While thymectomy has long been considered an option to treat myasthenia even if there is simply thymic tissue present rather than thymoma or thymic carcinoma, it has been uncertain how much benefit is achieved by undergoing this major surgical procedure. While there have been a number of retrospective reports of benefit, observational studies where the patients were also on modern immunosuppression did not show benefit, and some studies have indicated that any benefit that does exist is only present in the first 5 years after surgery. There has therefore been a call for a randomised study comparing thymectomy in non-thymoma patients (in thymoma there is an indication to operate anyway) combined with standard immunosuppressive treatment versus standard immunosuppressive treatment alone. Just recently the results of a long-awaited trial on this topic were published in the New England Journal of Medicine.
From 2006 to 2012, a total of 126 patients were randomised to the two arms as above. Eligible patients were adults under 65 with positive anti ACh antibodies, and non-ocular (i.e. at least mild generalised) myasthenia. Assessors of myasthenic severity were blinded (patients wore high necked clothing during assessment!). Patients did not have to have visible thymic tissue on imaging with CT or MRI; in fact visible thymoma was an exclusion criterion. The surgery removed any mediastinal tissue that could contain macroscopic or microscopic thymic tissue.
The primary measures of severity were the time-weighted average quantitative myasthenic score measuring fatigability in key muscle groups, and the steroid dose requirement to maintain minimally symptomatic disease. Assessment was over a three year period.
The study found a 2.8 point lower average quantitative myasthenia score (i.e. better) in the thymectomy group and also a lower requirement for steroids (44 mg versus 60 mg). Also fewer patients required azathioprine or hospitalisation for exacerbations (9% versus 37%). There was no difference in treatment-associated complications but fewer treatment-associated symptoms which was presumably reflective of the lower average doses of immunosuppression. . The study performed subgroup analysis by sex, and found no difference in myasthenia score for men, but still a reduction in steroid requirement. There was no stratification by age.
Thymectomy improves outcome in the first three years after surgery, even compared with modern immunosuppressive therapy regimes. The lower score was probably clinically significant given physicians determined clinical improvement at changes as little as 2.3 points. The study falls short of making any clear recommendations to treat everyone with thymectomy for whom surgery is not otherwise excluded.
Journal Club’s Conclusions and Comments
We wondered if there might be variability in how hard one looks for thymic tissue on imaging which would in this study trigger exclusion from the trial on the basis of thymic hyperplasia. The less sensitive the investigation, the greater the chance of entering into the trial patients operated upon with hyperplasia and therefore the greater the expectation of benefit from surgery.
One of the key questions was the duration of benefit of surgery, but with a three year trial this cannot obviously be answered. Will patients want surgery if the benefit is only three years of 15 mg lower prednisolone dose (where the error bars are missing from the figure) and fewer hospitalisations (the latter was not a primary outcome measure and obviously the patients themselves who decided to attend hospital were not blinded)? Probably we will get further updates on the same study results in the NEJM cropping up at intervals.
The lack of clear guidance on management as a result of this trial, probably the only such ever likely to be performed, is a little frustrating. Perhaps they are waiting for a longer term follow up. Our group discussed that current practice is to be selective in offering thymectomy. A young woman who wants to have children and who has already proven resistant to or dependent on high dose steroids, is clearly going to be a better candidate for thymectomy than a man aged 65 with mild easily controlled disease. What we need more guidance on is the tipping point in the balance between those two extremes. Nevertheless the study confirms that at least some patients without thymic tissue on imaging do have benefit over the first three years when compared with modern immunosuppressive regimes.
The journal club meeting upon which this report is based was presented by Dr Peter Arthur-Ferraj, Specialist Registrar in Neurology.