Article In Brief
The lead author of a practice advisory update from the AAN on thymectomy for myasthenia gravis discusses the updates and new recommendations for care.
The American Academy of Neurology has updated its 2000 practice parameter for myasthenia gravis (MG) patients with acetylcholine receptor antibodies, recommending that neurologists discuss emerging evidence that suggests superior benefits with thymectomy plus prednisone over prednisone alone.
The Guideline Development, Dissemination, and Implementation Subcommittee was not able to determine, however, whether or not minimally invasive thymectomy procedures carry equivalent benefits.
An estimated 70 percent to 90 percent of generalized myasthenia gravis patients test positive for acetylcholine receptor antibodies (AChR ab+), which cause abnormal transmission between the motor nerve terminals and muscle fibers at the neuromuscular junction. Although AChR antibody levels can be used to confirm a diagnosis of MG, they cannot predict the degree of weakness that a patient may experience or expect, nor their probable response to therapy.
Although thymectomy has been used in MG treatment for a number of years, no conclusive evidence of its benefits over prednisone versus the risks involved with surgery and other factors existed prior to the MGTX studies.
The new practice parameter reflects positive findings from the international, multicenter, and randomized 2016 MGTX clinical trial (Class I), and includes data from a two-year (Class III) extension study, published in 2019. Initial three-year results, published in 2016 indicated superior disease control with thymectomy plus prednisone, with maximum symptom management in 20 percent more patients than with prednisone alone.
The new practice update was published online March 25 in Neurology.
Neurology Today asked guideline panelist and practice parameter co-author Pushpa Narayanaswami, MD, FAAN, an associate professor of neurology at Harvard Medical School, who works in the neuromuscular division at Beth Israel Deaconess Medical Center in Boston, to go over the new recommendations.
Why was it time to update the 2000 AAN guideline?
The 2000 recommendations, based on an evidence-based review conducted for the AAN, identified 28 studies where outcome measurements were compared between patients who underwent thymectomy and those treated medically. But while that earlier analysis appeared to favor thymectomy—1.6 times higher rate of asymptomatic status, 1.7 higher rate of improvement, and 2.1 higher rate of medication-free remission—it was impossible to determine whether the associations were a result of thymectomy or differences in baseline characteristics between study groups. None of the studies allocated patients randomly to thymectomy versus medical therapy. So, we simply did not have high-quality evidence to make conclusive recommendations for practice at that time.
The 2016 study showed that among a total of 126 patients treated between 2006 and 2012, those who underwent thymectomy had lower average Quantitative Myasthenia Gravis (QMG) scores over a three-year period: 6.15 versus 8.99, respectively, and a 41 percent reduction in time-weighted average alternate-day prednisone dose (22 mg less in the prednisone-plus-thymectomy group). Also, fewer patients in the thymectomy group required immunosuppression with azathioprine—17 percent versus 48 percent—or were hospitalized for MG exacerbations—9 percent versus 37 percent.
Fewer patients who received thymectomy plus prednisone required intravenous immunoglobulin. In all, 22 percent more subjects in the prednisone-only group required IVIG, and 19.2 percent more required hospitalization for exacerbation of symptoms.
In the 2019 extension study, five-year outcome data were analyzed in 60 subjects, including 24 patients in the prednisone-alone arm and 26 in the prednisone plus thymectomy group. Patients in the latter group had significantly lower time-weighted mean QMG scores (5.47 versus 9.34) and required lower mean alternate-day prednisone doses (24 mg versus 48 mg).
Are any other antibodies useful in MG diagnosis or prognosis?
Approximately 10-30 percent of patients with generalized MG who do not have AChR ab+ have antibodies to muscle-specific tyrosine kinase (MuSK). The level of these antibodies appeared to correlate with disease severity and treatment response. Antibodies to other antigens of the neuromuscular junction may be found in subsets of patients, potentially providing clinically useful diagnostic information, but their clinical utility is currently unclear.
What were the AAN review panel's main conclusions?
We concluded that extended transsternal thymectomy plus prednisone is probably more effective than prednisone alone for increasing the chance of attaining minimal manifestation status. At 36 months, 20 percent more participants in the thymectomy plus prednisone group had no symptoms or functional limitations from MG. So, if five patients with MG are treated with thymectomy and prednisone, compared to prednisone alone, one additional patient will do well from the MG symptom standpoint.
We also concluded that because of the moderate benefits of thymectomy and the need for a major surgical procedure with its attendant discomforts and costs, there is likely to be considerable variability in patient treatment preferences, however, we anticipate that most patients would want to be aware of the availability of thymectomy as an option.
The guideline panel extracted the proportion of participants attaining maximum management of symptoms (MMS), based on the 2019 findings, and found that at three years, 47 percent of prednisone patients had achieved MMS, compared to 67 percent of those in the thymectomy group. In other words, for every five participants undergoing thymectomy, one additional subject was symptom-free and had no functional limitations from MG. At five years, participants receiving thymectomy plus prednisone had lower time-weighted average QMG scores (mean difference average time-weighted QMG score 3.87) and a 24mg reduction in average time-weighted prednisone dose.
How did the two approaches compare in terms of adverse events?
There was one death in the prednisone group, and one reported complication secondary to thymectomy: paralysis of a hemidiaphragm. Overall, treatment-related adverse events were more common in prednisone-alone group. A total of 93 events were reported in the prednisone patients, compared to 48 in patients who underwent thymectomy. At five years, at least one adverse event occurred in 42 percent of patients in the prednisone monotherapy group compared to 34 percent in the thymectomy plus prednisone patients.
What is the take-away for clinicians?
For patients with nonthymomatous AChR ab+ generalized MG, thymectomy plus prednisone is probably more effective than prednisone alone for increasing the chance of attaining MMS and improving other MG-related outcomes, including decreased use of azathioprine or IV immunoglobulin rescue therapy, and fewer MG-related hospitalizations.
Because of this, we recommend that clinicians discuss thymectomy with such patients if they are between the ages of 18 and 65 years, including anticipated benefits and uncertainties surrounding the magnitude of these benefits, together with risks involved in the procedures. It is also important for them to counsel patients that it remains unknown whether or not the reported benefits of transsternal thymectomy can also be achieved using minimally-invasive thymectomy procedures.
One other point: We always had this impression that thymectomy took 12-18 months for effect, but in this randomized controlled trial we saw benefits as early as six to nine months, which needs to be kept in mind when discussing thymectomy with patients.
Could you discuss these procedures and what is currently known about their utility?
There are several surgical thymectomy procedures, with the goal of removing as much thymic tissue as possible safely while preserving phrenic, left vagus, and recurrent laryngeal nerve function. The classical method of thymectomy is an external transsternal thymectomy, facilitating complete removal of thymic tissue and fat.
A transcervical approach uses smaller incisions but is rarely used alone because of inadequate visualization of the thymus; it may be combined with the transsternal approach. Minimally invasive techniques include video-assisted thoracoscopic thymectomy (VATS) or robotic-assisted thoracoscopic surgery, but both carry potentially higher risk of leaving residual thymic tissue.
It is uncertain whether results from an extended transsternal thymectomy study can be generalized to minimally invasive thymectomy techniques. A randomized trial with unblinded outcome assessment compared VATS with transsternal thymectomy and found reduced blood loss, shorter surgical times, shorter intensive care unit stay, and hospitalization days for patients undergoing VATS, but it was underpowered to detect significant differences in outcomes. It seems likely, if otherwise equally efficacious in removing all thymic tissue, that patients with MG would prefer minimally invasive thymectomy techniques without having to undergo a median sternotomy.
What other directions for future research are needed?
The 2016 study took 10 years, so it seems unlikely that in the future there will be another adequately-powered randomized controlled trial of thymectomy given the logistical challenges and costs. Much can be learned, however, from prospective cohort studies designed to identify characteristics that predict which patients with MG benefit from thymectomy. Such studies could also include pediatric and older patients, those with MuSK antibodies, as well as seronegative, and ocular types of MG. In addition, there is a need for well-designed observational studies comparing outcomes of minimally invasive thymectomy techniques with transsternal approaches. Finally, it will be informative to have registries of patients undergoing these procedures with long-term outcome assessments using both clinician- and patient-reported outcome measures.