Effects of thymectomy on late-onset myasthenia gravis without thymoma

doi:10.1016/j.clineuro.2007.08.006

Clinical Neurology and Neurosurgery

Volume 109, Issue 10, December 2007, Pages 858-861

https://doi.org/10.1016/j.clineuro.2007.08.006 Get rights and content

Abstract

Objectives

This study aims to investigate whether thymectomy is beneficial for late-onset (>50 years) myasthenia gravis patients with no thymoma, particularly for those with mild generalized weakness.

Patients and methods

A total of 34 patients were included in the study. The clinical course and long-term outcomes over 2 years were reviewed in 20 patients who underwent thymectomy and in 14 without thymectomy.

Results

Of the 34 patients, 20 (59%) underwent thymectomy. Thymectomized patients had more severe disability at entry than non-thymectomized patients, but outcome measures did not significantly differ between the two patient groups. Moreover, subgroup analyses including 22 patients with mild generalized weakness at entry showed that the thymectomized group (n = 10) showed a greater percentage of clinical remission (no symptoms; 50% versus 17%; p = 0.11) and a lower frequency of the presence of generalized symptoms (30% versus 75%; p < 0.05) than the non-thymectomized group (n = 12) at the end of follow-up (means 9.6 years after onset).

Conclusions

Thymectomy is a potentially effective treatment for late onset, non-thymomatous patients with mild generalized myasthenia gravis.

Introduction

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission generally mediated by antibodies specific to the human nicotinic acetylcholine receptor [1], [2]. Autoimmune MG is probably the best understood of the human autoimmune diseases, and our knowledge of its pathogenesis and treatment has increased [2], [3]. In the 1970s, thymectomy became an increasingly accepted form of therapy, and today, thymectomy is one of the most frequently employed treatments for MG. However, a recent evidence-based review failed to show conclusive benefits of thymectomy in non-thymomatous MG patients and only recommended thymectomy as an option to increase the probability of remission or improvement [4]. Another issue of controversy regarding thymectomy is whether it is beneficial in late-onset MG patients without thymoma. To evaluate the current status of thymectomy and the outcome of MG patients with mild severity of the disease and no thymoma, we reviewed the clinical course and outcomes of such patients in a retrospective cross-sectional multi-centre survey conducted in Japan.

Section snippets

Patients and methods

The survey was performed between 1999 and 2000, and a total of 470 patients with MG were recruited from 19 tertiary medical centres, which belonged to the Research Group for Neuroimmunological Disease supported by the Ministry of Health, Labour and Welfare of Japan [5]. Clinical profiles, treatments, and outcomes were reviewed from medical records. The clinical grade of disease severity was evaluated according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification: class

All patients

A total of 34 well-documented cases were obtained. The cases comprised 13 men and 21 women with a mean age of onset of 63.7 years (range, 50–78 years). The mean disease duration was 8.5 years (range, 2–25 years). Thymectomy was performed in 20 (59%) of the 34 patients.

Table 1 shows the clinical profiles and treatments in patients with thymectomy and those without thymectomy. Surgery was preferentially performed in patients with greater disability; the median MGFA class was greater in the

Discussion

Our results showed that the prognosis of late-onset MG patients without thymoma was generally favourable. Thymectomy was likely to be performed in MG patients with moderate weakness before treatment. For the subgroup of the MG patients with mild weakness, thymectomy appeared to be effective since minimal manifestations (no symptoms) were observed in 50% of the thymectomized patients compared with 17% of the non-thymectomized patients. Moreover, only 30% of the thymectomized patients as against

Acknowledgments

This study was supported by a grant for Neuroimmunological Diseases from the Ministry of Health, Labour and Welfare of Japan. We thank the members of The Study Group for Myasthenia Gravis in Japan for collecting the clinical data [5].

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Results of Robotic Thymectomy Performed in Myasthenia Gravis Patients Older Than 60 Years at Onset
2019, Annals of Thoracic Surgery
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Besides, patients with thymomatous MG had a shorter thymectomy delay (p = 0.022), smaller probability of purely ocular symptoms at onset (p = 0.036), and required fewer immunosuppressive medications (p = 0.010) compared with patients with non-thymomatous MG, similar to a previous study [15]. In our series, the percentage (70.6%) of the patients with MG older than 60 years at onset who required immunosuppressive medications was comparable with that (65% to 82.1%) reported previously [16–18]. Therefore, it would be advantageous if evidence on the steroid-sparing effect of robotic thymectomy in this population could be provided.
Data are limited on the safety and efficacy of robotic thymectomy in patients with myasthenia gravis (MG) older than 60 years at onset.
Patients older than 60 years at MG onset who underwent robotic thymectomy in Charite Universitaetsmedizin Berlin between 2003 and 2017 were potentially eligible for inclusion. The main outcomes were perioperative complications and clinical outcome according to the Myasthenia Gravis Foundation of America Post-Intervention Status.
Sixty-eight (25 women, 43 men) of 580 patients with MG who underwent robotic thymectomy were eligible for perioperative analyses (median age at MG onset 67 years, range: 61 to 85 years). The perioperative morbidity rate was 13.2%, and the only perioperative death was due to aortic dissection. Fifty-one patients were available for further analysis with a median follow-up time of 60 months (range: 12 to 263 months). The complete stable remission rate was 7.8%, the improvement rate was 68.6%, and the overall mortality rate was 11.8%. Compared with preoperative use, the mean daily dose of corticosteroid agents was significantly reduced at the last follow-up (17.6 ± 23.6 mg versus 2.6 ± 6.1 mg, p = 0.0001) without increased use of azathioprine (35.9 ± 61.9 mg versus 42.7 ± 59 mg, p = 0.427). After excluding 2 patients seronegative for the anti-acetylcholine receptor antibody, 10 of 49 seropositive patients achieved “good outcome” (including four complete stable remissions, three pharmacologic remissions, and three minimal manifestations 0) which was predicted by being free of concomitant disease (odds ratio 7.307, 95% confidence interval: 1.188 to 44.937, p = 0.032) and Myasthenia Gravis Foundation of America classification I before thymectomy (odds ratio 6.696, 95% confidence interval: 1.259 to 35.620, p = 0.026).
Robotic thymectomy seems to be safe and effective in patients with MG older than 60 years at onset with a statistically significant steroid-sparing effect.
Comparison of Conservative Treatment and Thymectomy on Myasthenia Gravis Outcome
2016, Annals of Thoracic Surgery
Citation Excerpt :
An additional 5 studies were analyzed in a separate subgroup because of the presence of some patients with thymoma in the published sample. This process left 27 studies [6–32] for inclusion in the present analysis; the studies in references 19 to 21, 24, and 25 included some patients with thymoma and were analyzed separately. Data were extracted by 1 investigator (P.K.P.) and entered into an Excel (Microsoft Corp, Redmond, WA) file that included author, year of publication, sample size of surgical and nonsurgical patients, type of medical treatment among nonsurgical patients, outcome (remission rates), adjustment for confounders according to Bayesian or Cox models, perioperative complications in surgical cases, median follow-up, and percentages of patients lost to follow-up over the total sample size of each study.
A systematic review of the literature was performed to compare long-term outcomes of thymectomy and medical treatment for generalized myasthenia gravis (MG).
A Medline search through June 2015 resulted in 71 studies, 27 of which were selected (10,140 patients: 5,275 thymectomies, 4,865 medication).
The pooled proportion of remission with thymectomy was 0.31 (95% CI, 0.25–0.37), with conservative treatment it was 0.15 (95% CI, 0.12–0.18). The odds ratio (OR) of remission with thymectomy in comparison with medication alone was 2.44 (95% CI, 1.91–3.12) overall and according to medication type and remission definitions.
Thymectomy is superior to conservative treatment with solely medication on remission in MG.
Late-onset myasthenia gravis is predisposed to become generalized in the elderly
2016, eNeurologicalSci
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Several studies reported that it was unlikely that attempts to remove the thymus of older patients would be rewarding [10,15]. On the other hand, Kawaguchi et al. indicated that thymectomy is a potentially effective treatment for LOMG without thymoma but with mild generalized symptoms [16]. Indeed, our results demonstrated no significant difference in MG-ADL score and PIS among thymectomized LOMG with thymoma, thymectomized LOMG without thymoma, and non-thymectomized LOMG groups.
The continuous increase in the number of patients presenting with late-onset myasthenia gravis (LOMG) underscores the need for a better understanding of the clinical course and the establishment of an optimal therapeutic strategy. We aimed to clarify factors associated with clinical outcomes in LOMG.
We retrospectively reviewed the clinical profiles of 40 patients with early-onset MG (EOMG) (onset age: 49 years or younger), 30 patients with non-elderly LOMG (onset age: 50–64 years), and 28 patients with elderly LOMG (onset age: 65 years or older) and compared the subgroups according to onset age and thymus status. The evaluated parameters were MGFA classification before treatment, MG-ADL score, complicating diseases, antibody titer, treatment, and MGFA post-intervention status.
Elderly LOMG patients showed transition to generalized symptoms at a higher frequency and underwent thymectomy less frequently than EOMG and non-elderly LOMG patients (p < 0.001). The frequencies of crisis and plasmapheresis were significantly lower in thymectomized LOMG patients without thymoma than in thymectomized LOMG patients with thymoma or non-thymectomized LOMG patients (p < 0.01, P < 0.05, respectively). However, the outcome was not significantly different. All of the thymectomized LOMG patients without thymoma presenting with hyperplasia or thymic cyst had a favorable clinical course.
Our study showed that elderly LOMG patients are more prone to severity, suggesting that they require aggressive immunomodulatory therapy.
Myf5 and Myogenin in the development of thymic myoid cells - Implications for a murine in vivo model of myasthenia gravis
2016, Experimental Neurology
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Patients with EOMG show a population of autoreactive T-cells which foster an intrathymic production of anti-AChR autoantibodies by autoreactive plasma cells (Hohlfeld et al., 1984; Vincent et al., 1978). The concept of intrathymic production of autoantibodies is supported by the observation that a substantial part of patients with EOMG benefits from thymectomy (Cea et al., 2013; Kawaguchi et al., 2007). The ways by which autoreactive lymphocytes escape the mechanisms of central and peripheral tolerance control are only partially understood.
Myasthenia gravis (MG) is caused by autoantibodies against the neuromuscular junction of striated muscle. Most MG patients have autoreactive T- and B-cells directed to the acetylcholine receptor (AChR). To achieve immunologic tolerance, developing thymocytes are normally eliminated after recognition of self-antigen-derived peptides. Presentation of muscle-specific antigens is likely achieved through two pathways: on medullary thymic epithelial cells and on medullary dendritic cells cross-presenting peptides derived from a unique population of thymic myoid cells (TMC). Decades ago, it has been hypothesized that TMC play a key role in the induction of immunological tolerance towards skeletal muscle antigens. However, an experimental model to address this postulate has not been available. To generate such a model, we tested the hypothesis that the development of TMC depends on myogenic regulatory factors. To this end, we utilized Myf5-deficient mice, which lack the first wave of muscle cells but form normal skeletal muscles later during development, and Myogenin-deficient mice, which fail to form differentiated myofibers. We demonstrate for the first time that Myf5- and Myogenin-deficient mice showed a partial or complete, respectively, loss of TMC in an otherwise regularly structured thymus. To overcome early postnatal lethality of muscle-deficient, Myogenin-knockout mice we transplanted Myogenin-deficient fetal thymuses into Foxn1^nu/nu mice that lack their own thymus anlage. We found that the transplants are functional but lack TMC. In combination with established immunization strategies (utilizing AChR or Titin), this model should enable us in the future testing the hypothesis that TMC play an indispensable role in the development of central tolerance towards striated muscle antigens.
The ageing and myasthenic thymus: A morphometric study validating a standard procedure in the histological workup of thymic specimens
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The thymus is believed to play an important role in the pathogenesis of myasthenia gravis (MG). The 80% of MG patients with anti-acetylcholine receptor autoantibodies fall into three clinical subgroups: 1) thymoma; 2) early-onset MG (< age of 40; EOMG) and 3) late-onset (LOMG; onset after 40). Thymectomy is widely used in EOMG, but its benefits have not been established in randomized controlled trials. A multicenter international trial (MGTX) currently seeks to determine whether thymectomy reduces corticosteroid requirements, and to look for correlations with thymic histology. We here describe the validated, standardized histological workup and reporting system used in this trial.
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Effects of thymectomy on late-onset myasthenia gravis without thymoma

Abstract

Objectives

Patients and methods

Results

Conclusions

Introduction

Section snippets

Patients and methods

All patients

Discussion

Acknowledgments

J Neurol Sci

Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study

Ann Neurol

Advances in myasthenia gravis

Curr Neurol Neurosci Rep

Treatment of myasthenia gravis. A call to arms

Neurology

Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Report from the Quality Standards Subcommittee of the American Academy of Neurology

Neurology