Table 1:
Best evidence papers
| Author, date, journal, country Study type (level of evidence) |
Patient group | Outcomes | Key results | Comments/weakness |
|---|---|---|---|---|
| Mantegazza et al. (1990), J Neurol, Italy [2] Retrospective study (level 2b) |
1152 patients with MG from 6 centres 829 (72%) underwent thymectomy, 531 transcervical, 249 trans-sternal and 49 unspecified Osserman classes I–IV were included Mean follow-up was 4.9 years |
Complete remission (CR) with thymectomy Pharmacological remission |
11% 6% |
Thymectomy seemed to raise the RR mostly for patients operated shortly after the diagnosis, generalized mild–moderate MG and normally involuted thymus Study period not specified, not clear indications for thymectomy; different and unspecified surgical techniques used; patients with missing data were included |
| Frist et al. (1994), Ann Thorac Surg, USA [3] Retrospective study (level 2b) |
A total of 46 MG patients from 1971 until 1992 operated at a single institution with combined surgical and medical therapy The surgical approach was trans-sternal for all patients NT n = 42 Thymoma n = 4 Mean follow-up 75 months Oosterhius classification used |
Age Sex Preoperative stage Duration of symptoms Mortality and morbidity |
Patients <45 years had a better outcome (P = 0.0044) Female patients showed a better outcome (P = 0.06) Response to thymectomy improved dramatically with a more advanced preoperative stage (P = 0.02) No significant influence on outcome No operative/hospital deaths No recurrent nerve injuries |
Thymectomy for MG is an effective therapeutic modality. Of the total, 87% patients had improvement and 28% achieved permanent remission Close correlation between postoperative status at 1, 6 and 12 months and status at last follow-up. Once patients clinically improve, they maintain that clinical state over time. Status at 1 month post-thymectomy strongly correlates with long-term outcome Retrospective uncontrolled study; small number of patients. Thymoma patients included |
| Masaoka et al. (1996), Ann Thorac Surg, Japan [4] Retrospective study (level 2b) |
384 MG patients (286 non-thymomatous, 98 thymomatous) operated at 2 institutions from 1973 until 1993 Surgical approach for all non-thymomatous patients was trans-sternal extended thymectomy (en bloc resection of anterior mediastinal fat tissue, around upper poles of thymus, both brachiocephalic veins and on pericardium) Severity of disease by their own MG classification system Mean age 35 years Female predominance Follow-up to 20 years |
Remission rate (RR) % (3 months, 6 months, 1 year, 3 years, 5 years, 10 years, 15 years, 20 years) Palliation rate (PR) % (3 months, 6 months, 1 year, 3 years, 5 years, 10 years, 15 years, 20 years) Age at time of operation Duration of disease Preoperative steroids Mortality |
15.2, 15.9, 22.4, 36.9, 45.8, 55.7, 67.2, 50 74.2, 79.5, 86.3, 91.6, 92.2, 98.2, 91.7 <34 years old showed better RR (P < 0.05) <23 months showed better RR No difference in outcome when comparing patients who received steroids preoperatively and patients who did not receive them No operative deaths |
Extended thymectomy is an excellent operative procedure in both non-thymomatous and thymomatous MG. The RR in the non-thymomatous group of patients continued to rise even after 5 years. PRs were stable after 3 years. These data suggest that the longer the postoperative period, the better are the results Thymoma patients included use of own classification system for disease severity; different protocols used for steroid administration |
| Venuta et al. (1999), Eur J Cardiothorac Surg, Italy [5] Retrospective study (level 2b) |
A total of 217 patients [155 with non thymomatous myasthenia gravis (NTMG)] underwent thymectomy over a 27-year period at a single institution MG was graded as per Osserman classification 3 surgical techniques were used (cervicotomy, partial upper sternal splitting and complete sternotomy) Female predominance Follow-up 6–234 months (mean 119) |
Complete remission Reduction of medication and/or clinical improvement Stable disease Age at operation Duration of symptoms Presence of thymoma MG severity Mortality (operative) |
25% 46% 18% <45 years old correlated with remission or clinical improvement <18 months’ duration correlated with increased RR (P = 0.049) and PR (P = 0.041) Negatively influenced the prognosis RR Class IIA 86.4%, Class IIB 55.8, 38.5% Class III (P = 0.028) 2 patients (0.92%) |
Thymectomy is effective in the management of patients with MG at all stages with low morbidity An upper split incision was favoured by this group as it allows extensive removal of thymic tissue; offers reduced surgical trauma with shorter length of stay Patients with thymoma present a less favourable outcome Different surgical techniques were employed Both patients with thymoma and non-thymomatous MG were included with no clear differentiation of results between the two groups |
| Gronseth et al. (2000), Neurology, USA [6] Meta-analysis (level 2a) |
A definitive study of the effectiveness of thymectomy has never been done A Medline search was carried out to find studies (controlled non-randomized and uncontrolled case series) describing outcomes in patients with or without thymectomy Patients with thymoma were excluded |
Survival Improvement since diagnosis Asymptomatic on or off medication Asymptomatic off medication MG severity Age and gender Medical therapy |
Positive associations in most studies between thymectomy and MG remission and improvement There are confounding differences in baseline characteristics of prognostic importance between thymectomy and non-thymectomy patient groups in all studies Persistent positive associations between thymectomy and improved MG outcomes after controlling for single confounding variables such as age, gender and severity of MG Conflicting associations between thymectomy and improved MG outcomes in studies controlling for multiple confounding variables simultaneously |
For patients with NTMG, thymectomy is recommended as an option to increase the probability of remission or improvement (Class II) There is no conclusive evidence of the superiority of one surgical technique to another as RRs data comes from uncontrolled studies |
| Budde et al. (2001), Ann Thorac Surg, USA [7] Retrospective study (level 2b) |
A total of 113 patients underwent thymectomy for MG between 1974 and 1999 at a single institution 2 surgical techniques were employed - T incision limited upper sternotomy in 84% (2 × 2 in. T-shaped skin incision with the horizontal limb over the second intercostal space and vertical limb from the midpoint of the T down to the fourth intercostal space. A superior skin flap is created and the sternum is divided from the notch to the fourth intercostal space) - Full sternotomy in 16% Both NTGM and thymoma patients were included Follow-up was obtained in 92 patients (81%). Mean follow-up 51 ± 59 months |
Remission Improved Remission + improvement (‘benefit’) Unchanged Worse Symptom duration Osserman classification Age Sex Thymic pathology Preoperative treatment Mortality Morbidity |
21% 54% 75% 14% 11% did not correlate with outcome (average length of symptoms for worse patients was the lowest) Class 2 of 3 tended to benefit more (79%) <50 years (81% benefit vs 55% if >50 years, P = 0.02) Improved outcome for female patients in univariate analysis No difference in non-thymomatous MG No significant correlation with the outcome 1 patient (2 weeks postoperatively of unknown causes) 14% |
Thymectomy may be safely performed by a limited T upper sternal incision. The proportion of overall improvement (75%) compares favourably with other large studies. The RR of 21% is slightly lower. However, comparison among studies is often difficult because of different exclusion criteria Complete stable remission (CSR) was achieved in patients at an average of 66 ± 71 months postoperatively, which is longer than the average follow-up of 51 months Multivariate analysis of patient sex was not statistically significant (P = 0.34) Preoperative stabilization of the disease included different regimes given along the period of study Two surgical techniques were employed The number of patients within each group is not clearly defined |
| De Perrot et al. (2001), Respiration, Switzerland [8] Retrospective study (level 2b) |
A total of 35 patients underwent thymectomy between 1979 and 1999 at a single institution (23 patients with non-thymomatous MG) Complete follow-up available for 33 patients, with a mean of 96 months Modified Osserman classification was employed 4 different surgical techniques employed: transcervical (preferred), median sternotomy (if thymoma was suspected or complete thymectomy could not be performed through a cervicotomy), right or left thoracotomy (for tumours extending into the pleural cavity) |
Age Sex Duration of symptoms Osserman stage Histological findings Mortality |
The cut-off was 40 years of age. Remission and improvement were not statistically significant (P = 0.8 and 0.7, respectively) There was no statistically significant difference between male and female rates for remission and improvement (P = 0.4 and 0.8, respectively) No statistically significant difference for remission or improvement (P = 0.4 and 0.9, respectively) Greater clinical improvement in IIB, III, IV Class patients (P = 0.04) RRs better in the presence of thymic hyperplasia (P = 0.04) None for the non-thymomatous group |
The large majority of patients (81%) improved after surgery. Postoperative clinical improvement was greater when extensive myasthenic involvement was present preoperatively RR was greater in patients with stage I and IIA (not statistically significant but this finding has been observed by other authors) Shorter duration of symptoms did not affect the RR in contrast to several other reports Small series including thymomatous and non-thymomatous MG Different surgical approaches |
| Gronseth et al. (2002), Neurology, USA [9] Review |
Patients with MG from non-randomized trials dating back to 1953 | Measured outcomes included survival, improvement since diagnosis, becoming asymptomatic on medication and medication-free remission | No Class I studies of the effectiveness of thymectomy have been performed. Most Class II studies demonstrated higher MG. RRs in patients undergoing thymectomy. However, these studies were consistently confounded by differences between MG patients | MG patients undergoing thymectomy in most studies were more likely to achieve medication-free remission, become asymptomatic and improve Due to the confounding differences between MG patients receiving and not receiving thymectomy, a benefit of thymectomy in MG patients has not been established |
| Mantegazza et al. (2003), J Neurol Sci, Italy [10] Prospective cohort study (1b) |
A total of 206 NTMG patients Video assisted thoracoscopic extended thymectomy (VATET) n = 159 (transcervical incision with removal of thymic tissue in the neck. Subsequently, the sternum is lifted and trocars are introduced in the left pleural cavity to proceed via video-assisted thoracoscopy) Extended trans-sternal n = 47 Osserman classification I–V patients were included 6-year follow-up |
CSR at the 6-year follow-up Mortality |
Thymic hyperplasia, treatment with anticholinesterase drugs and age of onset <40 years were associated with a significantly greater probability of achieving CSR (P = 0.0001, <0.0001 and 0.037, respectively) Sex, time of onset to surgery, presence of anti-Ach-R antibody and type of surgery did not affect CSR 0 |
The absence of perioperative mortality and very low morbidity during the postoperative period demonstrate that VATET is safe CSR was achieved in 53.9% of patients at 6 years |
| Tansel et al. (2003), Surg Today, Turkey [11] Retrospective study (level 2b) |
A total of 204 NTMG patients underwent thymectomy between 1980 and 2001 Surgical technique via partial median sternotomy (94%) and median sternotomy (6%) Modified Osserman classification employed Medical treatment included anticholinesterase therapy, steroids, combination of both, steroids + immunosuppressant or no medication Mean follow-up 7.2 ± 1.2 years with last follow-up in 79% of patients |
Preoperative classification Preoperative treatment Age Duration of symptoms Gender Histological findings. Mortality |
No significant correlation was found (P = 0.43) although patients with Class I and IIc2 tended to benefit more Not significant influence on outcome (P = 0.35) Did not influence remission or improvement rates (P = 0.42) Did not influence remission or improvement rates (P = 0.67) No influence on remission (P = 0.97) Favourable trend towards remission in patients with thymic hyperplasia (P = <0.001) No perioperative deaths |
The early RR (44%) achieved after thymectomy had increased significantly by the end of the first year (72%, P = <0.001) Early and late RRs of 6 months and 1 year seem arbitrary |
| El-Medany et al. (2003), Asian Cardiovasc Thorac Ann, Saudi Arabia [12] Retrospective study (level 2b) |
A total of 100 MG patients at a single institution between 1986 and 2001 (93 non-thymomatous and 7 thymoma-associated MG) Surgical technique: maximal thymectomy (combined transcervical and trans-sternal approach. Through the transcervical incision, thymic and fatty tissue anterior and anterolateral to the trachea from below the thyroid gland to the superior mediastinum is removed. In the mediastinum, the removal of tissue extends fatty tissue extending down to the diaphragm, between phrenic nerves, cardiophrenic tissue, retroinnominate and AP window) Osserman classification employed Follow-up 8–180 months (mean 91 months) |
CR BR Age Sex Duration of symptoms (<1 year) Preoperative steroids Histology Ectopic thymic tissue |
38.7% at last point of follow-up (increased progressively to reach a peak of 75% at 15 years) 86% (increased to 100% at 15 years) <50 years had better outcome (P = 0.0044) No statistically significance between female and male (BR 85 vs 75%) No significant correlation found with CR (36 vs 35.5%) CR in 27% of patients on steroids compared with 40% not on steroids (not statistically significant) CR in 42% of patients with hyperplastic thymus Poor prognostic factor (P = 0.0001) |
Maximal thymectomy is an effective and safe procedure for treatment of MG The CR and total BR are prone to increase over time Univariate analysis showed that age, histology and ectopic thymic tissue are significant prognostic factors for outcome |
| Kawaguchi et al. (2007), Clin Neurol Neurosurg, Japan [13] Retrospective study (level 2b) |
A total of 34 late-onset (age of onset >50 years) NTMG patients were selected 20 patients underwent thymectomy (approach not specified) and 14 medical treatment Clinical grade evaluated according to MGFA Subgroup analysis of MGFA Class 2 was performed Clinical course and outcomes over 2 years Mean follow-up for thymectomy patients was 11.7 years and 7.8 years for non-thymectomy patients |
Minimal symptoms Generalized symptoms (thymectomy group vs non-thymectomy) Clinical remission |
Present in 50% of thymectomy group patients at the end of the follow-up period 30 vs 75% (P < 0.05) 50 vs 17% (P = 0.11) |
Thymectomy is a potentially effective treatment for late-onset NTMG with mild generalized symptoms Small sample, only assessing subgroup analysis |
| Sonett et al. (2008), Ann N Y Acad Sci, USA [14] Review |
Review attempting to clarify some of the controversial issues concerning the selection of a thymectomy technique in the treatment of NTMG and to make limited recommendations based on the best available evidence This analysis consists of uncontrolled retrospective studies with an extense number of confounding factors making the analysis speculative |
Extent of thymic tissue removal Remission Disease severity Duration of symptoms Surgical technique |
The more thymus removed, the higher the RR 51 and 50% at 5 years for VATET and combined transcervival–trans-sternal Less severe disease has better outcomes Better outcomes for shorter duration Combined transcervical and trans-sternal maximal thymectomy should remain the benchmark |
At 5 years maximal thymectomy continues to produce the most effective overall response Controlled well-designed studies are required to begin to resolve the many conflicting statements and unanswered questions that exist concerning the selection of thymectomy in the treatment of MG |
| Pompeo et al. (2009), Eur J Cardiothorac Surg, Italy [15] Retrospective study (level 2b) |
A total of 32 patients with NTMG underwent extended thoracoscopic thymectomy (4-trocars access with removal of the entire thymus, anterior mediastinal perithymic tissues, fatty tissue in the aortocaval groove, AP window, cardiophrenic sinuses and lower cervical area) MGFA clinical classification was used CR and symptomatic improvement were assessed Follow-up 60–156 months (median 119) |
Sex Symptom duration (<12 months) MGFA class Oropharyngeal involvement Histology Ectopic thymic tissue Anti-AChRab Anti-MuSKab Mortality |
No significant difference between male and female (P = 0.1) Shorter duration significantly correlated with CR and improvement (P = 0.006) Did not impact on CR or improvement (P = 1.0) No involvement significantly correlated with CR and improvement (P = 0.01) No statistically significant difference (P = 0.06) Presence was associated with negative impact on CR and improvement (P = 0.05) Does not influence outcome (P = 0.12) Significant correlation with CR and improvement (P = 0.0007) None |
Extended thymectomy results in highly satisfactory long-term outcome in non-thymomatous MG with a 10-year remission of 50% and an overall response rate of 90% Patients who did not respond to thymectomy had a positive titre of anti-MuSKab (predictor of no response at univariate analysis) Results of thymectomy continue to improve over time and adequate length of follow-up is needed to assess the efficacy of any thymectomy technique Small cohort |
| Lin et al. (2010), Eur J Cardiothorac Surg, Taiwan [16] Retrospective study (level 2b) |
A total of 60 NTMG patients underwent thymectomy from 1995 to 2004 at a single institution Preoperative status was classified according to MGFA classification Two surgical approaches were employed (trans-sternal thymectomy n = 22 and video assisted thoracoscopic surgery (VATS) thymectomy n = 38) Follow-up range 12–131 months (median 44 months) |
Crude CSR rate Sex, disease duration, MGFA classification, anti-AchR antibody, preoperative plasma exchange, preoperative medication and operative method Age of onset (<40 years), presence of hypothyroidism and thymic hyperplasia Mortality Morbidity |
32% at 38.5 month mean follow-up Did not influence CSR rate (P = 0.7, 0.21, 0.79, 0.32, 0.88, 0.3, 0.91, respectively) Higher probability of achieving CSR (P = 0.022, 0.003, 0.041, respectively) 0 5% |
VATS thymectomy is an advantageous procedure for treating NTMG patients compared with trans-sternal approach offering equivalent CSR rates The acceptable CSR, high improvement rate, short hospital stay, low conversion rate, low morbidity rate and no mortality demonstrate that VATS thymectomy is a safe and effective method for NTGM patients The role of thymectomy for ocular MG remains controversial Small sample including 2 surgical techniques and comparing data between them MGFA classification was different in both groups |
| Spillane et al. (2013), J Neurol, UK [17] Retrospective study (level 2b) |
A total of 89 MG patients underwent extended trans-sternal thymectomy over a 12-year period (1999–2011) Thymoma and non-thymoma patients included MGFA classification used for preoperative assessment of disease severity and post-intervention status Follow-up 0.5–11 years, last clinical review mean of 3.8 years |
CSR (at last clinical review) PR Improved status Steroid requirement after thymectomy Duration of symptoms (<2 years) Thymic histology (hyperplasia vs other histology) Mortality Morbidity |
34% 33% 13% Fell from 73% preoperatively to 47% (P < 0.01) CSR 40 vs 33% (P = 0.19) CSR 42 vs 26% (P < 0.05) 0 9% |
Thymectomy is a safe and well-tolerated procedure generally followed by a long-term substantial improvement in myasthenic symptoms in the majority of patients. No correlation between duration of symptoms and response to thymectomy |