onset MG (CMG) in North America [1]. However, in China, CMG cases were estimated to account for more than half of the MG population [2]. Both the childhood-onset and adult-onset MG (AMG) share common aspects in clinical presentation and immunological profiles, but differences in onset age distribution, clinical types and the outcome between the two different groups have rarely been reported [3, 4, 5].

Previous studies suggested that about half of AMG patients who initially present with ocular muscle involvement may converse into generalized muscle weakness within 2 years after onset [6, 7, 8]. However, as far as we knew, there have been few reports about the long-term outcome of CMG cases, especially the transformation from ocular type to the generalized forms of the disease. Here, we retrospectively reviewed the clinical characteristics and outcome of a cohort of 424 CMG patients who have been followed up for at least 5 years at Tongji Hospital, to see the long-term outcome and the potential factors which may influence the outcome.

Methods and patients

The study has been approved by the Committee of Clinical Investigation at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. 20140903) and conformed to the principles of the Declaration of Helsinki.

All patients were diagnosed to have MG before the age of 14 years and have followed up since Jan, 1987 to Dec 2013 at the Department of Neurology, Tongji Hospital. The informed consents have been signed by the patient’s parents or custodies for the permission of clinical evaluation and follow-up prior to their inclusion in this study. The inclusion criteria of the study were all the MG cases who developed MG symptoms before age of 14 years and had been followed up for a minimum of 5 years (ranged from 5 to 45 years) at the Hospital, the cases who presented as a transitory form of MG in neonates due to the passive transfer of acetylcholine receptor antibodies (AChR-abs) from their mothers who had MG were excluded.

The MG diagnosis was made based on the typical clinical presentation characterized by fluctuating weakness and fatigability of the affected muscle weakness, and the dramatic response to intramuscular injection of a bolus of neostigmine sulfate. In addition, repetitive nerve stimulation (RNS) was only performed in children older than 8 years. Thymic abnormalities have been checked by computed tomography (CT), magnetic resonance imaging (MRI) or chest X-ray. AchR-abs were determined using ELISA (RSR Limited, Cardiff, UK). In addition, thyroid function, anti-thyroid antibodies and connective tissue diseases associated autoantibodies were determined as well in all the cases. In the cases who presented as atypical manifestations, screening of mutations for Kearns–Sayre syndrome (KSS) and congenital myasthenic syndromes was performed and MRI of extra-ocular muscles was routinely carried out to exclude the possibility of atypical Graves’s disease [9, 10, 11].

The severity of the disease at onset is classified as type I, IIa, IIb, III or IV according to the modified Osserman classification [12].

The clinical paradigms were documented for each child, including demographic data, age of onset, duration, types, remission period, relapses, triggers of relapses or worsening of the symptoms, associated diseases, and the responses to therapy.

A therapeutic regimen is usually used to treat all the children patients at Department of Neurology, Tongji Hospital. Initially, oral pyridostigmine is usually employed for all MG cases to improve the symptoms. If the symptoms are not improved significantly or become deteriorated after administration of oral pyridostigmine for a few months, oral prednisone at a daily dosage of 0.75 mg/kg will be started after informing the patients’ custodies. The prednisone will be tapered on schedule after the symptoms are significantly improved and eventually discontinued after the symptoms have totally disappeared for at least 6 months. If the symptoms relapse, oral prednisone will be re-started. If both pyridostigmine and prednisone does not stop the progression of the disease or/and the symptoms severely affect the daily life of the sufferers, thymectomy will be an optional method based on the aspect of thymic abnormalities on chest imaging and AChR-abs titers. Intravenous immunoglobulin (IVIG) or plasma exchange will be indicated for severely progressive cases with generalized forms of MG. Immunosuppressants are not usually administered for CMG cases that do not show satisfactory responses to both pyridostigmine and prednisone because the Chinese custodies are very reluctant to take these agents.

According to our protocol, all patients were usually asked to visit the neurologists for evaluation and adjustment of the therapeutic regimen at least every 2 months. If patients had been symptom free for at least 6 months, the visit intervals would be 6 months or longer. Telephonic interviews or online communications were usually used if the patients were asymptomatic for years.

At the end of the follow-up, the current clinical status was evaluated as complete stable remission (CSR), pharmacologic remission (PR) and minimal manifestation (MM). The change of clinical status was determined as improved, unchanged, worsened, exacerbated and death of MG according to MGFA post-intervention status [13].

To analyze the factors which may potentially affect the long-term outcome, the patients have been divided into two subgroups according to transformation of the ocular type into the generalized types 2 years after onset of the disease. The ocular myasthenia gravis (OMG) group included the patients who still presented as isolated ocular symptoms throughout the follow-up period, and the transformed form of MG (TMG) group consisted of the ocular CMG cases that developed generalized symptoms 2 years after onset of MG.

All AMG cases were treated as the same protocol, except thymectomy was encouraged in the cases with thymoma or with generalized myasthenia gravis (GMG), and immunosuppressants such as azathioprine or FK606 were more commonly prescribed for the cases that did not show satisfactory responses to pyridostigmine and prednisone.

Statistical analysis

For comparison study, the t test and the χ2 test were used. Differences are considered significant when two-sided p values are less than 0.05. Bivariate correlation analysis was used to analyze the correlation of stratified intervals between time of diagnosis and time of thymectomy to the clinical outcome in the thymectomized patients. All statistical analyses were done with the SPSS 19.0 (SPSS Inc. Chicago, IL, USA).

Results

The general aspects and outcome of 424 CMG patients

Totally, 424 CMG patients (including 241 females and 183 males) met the inclusion criteria. The basic clinical data of all the participants are summarized in Table 1. The mean onset age was 5.4 ± 3.6 years old (ranged from 1 to 14 years old), with a clear peak before 5 years. Within 2 years after the onset, 403 cases (95.0 %) presented as the sole symptoms of ocular MG type, and 21 patients (5.0 %) presented as the symptoms of generalized MG types. Preceding events which might provoke the first appearance of MG symptoms had been reported in 24 cases. The mean duration of the disease at the end of the follow-up was 11.3 ± 6.2 years (ranged from 5 to 45 years). The mean follow-up period of this group was 9.8 ± 5.4 years (ranged from 5 to 27 years).
Table 1

The clinical characteristics of 424 CMG patients

Characteristics

Patients

Percentage (%)

Gender

 Female

241

56.8

 Male

183

43.2

Age at onset

5.4 ± 3.6 (1–14)

 

 1–5 years

251

59.2

 5–10 years

115

27.1

 10–14 years,

58

13.7

Duration (years)

11.3 ± 6.2

Follow-up duration (years)

9.8 ± 5.4

Classification

 OMG

403

95.0

 GMG

21

5.0

Comorbidities

81

19.1

 Hyperthyroidism

67

82.7

 Hypothyroidism

4

4.9

 Epilepsy

2

2.5

 Leukoderma

2

2.5

 Ulcerative colitis

1

1.2

 Grave’s disease

1

1.2

Neostigmine test (+)

424

100

AChR-ab (+)

89/128

69.5

Thymus abnormalities

139

27.4

 Hyperplasia

116

83.5

 Thymoma

23

16.5

Based on chest MRI or CT, thymic hyperplasia was radiologically suggested in 116 cases, and thymomas were highly suspected in 23 patients. At last, thymectomy was carried out in 34 patients. Thymomas were pathologically confirmed in only 6 cases out of the 34 thymectomized patients. AChR-abs determination revealed that 69.5 % of the detected cases (89/128) were positive. All the patients had received pyridostigmine and prednisone therapy, and five patients had been treated with azathioprine. IVIG was used in two cases that experienced severely generalized weakness triggered by respiratory infection.

After the multimodal treatment, the long-term outcome of CMG patients was generally not so satisfactory by the end of the follow-up. In all, only 71 patients (16.7 %) attained CSR, PR, MM and Improvement. However, 66 patients (15.6 %) remained unchanged, and 53 patients (12.5 %) were clinically worsened. More importantly, 234 patients (55.2 %) developed the symptoms more severe than ever, after they had once attained satisfactory improvement such as CSR, PR or MM for a minimum of 1 year (Table 2). Before the symptoms became exacerbated, the period of significant improvement or remission varied from case to case. In the 234 exacerbated patients, 177 patients (76.3 %) experienced a remission lasting longer than 1 year (5.6 ± 4.7 years, from 1 to 26 years), and 55 patients experienced 2 cycles of remission–relapsing (remission period was 3.1 ± 2.7 years, ranged from 1 to 13 years), and 9 patients experienced 3 cycles of remission–relapsing (2.4 ± 2.9, 1–10 years) (data not shown).
Table 2

The outcome of 424 patients

 

Total (n = 424)

Improved (n = 71)

Unchanged (n = 66)

Worse (n = 53)

Exacerbation (n = 234)

p value

Gender

 Female

241

37

40

33

131

0.63

 Male

183

34

26

20

103

Onset age (years old)

5.4 ± 3.6

4.7 ± 3.7

5.3 ± 3.5

6.6 ± 4.4

5.4 ± 3.4

0.28

Duration (years)

11.3 ± 6.2

8.8 ± 3.9

11.4 ± 7.8

14.5 ± 7.6

11.4 ± 5.6

0.82

Autoimmune diseases

81

11

11

13

46

0.59

AChR-ab (+)

89/128

16/28

9/12

12/16

52/72

0.45

Thymic abnormalities

142

21

25

18

78

0.49

 Hyperplasia

128

18

23

13

74

 Thymoma

14

3

2

5

4

– comparison not needed

The comparison between OMG and TMG

Transformation from OMG to GMG was an important endpoint at the end of the follow-up. In addition to 21 cases that developed generalized symptoms of MG within 2 years after onset, 50 out of the 403 OMG cases (12.4 %) had transformed into GMG 2 years after the onset, and the remaining 353 cases still manifested as the isolated ocular symptoms. In light of the intervals that the transformation happened from the disease onset, transformation happened in 11 patients (22.0 %) 2–5 years, in accumulated 32 cases (64.0 %) 2–10 years, and in 44 cases (88.0 %) 2–20 years after the onset. Longer follow-up period revealed that the transformation occurred in 6 cases over 20 years after the onset. The cohort of CMG patients showed that the transformation occurred about 11.0 years after onset (ranged from 2 to 35 years).

Concerning the factors that might predict the transformation, none was closely associated with the transformation, such as genders, onset ages, disease courses, presence of thymic abnormalities or other kinds of autoimmune diseases or the titer of AChR-abs (Table 3, p > 0.05).
Table 3

The comparison of TMG and OMG groups

 

TMG (n = 50)

OMG (n = 353)

p value

Gender

 Female

31

197

0.41

 Male

19

156

Age of onset (years old)

6.6 ± 4.3

5.2 ± 3.5

0.40

Duration (years)

14.3 ± 7.6

11.0 ± 5.9

0.69

Other autoimmune diseases

13

64

0.19

AChR-ab (+)

11/15

74/105

1.0

Thymic abnormalities

17

113

0.18

 Hyperplasia

12

105

 Thymoma

5

8

Transformed time (years)

11.0 ± 7.1

0

– comparison not needed

Preceding events which may trigger relapses were reported in over 50 % of the CMG cases. Out of them, discontinuation of drugs (the intervals between the withdrawal and relapses of symptoms were ranged from 1 month to 21 years) was the predominant one (154 cases). Other preceding events were respiratory tract infection (24 cases), vaccination (7 cases), surgery (6 cases), pregnancy or delivery (5 cases), administration of other drugs (5 cases), alcohol intake (3 cases), trauma (3 cases), emotional stress (3 cases) and other diseases (3 cases).

Thymectomy did not show definite efficacy in CMG patients with OMG

The benefit of thymectomy in CMG cases, especially in OMG patients, is still controversial [14, 15]. In the present study, 34 CMG patients (16 females and 18 males) underwent transsternal extended thymectomy because they failed to respond well to routine therapy. The mean onset age of the thymectomized cases was 6.5 years. Before thymectomy, 26 cases presented OMG and 8 patients had GMG. All the patients had received oral pyridostigmine and prednisone for a mean duration of 9 years prior to thymectomy. At thymectomy, these patients aged about 15 years (3–39 years) old (Table 4). Hyperplasia was pathologically verified in 28 cases (82.4 %), and thymoma in 6 patients (17.6 %). At the end of the follow-up, 6 out of the 8 patients (75%) who presented GMG before thymectomy were significantly improved, 1 GMG case (12.5%) remained unchanged and 1 GMG patient (12.5%) was clinically worsened. Meanwhile, 21 out of the 26 OMG patients (80.8%) remained unimproved and 5 cases (19.2%) transformed into GMG during the observation (Table 4). However, no strong correlation of the stratified intervals (≤2, 2–5, 5–10, 10–20, and >20 years, respectively) between time of diagnosis and time of thymectomy to the clinical outcome was found in the thymectomized patients, though no dynamic changes of AChR-abs titers were available (OR 0.023, p 0.90).
Table 4

The outcome of 34 thymectomized CMG patients

Characteristics

Numerical value

Percentage (%)

Gender

 Female

16

47.1

 Male

18

52.9

Age at onset (years old)

6.5 ± 4.3

Classification before thymectomy

 OMG

26

76.5

 GMG

8

23.5

Age at thymectomy (years old)

15.7 ± 8.5

Course at thymectomy (years)

9.1 ± 7.8

Classification after thymectomy

 OMG

27

79.4

 GMG

7

20.6

Histopathology

 Hyperplasia

28

82.4

 Thymoma

6

17.6

OMG ocular myasthenia gravis, GMG generalized myasthenia gravis

The aspects of CMG patients differ from those of AMG cases

To better delineate the characteristics of CMG patients, the clinical data and the outcome of CMG patients have been compared to those of the AMG cases who have been documented and followed up simultaneously at the Department of Neurology using the same protocol (Table 5). In parallel, 220 AMG cases were included in this study. In a sharp contrast, within 2 years after onset, the OMG cases only accounted for 51.8 % of the AMG patients, far lower than 95 % of the CMG patients (p < 0.001). The percentage of positive AChR-abs in CMG cases was not significantly lower than that in the AMG cases (p > 0.05). However, thymic abnormalities were much more frequently seen in the AMG cases, especially the thymoma (p < 0.01, Table 5). At the end of the follow-up, the transformation rate in AMG patients 2 years after onset was 32.5 %, significantly higher than 12.4 % in the CMG patients (p < 0.001). Regarding the difference of outcome between the CMG and AMG patients, the rates of improved and unchanged cases were similar (16.7 vs. 19.5 %, and 15.6 vs. 18.6 %, respectively, p > 0.05), but the exacerbation rate in the CMG patients was much higher than that in the AMG cases (55.2 vs. 28.6 %, p < 0.01). Particularly, the worsened cases were much more in the AMG patients (32.3 vs. 12.5 %). Fortunately, no CMG cases died, but 2 AMG patients died of myasthenic crisis.
Table 5

Comparison of CMG and AMG patients

 

CMG (n = 424)

AMG (n = 220)

p value

Gender (F:M)

1.3:1

1.4:1

 

 Female

241

129

0.66

 Male

183

91

Onset age (years old)

5.4 ± 3.6

32.2 ± 12.5

<0.001*

Disease course (years)

11.3 ± 6.2

9.2 ± 5.8

0.13

Follow-up duration (years)

9.8 ± 5.4

9.6 ± 5.2

0.15

Presentation at onset

 OMG

403

114

<0.001*

 GMG

21

106

Thymus abnormalities

142

99

0.004*

 Hyperplasia

128

48

 Thymoma

14

51

AChR-ab (+)

89

48

0.46

Treatment

 Pyri + pred

424

220

 Immunosuppressants

5

19

 Thymectomy

34

50

Rate of transformation

12.4

32.5

<0.001*

Outcome

 Improved

71

43

0.38

 Unchanged

66

41

0.32

 Worse

53

71

<0.001*

 Exacerbation

234

63

<0.001*

 Death

0

2

0.12

pyri pyridostigmine, pred prednisone, – comparison not needed

p < 0.01

Discussion

The study uncovered the features of CMG in China that the majority of MG children manifested by isolated ocular symptoms, and generally responded well to immunotherapy but the symptoms tended to relapse after discontinuation of immunotherapy. When compared to other studies concerning CMG, the number of CMG patients in our study is the largest and the follow-up period is the longest (Table 6). The longer observation could provide more reliable data about the outcome of CMG patients. Regarding the types of MG, the Chinese CMG patients predominantly presented OMG type, in a sharp contrast to low percentages of OMG in Indian and Jamaican CMG patients [5, 16], which ranged from 30 to 59 %. The possibilities of KSS, congenital myasthenic syndrome, and Graves’s disease have been excluded in the suspected cases. The difference in the outcome of our CMG patients from those of other reports listed in Table 6 could be explained by the differences in HLA genotyping [17, 18, 19], and the follow-up periods. Since MG symptoms tend to fluctuate throughout the duration and the autoimmune nature of the diseases defines the intermittent course, the long-term follow-up period would provide the chance to see the intrinsically defined course of autoimmune CMG, which was illustrated by our observation that many cases relapsed after they have attained CSR for many years.
Table 6

The comparison of major series of CMG reports

 

R. Melbourne Chambers [16]

Pineles [35]

Ashraf [5]

Wong [36]

Present study

Place

Jamaica

USA

India

China

China

Years

2012

2010

2006

1992

N

34

39

77

103

424

Age of onset (mean, years old)

7.5

5.4

8.1

5.6

5.4

Follow-up length (mean, years)

3.2

4.8

6.2

5.7

9.8

F:M ratio

1.3:1

1.2:1

1:1

1.1:1

1.3:1

Classification

 OMG (%)

59

100

30

71

95.0

 GMG (%)

41

0

70

29

5.0

Treatment type

 CH (%)

91

100

36

92

100

 Prednisone (%)

63

49

67

23

100

 Thymectomy (%)

25

38

14

12

8.1

Outcomes

 Improved (%)

12

77

83

49

16.7

 Unchanged (%)

45

15.6

 Worse/exacerbation (%)

23

14

3

67.7

 Death (%)

6

0

3

2

0

Transformed (%)

47

23

10

5

12

Time of transformation (mean, years)

11.0

0.75

10.9

11.0

CH cholinesterase inhibitor; – data were blank

Transformation to a generalized form from OMG has not been as clearly delineated in CMG patients as in AMG cases [20]. Interestingly, the rate of transformation (12.4 %) in the present study was significantly lower than the rate (32.5 %) in the 220 AMG patients who have been followed up in the same way at the Hospital (Table 5), and by far lower than the expected rate (up to 80 %) in AMG population [21]. This difference between the CMG and AMG highlights the idea that CMG may constitute a distinctive clinical entity different from AMG patients in some aspects such as the rare presence of thymoma, high percentage of OMG and a tendency to relapse in CMG patients. However, the auto-immunological characteristics of CMG patients were similar to those of AMG sufferers, such as the presence of AChR-abs and the responsiveness to immunotherapy. In our study, all the patients at last had received both pyridostigmine and prednisone therapy (Table 6), whether the combined therapy was the reason for the lower transformation rate in the CMG patients needs more detailed clinical trials, because there were a few reports suggesting that treatment with prednisone alone or in combination with azathioprine at onset of MG was able to reduce the possibility of transformation from OMG to GMG [14]. Unfortunately, no responsible factors were identified to predict the transformation. Whether the higher frequent thymoma linked with the higher GMG percentage in our AMG patients implies a possible role of thymic abnormalities in the transformation needs to be uncovered further.

A major concern for treating CMG children is the side effects of long-term use of prednisone, especially the growth failure and Cushing’s reaction [22, 23]. Neurologists and patients’ custodies have been struggling in balancing the improvement of MG symptoms and the side effects. Long-term therapy with prednisone should be theoretically administrated to prevent relapses of MG symptoms, but in reality the failure to grow taller in very young CMG kids is the major reason for failure of treatment. What we usually do is to taper after patients’ symptoms are significantly improved, and at last to discontinue prednisone when they have been asymptomatic for at least 6 months. However, 65.8 % patients (154 out of the 234 exacerbated patients) who stopped taking pyridostigmine or prednisone after they obtained so-called CSR for longer than 1 year became exacerbated (relapsed). The high tendency to relapse induced by discontinuation may indicate that discontinuation of drugs was a dominant risk factor triggering exacerbation. In attempt to prevent the relapses or transformation, azathioprine and thymectomy have been suggested to the CMG patients. However, the Chinese custodies are traditionally reluctant to accept any immunosuppressants for treating the patients with isolated ocular symptoms. The efficacy of azathioprine alone or in combination with low dosage of prednisone needs more controlled studies.

Thymectomy is generally considered an important option for treating MG in adult MG patients if medical treatment proved unsatisfactory [24, 25, 26]. However, it is not generally recommended for non-thymomatous OMG patients [24, 27, 28]. The 34 CMG patients in our study did not generally benefit very much from the surgery (Table 5). Only six out of the CMG patients with GMG had achieved significant clinical improvement, implying that thymectomy could be suggested for CMG patients with GMG (Table 5). Unfortunately, the transformation in the CMG patients had not been efficiently stopped after thymectomy and pharmaceutical therapy, and the symptomatic improvement was not evidently observed in 26 CMG cases with OMG. Since the thymectomized cases had not received the operation until they showed refractory responses to pharmaceutical treatment, whether the timing of the surgery influences the efficacy of thymectomy needs further clinical trials.

Relapses after remission constituted the major concern about the CMG. After the relapses, re-usage of prednisone was proved to be effective in majority of the exacerbated cases. Until now, we failed to pinpoint the factors which may predict the relapsing of MG symptoms. However, half of the cases experienced a preceding event (trigger) before relapses. Discontinuation of prednisone was the major trigger. Notably, infection (especially the upper respiratory tract infection, even the minor ones) was a very common discernible trigger. The possible role of infections even the occult ones in triggering activity of autoimmune diseases has been speculated [29, 30, 31, 32, 33, 34]. The challenging question is after an OMG child has attained so-called pharmaceutical remission for 1 year or longer on low dosage of prednisone, we lack guidelines or markers to discontinue the corticotherapy since long-term usage of prednisone would handicap the children.

Though there were several limitations in the retrospective study, such as the incomplete data of determination of AChR-abs in all cases, and lacking the data of CMG cases who did not receive prednisone therapy, the large number of CMG cases and nearly 10 years follow-up indicate that OMG is far more frequent than GMG in Chinese children. The CMG has a high tendency to relapse after remission. Efforts should be done to reduce the relapses such as developing new drugs or methods with less side effects, and further evaluating efficacy of thymectomy in the treatment of ocular CMG.

Notes

Acknowledgments

We thank Dr. Minhong Sun for her assistance in statistical work. The research was partly supported by a grant from Natural Science Foundation of China (No. 81271320 to Dr. Bu).

Conflicts of interest

All the authors declare no potential conflicts of interest, including relevant financial interests, activities, and relationships.

Ethical standard

The Bu Bitao's study concerning the client's right to privacy. The study was approved by the Ethical Commitee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology and was conducted according to the principles of the Declaration of Helsinki. Written informed consent was obtained from the subject, and his study considered Declaration of Helsinki as a statement of ethical principles.

References

  1. 1.
    Phillips LN, Torner JC, Anderson MS, Cox GM (1992) The epidemiology of myasthenia gravis in central and western Virginia. Neurology 42:1888–1893CrossRefPubMedGoogle Scholar
  2. 2.
    Huang X, Liu WB, Men LN, Feng HY, Li Y, Luo CM, Qiu L (2013) Clinical features of myasthenia gravis in southern China: a retrospective review of 2,154 cases over 22 years. Neurol Sci 34:911–917CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W, Vincent A (2007) Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry 78:386–390PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Wang W, Chen YP, Wang ZK, Wei DN, Yin L (2013) A cohort study on myasthenia gravis patients in China. Neurol Sci 34:1759–1764CrossRefPubMedGoogle Scholar
  5. 5.
    Ashraf VV, Taly AB, Veerendrakumar M, Rao S (2006) Myasthenia gravis in children: a longitudinal study. Acta Neurol Scand 114:119–123CrossRefPubMedGoogle Scholar
  6. 6.
    Bever CJ, Aquino AV, Penn AS, Lovelace RE, Rowland LP (1983) Prognosis of ocular myasthenia. Ann Neurol 14:516–519CrossRefPubMedGoogle Scholar
  7. 7.
    Kupersmith MJ, Latkany R, Homel P (2003) Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol 60:243–248CrossRefPubMedGoogle Scholar
  8. 8.
    Oosterhuis HJ (1989) The natural course of myasthenia gravis: a long term follow up study. J Neurol Neurosurg Psychiatry 52:1121–1127PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Huze C, Bauche S, Richard P et al (2009) Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet 85:155–167PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Maselli RA, Ng JJ, Anderson JA et al (2009) Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet 46:203–208PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Selcen D, Juel VC, Hobson-Webb LD et al (2011) Myasthenic syndrome caused by plectinopathy. Neurology 76:327–336PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Busch C, Machens A, Pichlmeier U, Emskotter T, Izbicki JR (1996) Long-term outcome and quality of life after thymectomy for myasthenia gravis. Ann Surg 224:225–232PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Jaretzki AR, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB (2000) Myasthenia gravis: recommendations for clinical research standards. Task force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 55:16–23CrossRefPubMedGoogle Scholar
  14. 14.
    Wong SH, Huda S, Vincent A, Plant GT (2014) Ocular myasthenia gravis: controversies and updates. Curr Neurol Neurosci Rep. doi:10.1007/s11910-013-0421-9 PubMedGoogle Scholar
  15. 15.
    Liew WK, Kang PB (2013) Update on juvenile myasthenia gravis. Curr Opin Pediatr 25:694–700CrossRefPubMedGoogle Scholar
  16. 16.
    Melbourne CR, Forrester S, Gray R, Tapper J, Trotman H (2012) Myasthenia gravis in Jamaican children: a 12-year institutional review. Paediatr Int Child Health 32:47–50CrossRefGoogle Scholar
  17. 17.
    Bu B, Yang M, Xu J, Gong F, Jiang X, Nie X (1999) The clinical study and HLA genotyping of 112 familial myasthenia gravis patients. J Tongji Med Univ 19:46–49CrossRefPubMedGoogle Scholar
  18. 18.
    Fekih-Mrissa N, Klai S, Zaouali J, Gritli N, Mrissa R (2013) Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients. Clin Neurol Neurosurg 115:32–36CrossRefPubMedGoogle Scholar
  19. 19.
    Matsuki K, Juji T, Tokunaga K, Takamizawa M, Maeda H, Soda M, Nomura Y, Segawa M (1990) HLA antigens in Japanese patients with myasthenia gravis. J Clin Invest 86:392–399PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Luchanok U, Kaminski HJ (2008) Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 21:8–15CrossRefPubMedGoogle Scholar
  21. 21.
    Kalb B, Matell G, Pirskanen R, Lambe M (2002) Epidemiology of myasthenia gravis: a population-based study in Stockholm, Sweden. Neuroepidemiology 21:221–225CrossRefPubMedGoogle Scholar
  22. 22.
    Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, Raissy HH, Van Natta ML, Tonascia J, Strunk RC (2012) Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 367:904–912PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Wang SJ, Yang YH, Lin YT, Yang CM, Chiang BL (2002) Attained adult height in juvenile rheumatoid arthritis with or without corticosteroid treatment. Clin Rheumatol 21:363–368CrossRefPubMedGoogle Scholar
  24. 24.
    Ionita CM, Acsadi G (2013) Management of juvenile myasthenia gravis. Pediatr Neurol 48:95–104CrossRefPubMedGoogle Scholar
  25. 25.
    Raica M, Cimpean AM, Ribatti D (2008) Myasthenia gravis and the thymus gland. A historical review. Clin Exp Med 8:61–64CrossRefPubMedGoogle Scholar
  26. 26.
    Spillane J, Hayward M, Hirsch NP, Taylor C, Kullmann DM, Howard RS (2013) Thymectomy: role in the treatment of myasthenia gravis. J Neurol 260:1798–1801CrossRefPubMedGoogle Scholar
  27. 27.
    Chiang LM, Darras BT, Kang PB (2009) Juvenile myasthenia gravis. Muscle Nerve 39:423–431CrossRefPubMedGoogle Scholar
  28. 28.
    Mineo TC, Ambrogi V (2013) Outcomes after thymectomy in class I myasthenia gravis. J Thorac Cardiovasc Surg 145:1319–1324CrossRefPubMedGoogle Scholar
  29. 29.
    Liu N, Liu Q, Wu X, Liu K, Vadis Q (2014) Predictors of outcome of myasthenic crisis. Neurol Sci 35:1109–1114CrossRefGoogle Scholar
  30. 30.
    Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920CrossRefPubMedGoogle Scholar
  31. 31.
    Correale J, Fiol M, Gilmore W (2006) The risk of relapses in multiple sclerosis during systemic infections. Neurology 67:652–659CrossRefPubMedGoogle Scholar
  32. 32.
    Andersen O, Lygner PE, Bergstrom T, Andersson M, Vahlne A (1993) Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. J Neurol 240:417–422CrossRefPubMedGoogle Scholar
  33. 33.
    Esposito S, Bosis S, Semino M, Rigante D (2014) Infections and systemic lupus erythematosus. Eur J Clin Microbiol Infect Dis 33:1467–1475CrossRefPubMedGoogle Scholar
  34. 34.
    Panda S, Goyal V, Behari M, Singh S, Srivastava T (2004) Myasthenic crisis: a retrospective study. Neurol India 52:453–456PubMedGoogle Scholar
  35. 35.
    Pineles SL, Avery RA, Moss HE, Finkel R, Blinman T, Kaiser L, Liu GT (2010) Visual and systemic outcomes in pediatric ocular myasthenia gravis. Am J Ophthalmol 150:453–459CrossRefPubMedGoogle Scholar
  36. 36.
    Wong V, Hawkins BR, Yu YL (1992) Myasthenia gravis in Hong Kong Chinese. 2 Paediatric disease. Acta Neurol Scand 86:68–72CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mengcui Gui
    • 1
  • Xuan Luo
    • 1
  • Jing Lin
    • 1
  • Yue Li
    • 1
  • Min Zhang
    • 1
  • Xiaofan Zhang
    • 1
  • Mingshan Yang
    • 1
  • Wei Wang
    • 1
  • Bitao Bu
    • 1
  1. 1.Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations