Point Counter-Point: Thymectomy in Ocular Myasthenia Gravis

There is high-quality evidence that thymectomy is an effective treatment option for patients with seropositive generalized; myasthenia gravis (GMG).

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Point Counter-Point: Thymectomy in Ocular Myasthenia Gravis Aroucha Vickers, DO, Ore-ofe Adesina, MD, Andrew G. Lee, MD, Gregory P. Van Stavern, MD Drs. Lee and Van Stavern There is high-quality evidence that thymectomy is an effective treatment option for patients with seropositive generalized myasthenia gravis (GMG). However, the benefits of thymec- tomy for ocular myasthenia gravis (OMG), either seropositive or seronegative, remain ill-defined. Two neuro-ophthalmology experts debate the topic of thymectomy in OMG. Pro: Thymectomy has a Role in the Treatment of Ocular Myasthenia Gravis to prime helper T cells, which initiate the inflammatory Ore-ofe Adesina, MD Thymectomy plays a role in the management of both GMG and OMG because there is pathophysiologic and clinical evidence to support its use in patients with and without thymomas. While there are various forms of MG, we will be discussing the acquired autoimmune disorder of the neuromuscular junction characterized by weakness and fatigability of skeletal muscles. It is caused by immunoglobulin, G1 (IgG1) and G3 (IgG3), autoantibodies that produce an inflammatory attack on the postsynaptic acetylcholine receptor (AChR) and induce MG by interfering with Ach binding, fixing, and activating complement; AChR cross-linking; and internalization of the AChRs, reducing the number of AChRs over time (1). In GMG, AChR Abs are present in 90% of patients, while in OMG, they are present only about 40%–60% of the time. These autoantibodies are believed to originate in hyperplastic germinal centers in the thymus where myoid cells expressing AChR are clustered. Myoid cells carry striations and AChR on their surface and are the only known cells to express intact AChR outside of muscle. In addition, thymic epithelial cells produce unfolded AChR subunits that are believed Neuro-Ophthalmology Department (AV), Las Vegas Neurology Center; Neurology Residency Program at Valley Hospital Medical Center (AV), Las Vegas, Nevada; College of Osteopathic Medicine (AV), Touro University Nevada; Cizik Eye Clinic (O-oA), The University of Texas Houston, Texas; Blanton Eye Institute (AGL), Houston Methodist Hospital, Houston, Texas; and Department of Ophthalmology and Visual Sciences (GPVS), Washington University in St. Louis School of Medicine, St Louis, Missouri. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St Louis, MO 63110; E-mail: [e-mail] Vickers et al: J Neuro-Ophthalmol 2022; 42: 541-546 autoimmune process. Most of the patients with AChR antibody-positive MG have thymic abnormalities: hyperplasia in 60%–70% and thymoma in 10%–12% (2). The relationship of MG to thymic tumors was first described in 1901 by Wiegert (2), and chance observations of improved symptoms were seen in patients with MG undergoing thyroidectomy for goiters with concomitant resection of the adjacent thymus gland. This was first reported by Schumacher and Roth who reported the symptomatic improvement after the first transcervical total thymectomy for thyrotoxicosis performed by Ernst Ferdinand Sauerbruch (1875–1951) in 1911 on a 19year-old woman with MG (4). Enlargement of the thymus or a thymoma was mentioned in 28% of the first 250 patients with MG, described until 1912 (5). MG is a well-recognized paraneoplastic manifestation of thymoma, affecting up to one-half of patients with thymoma, and almost all (95%–100%) patients with thymomatous MG have AChR antibodies. The role of thymoma in autoimmunity is not as clear, however, and it is still unknown why some patients with thymoma develop myasthenia while others do not. It is believed that the subtype of thymoma may be important because the development of myasthenia has been seen to be significantly associated with mixed thymomas but not with thymomas of the cortical type (6). Moreover, in addition to AChR antibodies, some individuals with thymoma have muscle autoantibodies directed against titin or the ryanodine receptor and other intracellular muscle proteins (7). Among patients with MG, the presence of antititin antibodies is predictive of a thymic epithelial tumor (sensitivity 69%–80% and specificity 90%–100%) (7,8). Thymoma is a malignant neoplasm, with the potential for 541 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point local invasion and distant metastasis; thus, thymectomy is required for patients who have a thymoma and MG regardless of antibody status or MG subtype (GMG or OMG). Disease-free survival rates at 20 years depend on the histopathology and range anywhere from 36% to 100%. Regarding MG prognosis, data are limited, and patients with MG and thymoma tend to be more severely affected at MG diagnosis and do not respond to thymectomy as well as nonthymomatous patients (8,9). For patients who have nonthymomatous MG, the role of thymectomy as a therapeutic intervention for MG generally depends on AChR antibody status, MG type, and patient age. Currently, the evidence supporting thymectomy for nonthymomatous MG is strongest in patients with generalized, AChR-Ab associated MG because thymectomy in these patients may improve clinical outcomes, minimize immunotherapy requirements, and reduce exacerbations and hospitalizations. For most of these patients, thymectomy is recommended to improve disease control and reduce immunosuppression requirements compared with pharmacotherapy alone (10). In 2016, Wolf et al, in a multicenter randomized trial, reported on 126 patients with generalized nonthymomatous MG comparing extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone over a 3-year period. Patients who underwent thymectomy had a lower time-weighted average quantitative myasthenia gravis score over a 3-year period than those who received prednisone alone (6.15 vs 8.99, P , 0.001), and patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (17% vs 48%, P , 0.001). In addition, fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine or were hospitalized for exacerbations (9% vs 37%, P , 0.001). The number of patients with treatmentassociated complications did not differ significantly between groups (P = 0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P , 0.001) and lower distress levels related to symptoms (P = 0.003). There were no gender differences in outcome despite a higher number of women enrolled than men (11). Regarding age, the evidence of benefit of thymectomy is more robust for those aged 18–50 years. There is limited experience with thymectomy in older adults, and the benefits of thymectomy are less certain for some adults older than 50 years. The 2020 AAN updated Practice Advisory level B recommendation was for consideration of thymec- 542 tomy in nonthymomatous, antibody-positive GMG. This was corroborated by the International Consensus Guidance for Management of Myasthenia Gravis in their 2020 Update, suggesting early thymectomy in antibody-positive GMG and consideration of thymectomy in patients not responding well to treatment in antibody negative GMG (10). While there are no prospective studies for thymectomy in nonthymomatous OMG, and the role of thymectomy in this cohort varies, it can and does play a role in OMG management. In the past, the recommended surgical technique of transsternal thymectomy was considered a too aggressive option for a limited disease. Currently, however, minimally invasive surgery can make thymectomy more acceptable in this population (12,13). Several case series have demonstrated a similar response to thymectomy in OMG as with GMG. Remission rates of 57%–71% over more than 5 years have been reported after thymectomy in OMG (12–16). Regarding generalization after thymectomy, no patients in 2 series of 96 total patients (14,17), and only 1 in a series of 61 patients (16), developed GMG after thymectomy. This contrasts with the expected 50% generalization rate over this time frame. Li et al investigated the association between thymectomy and the risk of generalization in patients with MG, performing a retrospective review of patients with OMG from 7 neurological centers in China. Of 519 eligible patients, 31 (23.7%) of 131 generalized in the thymectomized group and 122 (31.4%) of 388 did in the nonsurgical group during a median follow-up of 19 months. Thymectomy was independently associated with reduced generalization risk, and the 5-year cumulative rate was significantly lower in the thymectomized group than in the nonsurgical group. They concluded that thymectomy may be considered effective in modifying the progression from ocular to generalized MG irrespective of thymoma (18). In a systematic review and meta-analysis of 26 studies, thymectomy was beneficial for nonthymomatous OMG, with complete stable remission of 51%, although heterogeneity among studies limits the certainty of this estimate (19). In their 2020 update, the International Consensus Guidance for Management of Myasthenia Gravis recommended that thymectomy may be offered to patients with seropositive nonthymomatous OMG who do not respond to acetylcholinesterase inhibitors or immunosuppressive agents or who have contraindications or cannot tolerate immunosuppressants (19). These data suggest a definite role for thymectomy in nonthymomatous OMG. Vickers et al: J Neuro-Ophthalmol 2022; 42: 541-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Con: Thymectomy Does Not Have a Role in the Treatment of Ocular Myasthenia Gravis Aroucha Vickers, DO discrepancies in the retrospective studies regarding thymecOMG accounts for approximately 15% of MG with an overall incidence of 1.13 per 100,000 per year (20,21). OMG is categorized as stage I by the modified Osserman classification and the Myasthenia Gravis Foundation of America classification. Manifestations of OMG may include variable and fatigable binocular diplopia and ptosis due to weakness of the extraocular muscles including the recti and oblique muscles, levator palpebrae superioris, and occasionally the orbicular oculi muscles. Treatment options include symptomatic management with an acetylcholinesterase inhibitor and/or chronic immunotherapy. The role of thymectomy in thymomatous and nonthymomatous OMG has long been a source of controversy. Thymectomy however does not have a role for OMG at this time based on the factors outlined below. Onset of symptoms Several studies have alluded to better outcomes after thymectomy if performed early in the disease course. A comparative retrospective study by Mineo reported that surgical intervention within the first 6 months of symptom onset proved to have better outcomes and may decrease the risk of developing generalized MG (22). This timing can pose a challenge because diagnosis of OMG can often be delayed. This delay in diagnosis may be attributed to the wide differential diagnosis for ophthalmoparesis and the high false-negative rate of serology testing. Further studies are needed to establish the true long-term efficacy of thymectomy if performed after 6 months of symptoms onset. Serology Positive serology for acetylcholine receptor (AchR) antibody in OMG can be between 45% and 70% (23). Some of these seronegative patients are then found to have positive muscle-specific kinase (MuSK) or low-density lipoprotein-4 (LRP4) antibodies (24,25). Although thymic abnormalities may be an antigenic source for autoimmunity in patients with AchR antibody MG, patients with MuSK and LRP4 positivity have a much lower frequency of having thymic pathology. Caution should be advised if considering thymectomy in patients with seronegative AChR OMG. Medical management Patients with mild disease may experience relief with symptomatic treatment alone using acetylcholinesterase inhibitors (26). In Deymeer’s (27) recent review of 576 patients over a 10-year period, patients with OMG on immunotherapy were found to be well-controlled or go into remission without developing generalized MG. Furthermore, the 2020 updated International Consensus for Management of MG also has clear recommendations regarding the management of patients with OMG. They have noted Vickers et al: J Neuro-Ophthalmol 2022; 42: 541-546 tomy in OMG and recommend immunosuppression as first-line therapy. They advise starting with low-dose corticosteroids, which have shown minimal side effects, followed by steroid-sparing agents if indicated. If the patient were to fail immunosuppression, then they recommend thymectomy, but only for the AchR OMG cohort (10). Risks Surgical complications that have been associated with thymectomy are by no means benign. Among these complications are myasthenic crisis, respiratory compromise requiring prolonged intubation, pneumonia, pneumothorax, pleural effusion, phrenic nerve injury leading to diaphragmatic compromise, recurrent laryngeal nerve injury resulting in vocal cord paralysis, surgical site infections, and mediastinitis (28–32). In addition, Yamada et al (33) showed that perioperative use of corticosteroids, a mainstay of treatment for MG, had a significant increase in wound dehiscence when compared with patients without corticosteroid treatment. Various surgical techniques have been proposed for thymectomy. They include transsternal, transcervical, and minimally invasive thymectomy with video-assisted or robotic approaches. Newer and less-invasive approaches for patients with MG are preferred but not readily offered or available in all hospitals or surgical centers. Patients therefore need to be made aware of which techniques and services are available in their area because operative risks and financial burdens may shift depending on the procedure being offered. Finally, patients with purely ocular MG may have an unpredictable response to anesthetic agents, including both depolarizing and nondepolarizing neuromuscular blocking agents. Reversal of these agents may lead to a cholinergic crisis further fueling patients’ physical, emotional, and financial toll. Outcomes A retrospective analysis by Sommer et al showed no apparent advantage regarding medical management after thymectomy in patients with OMG (34). Another retrospective study by Evoli et al showed no improvement after thymectomy in thymomatous and nonthymomatous OMG patients (35). In Mineo’s case–control study, there was no significant difference in achieving stable remission between nonthymomatous OMG patients who underwent thymectomy and those who opted for pharmacological treatment alone (22). A previous 15-year review by Hatton et al (36) showed no benefit from transsternal radical thymectomy in patients with OMG. In addition, thymectomy is not a cure. A retrospective analysis on thymomas by Evoli et al (37) showed that less 543 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point than 10% of patients achieved remission and 80% of patients with MG still required immunosuppressive therapy after thymectomy at 10-year follow-up. Recurrence of thymomas can also occur and lead to MG exacerbation. An international randomized single-blind trial by Wolfe et al (38) regarding thymectomy in nonthymomatous MG failed to include the OMG cohort in their trial. In addition, another large systemic review and meta-analysis of risk factors for developing myasthenic crisis after thymectomy also failed to include Stage I MG in their review (28). Without proper high-powered studies regarding thymectomy that include patients with OMG, the strength of recommendation is necessarily lacking. In conclusion, OMG is not a life-threatening disease, and symptomatic relief is often satisfactory with medical management alone. Thymectomy is not a cure, and the risks it may pose from a socioeconomic, financial, and emotional standpoint far outweighs its benefits. A large randomized prospective controlled double-blinded study is probably not feasible, and studies thus far have been uncontrolled, retrospective, or observational. These often have flawed methodology or biases that can muddle study results. We, therefore, cannot recommend thymectomy for OMG until the risks, benefits, and long-term efficacy can be clearly established. Given the effective response to medical therapy in patients with OMG, advocating for thymectomy over medical management is premature until more studies are performed and more data are gathered. Rebuttal—Dr. Adesina My esteemed colleague makes several arguments against the role of thymectomy for OMG, which at face value are reasonable, but can be readily countered. She refers to the study by Mineo et al (22) alluding to better outcomes of thymectomy performed early in the disease course; however, this does not rule out the potential efficacy of later thymectomy in OMG. The study itself argues that there is a strong rationale for thymectomy in class I (OMG) MG because (1) there is a consistent production of AChR Ab in more than 50% of patients and (2) removal of as much thymic parenchyma as possible in active tissue should be an effective treatment (1). The study by Mineo et al also found that surgery had a more rapid effect than pharmacologic therapy, supported by the shorter median time to remission. While I do agree with my colleague that initiation of medical therapy should be considered as first-line treatment for mild OMG, there is no treatment, surgical or medical with zero risk, and progressive or unresponsive disease should warrant strong consideration of thymectomy for the reasons mentioned in the PRO section above. When reviewed, the newer minimally invasive thoracic surgical (MITS) procedures provide safe, effective, and successful surgery when patients are selected appropriately. The indications have expanded as technology has improved, and extended thymectomy (removal of all visible thymus tissue) is proven to be a safe and effective to achieve stable remission. While likely not available universally, MITS procedures, such as video-assisted thoracoscopic surgery (VATS) and robotic- assisted thoracoscopic surgery (RATS), amenable to thymectomy are widely available and VATS are the most commonly performed surgeries by thoracic surgeons in the United States (2) increasing 5-fold between 2006 and 2014. Minimally invasive surgical techniques have been shown to be as effective in removing tumors with similar, low complication and recurrence rates as open thymectomy with shorter hospital and ICU stays, significantly 544 less blood loss, and shorter follow-up periods. They were also as effective in management of myasthenia gravis which requires removal of all thymic tissue, active and inactive which are interspersed within the gland (5). On the medical side, in a study by Sanders and Evoli, immunosuppressive treatment was considered along with or as an alternative to thymectomy in patients with MG not adequately controlled with anticholinesterases. Overall, 82% of patients received immunosuppressants for at least 1 year, with frequencies varying according to disease severity with 72% of those with ocular myasthenia receiving treatment. Prednisone was used in the great majority of patients, and azathioprine was the first-choice immunosuppressant followed by mycophenolate mofetil and cyclosporine. All clinical forms of MG benefited from immunosuppression; however, there was a risk of drug complications that seemed to depend on drug dosage, treatment duration, and patient characteristics. The highest rate of serious side effects (20%) was found in late-onset MG and the lowest (4%) in early-onset disease (4). This is in contrast to bleeding rates in video-assisted thoracoscopic surgery (VATS) series that range from 0.4% to 2% (6). Finally, while pure OMG is not a life-threatening disease per se, it has a potential association with thymoma (a malignant tumor of the thymus) and the potential for generalization to GMG or crisis which is not predictable and can cause serious morbidity or mortality. The lack of data from level 1 randomized controlled clinical trials investigating the role of thymectomy in OMG is due to the relative paucity of cases available for study and does not preclude the available evidence of its effectiveness in the appropriate patient with MG. For comparison, there are no randomized clinical trials investigating the role of lung transplant in cystic fibrosis; nevertheless, there is evidence that it is effective in patients in the right clinical setting. In Vickers et al: J Neuro-Ophthalmol 2022; 42: 541-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point conclusion, thymectomy can and should be offered to patients with acetylcholine receptor antibody (AChR Ab)– positive nonthymomatous OMG (active thymic tissue) who do not respond to acetylcholinesterase inhibitors or immunosuppressive agents or who have contraindications or cannot tolerate immunosuppressants. All MG and OMG patients with thymoma, generalized or not, should be offered thymectomy. Rebuttal—Dr. Vickers Dr. Adesina has done an exceptional job reviewing the pertinent literature supporting thymectomy in OMG. Although our designated roles were to prove opposite opinions, our conclusions are relatively comparable. However, I will point out several key issues in his arguments. First, the data presented largely focused on thymectomy in GMG which has already been well studied and established in the scientific literature. His mention of the 2016 study by Wolf et al and the 2020 AAN updated Practice Advisory level B recommendations are exclusively for patients with GMG and not OMG. There were also no findings or data pertaining to the seronegative OMG, MuSK, or LRP4 subset of patients. Finally, his mention of the 2020 updated International Consensus for Management of MG is quite noteworthy because this consensus clearly recommends medical management first and foremost in all patients with OMG, reserving thymectomy as a last resort and only for AchR seropositive patients. In conclusion, I think both Dr. Adesina and I can agree that there is insufficient high-level evidence to recommend thymectomy in several groups of patients including nonthymomatous patients and non-Ach receptor antibodypositive MG patients. Thymectomy in OMG should be considered on an individual basis after evaluating seropositivity and response to current medical management, along with advantages, availability, and associated surgical risks. Further larger, robust, and ideally prospective studies might elucidate this intriguing and controversial topic. Conclusion—Drs. Lee and Van Stavern Thymectomy remains a potential treatment option for patients with MG. The precise role however for thymectomy in OMG versus GMG remains controversial. Both experts recognize that specific subsets of patients with MG (e.g., seropositive, more severe) may have greater response from the procedure and thus warrant consideration for the surgical and other risks of thymectomy. Future prospective studies including potentially a randomized, controlled clinical trial might provide better guidance for clinicians regarding the question of thymectomy in OMG. 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Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, Ströbel P, Mazia C, Oger J, Cea JG, Heckmann JM, Evoli A, Nix W, Ciafaloni E, Antonini G, Witoonpanich R, King JO, Beydoun SR, Chalk CH, Barboi AC, Amato AA, Shaibani AI, Katirji B, Lecky BR, Buckley C, Vincent A, Dias-Tosta E, Yoshikawa H, Waddington-Cruz M, Pulley MT, Rivner MH, Kostera-Pruszczyk A, Pascuzzi RM, Jackson CE, Garcia Ramos GS, Verschuuren JJ, Massey JM, Kissel JT, Werneck LC, Benatar M, Barohn RJ, Tandan R, Mozaffar T, Conwit R, Odenkirchen J, Sonett JR, Jaretzki A III, Newsom-Davis J, Cutter GR; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511–522. Vickers et al: J Neuro-Ophthalmol 2022; 42: 541-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.