Title | Does Treatment of Ocular Myasthenia Gravis With Early Immunosuppressive Therapy Prevent Secondarily Generalization and Should It Be Offered to All Such Patients? |
Creator | Sui H. Wong, MRCP; Gordon T. Plant, FRCP, FRCOphth; Wayne Cornblath, MD |
Affiliation | Department of Neuro-ophthalmology (SHW, GTP), Moorfields Eye Hospital, London, United Kingdom; Medical Eye Unit (SHW, GTP), St. Thomas' Hospital, London, United Kingdom; Department of Neuro-ophthalmology (SHW, GTP), National Hospital for Neurology and Neurosurgery, London, United Kingdom; and Departments of Neurology and Ophthalmology (WC), University of Michigan, Ann Arbor, Michigan |
Subject | Humans; Immunosuppressive Agents; Myasthenia Gravis; Secondary Prevention |
OCR Text | Show Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Does Treatment of Ocular Myasthenia Gravis With Early Immunosuppressive Therapy Prevent Secondarily Generalization and Should It Be Offered to All Such Patients? Sui H. Wong, MRCP, Gordon T. Plant, FRCP, FRCOphth, Wayne Cornblath, MD Neuro-ophthalmologists frequently diagnose and manage patients with ocular myasthenia gravis (OMG), either primarily or in conjunction with a neurologist. Although there is an abundance of literature regarding treatment strategies for generalized myasthenia gravis (GMG), many studies exclude patients with OMG or do not specifically differentiate OMG from GMG patients. Since a variable number of patients who present with OMG will ultimately develop generalized symptoms, it is possible that treatment with immunosuppressive therapy could prevent generalization, but the literature is conflicted on this topic and relatively sparse. We have invited several experts on this subject to debate this topic. Pro: Early Immunosuppressive Therapy Prevents Secondary Generalization in Ocular Myasthenia Gravis: Sui H. Wong, MRCP and Gordon T. Plant Opening Statement The timing and use of immunosuppression in OMG is controversial. The lack of randomized controlled trials (RCTs) of patients with OMG, and the exclusion of OMG patients from many MG trials, contributes to this. One of the barriers to RCTs is the relative rarity of OMG, that is, multicenter collaborations and long-running studies will be needed to address some of the questions surrounding this controversy. In the meantime, what can we surmise from the current evidence with regards to immunosuppression for OMG? One of the key controversies is whether immunosuppression can reduce the risk of secondary generalization. OMG is defined as MG limited to ocular symptoms and signs. Such manifestations are the presenting features in 50%-85% of patients with MG (1,2). The majority of these patients (50%-80%) will develop neuromuscular weakness elsewhere, that is, secondary generalization (GMG), usually within 2 years of disease onset (1,2). The possible disease-modifying effect of early immunosuppression was first suggested in a retrospective case series by Department of Neuro-ophthalmology (SHW, GTP), Moorfields Eye Hospital, London, United Kingdom; Medical Eye Unit (SHW, GTP), St. Thomas' Hospital, London, United Kingdom; Department of Neuro-ophthalmology (SHW, GTP), National Hospital for Neurology and Neurosurgery, London, United Kingdom; and Departments of Neurology and Ophthalmology (WC), University of Michigan, Ann Arbor, Michigan. The authors report no conflicts of interest. Address correspondence to Sui H. Wong, MRCP, Department of Neuroophthalmology, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, United Kingdom; E-mail: suiwong@doctors.org.uk 98 Kupersmith et al (3). This observation was subsequently supported by other retrospective cohort studies (4-8). These studies report the reduced risk of secondary generalization in patients treated with corticosteroids, azathioprine, or both. Unfortunately, the retrospective nature of these reports comes with limitations, which we have recently reviewed (9). These include the timing of corticosteroids from symptom onset, which was not clearly documented; the fact that some patients developed GMG within 3 months of symptom onset, as such patients may arguably have been recruited too early to the studies; the observation that a slightly higher proportion of seronegative patients were in included in some treated groups, as such patients may have an inherently reduced risk of generalization (ROG); and finally, nonrandomized treatment. It should be noted that patients were seronegative to anti-acetylcholine receptor (anti-AChR) antibodies. These studies did not include later serological developments, that is, cell-based assays to improve detection of anti-AChR antibodies, anti-muscle specific kinase (MuSK), and anti-lipoprotein receptor 4 (LRP4) antibodies. In addition to the above reports, epidemiological studies demonstrated that the conversion rate to secondary generalized disease was 60% before the era of immunosuppression (10,11) compared with 30% after the use of immunosuppression in OMG (6). Furthermore, thymectomy studies on OMG suggest reduced rate of conversion to GMG (12-16), lending further weight to the hypothesis of disease-modifying effect of early immunosuppression. Another controversy, also important to highlight in this discussion, is whether in OMG, that is, patients with ocular Wong et al: J Neuro-Ophthalmol 2016; 36: 98-102 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point symptoms only without the associated mortality risks of generalized disease, exposure to the risks of immunosuppression is justified. An alternative approach would be to wait until the patient has clear evidence of GMG, when the decision to immunosuppress would be as for any other GMG patient. Corticosteroids are still recommended as the first line immunosuppression in MG (17,18). Potential adverse reactions range from mild to severe, for example, from cataracts, weight gain, and glucose intolerance, to diabetes, opportunistic infections, and avascular bone necrosis. Until recently, the incidence of adverse effects of corticosteroids in OMG has not been robustly studied and have reportedly ranged from 0% to 33% (3,5-7). One study reported 67% in a cohort of unselected GMG and OMG cases (19). Such disease-specific information is necessary for OMG as the incidence of adverse effects will depend on factors such as the age, gender, ethnicity, and corticosteroid dose and duration required. Patients starting corticosteroids should be warned of the potential risks. We are not aware of additional risks for this patient group, but specific evidence is lacking. The first RCT on OMG, currently in progress in North America, may clarify this issue. The EPITOME (Efficacy of Prednisone in the Treatment of Ocular Myasthenia) study is a prospective, multicenter, double-blind, randomized, placebocontrolled trial evaluating the efficacy and tolerability of corticosteroids in newly diagnosed OMG patients (20). This study will actively screen for adverse events including glucose tolerance tests in patients without diabetics, pre- and postophthamic exams for glaucoma and cataracts. The trial is due to be completed in September 2015. Unfortunately, the EPITOME study is only powered to assess safety and efficacy. The investigators have stated that the cost of running a study large enough or long enough to answer the question of disease-modifying risk effect of corticosteroids was prohibitive (20). It is possible that not all patients with OMG have the same risk of secondary generalization, and perhaps targeting the higher risk group may be more justified in exposing them to the side effects of immunosuppression. Retrospective studies suggest that patients at higher risk of secondary generalization include those with older age of onset, seropositivity, abnormal repetitive nerve stimulation, and severity of symptoms (1,2,4- 7,21,22). Unfortunately, these studies included patients treated with immunosuppression which, as already stated, may modify risk of secondary generalization. With this in mind, we are currently undertaking a prognostic study assessing the risk in untreated OMG patients, with the aim of creating a prognostic model that stratifies patients to "low" or "high" risk. Our current practice is based on the assumption that corticosteroid therapy, if used judiciously and with careful monitoring, justifies the associated risks. We start with a trial of pyridostigmine and add corticosteroids if ocular symptoms are still disabling. Our preferred regimen is to introduce corticosteroids up to 1 mg/kg over 2 weeks and to taper this as the patient's symptoms come under control. Azathioprine, unless contraindicated, is started at the same time, for its steroid-sparing effect, with methotrexate and mycophenolate mofetil as alternatives. The third controversy to highlight is whether seronegative patients should be treated with immunosuppression. Only approximately half of patients with OMG have antiAchR antibodies using the widely available radioimmunoprecipitation assay (23). Undoubtedly, corticosteroids can effectively resolve diplopia (24). However, there may be reluctance to immunosuppress seronegative patients, particularly those who also have negative ancillary investigations (e.g., neurophysiology or edrophonium tests). We suspect that lack of diagnostic confidence and the worry of exposing such patients without diagnostic certainty to the risks of immunosuppression may influence the decision not to treat. It is our opinion that immunosuppression can be very helpful in such patients. First, response to treatment could support the diagnosis of OMG. Second, if left untreated for an extended period, patients with OMG may develop extraocular muscle atrophy (25,26) and become refractory to all treatment (25). In summary, we propose that early immunosuppression should be considered in patients with OMG both for the beneficial effect of resolution of ocular symptoms-rarely achieved with pyridostigmine alone-and for a potential disease-modifying effect. However, this is an unpredictable disease, and the decision to use immunosuppression early remains controversial due to the lack of RCTs. It is hoped that future multicenter prospective trials, including an ongoing RCT on the efficacy of prednisone in OMG, and prognostic studies such as ours will guide our future management decisions. Con: Early Immunosuppressive Therapy Does Not Prevent Secondary Generalization in Ocular Myasthenia Gravis: Wayne Cornblath, MD Opening Statement The timing and use of immunosuppression in OMG should not be controversial. Although there is a dearth of RCTs, data from natural history studies, GMG RCTs and retrospective studies on OMG along with common sense Wong et al: J Neuro-Ophthalmol 2016; 36: 98-102 and clinical judgment make the treatment decisions in OMG straightforward. The key controversy is whether immunosuppression can reduce the risk of secondary generalization and should be the standard of care in patients with newly diagnosed OMG. In 99 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point thinking about this statement, we should consider the different types of patients with OMG clinicians encounter and when this standard would apply. A useful division is into groups based on response to pyridostigmine and diagnostic certainty. Pyridostigmine is generally safe, and in our practice, we will frequently start a trial of pyridostigmine while awaiting the results of anti-AchR antibody testing or single fiber electromyography (sfEMG). This two-by-two table approach leaves us 4 groups to consider: 1. 2. 3. 4. Positive testing and no response to pyridostigmine. Positive testing and response to pyridostigmine. Negative testing and no response to pyridostigmine. Negative testing and response to pyridostigmine. Before we discuss the 4 groups, we need to review the diagnosis of OMG, which can be difficult. First, one must have a clinical suspicion (e.g., what appears to be an internuclear ophthalmoplegia (INO) is actually a pseudoINO from OMG or an isolated sixth nerve palsy is not ischemic but OMG). Second, one must generally confirm the clinical suspicion with additional testing. Unlike the McDonald criteria for multiple sclerosis, there are no generally recognized diagnostic criteria for OMG or GMG. One published article, "Myasthenia gravis: Recommendations for clinical research standards" sets up standards for severity and classification (OMG vs GMG) but does not comment on diagnostic criteria (27). Although all would agree that a positive anti-AchR antibody or MUSK test will help to establish the diagnosis of OMG, in 30%-50% of OMG patients these tests are negative (2). One is then left with the edrophonium test, rest or ice test, sfEMG or response to therapy to make a diagnosis. The sensitivity and specificity of each of these tests varies and, in general, is poorly studied (28). In our experience with 158 patients, the combination of blood testing and sfEMG lead to a diagnosis in 93% of patients. Let us start with a case from Group 1 (positive testing and no response to pyridostigmine). A 40-year-old man with no other medical problems develops diplopia and ptosis, and OMG is confirmed with a positive anti-AchR antibody test. A trial of pyridostigmine is undertaken with inadequate relief of symptoms (18). After discussion of risks and benefits, the patient is started on prednisone and mycophenolate mofetil with relief of symptoms (29). In this case, there are 4 points for discussion. First, the diagnosis of OMG is confirmed given the positive antibody test. Second, treatment with an immunosuppressive agent is the next step after failure of pyridostigmine (18). Third, the choice of immunosuppressant is unclear with a wide range of options from daily prednisone, alternate day prednisone, mycophenolate mofetil, cyclosporine, azathioprine or prednisone plus a second agent. Unfortunately, there is no good evidence comparing these options. The final point is that it does not matter if there is any benefit of immunosuppression in preventing secondary 100 generalization as the decision to treat with immunosuppression has already been made in this group on clinical grounds. In Group 2 (positive testing and response to pyridostigmine), the largest dilemma arises. Do we treat this group of patients who are clinically doing well to prevent the possible future development of GMG? Several factors play a role. What is the rate of generalization? What is the success of preventing generalization? What are the risks of treatment? And perhaps most importantly, is there any risk in delaying treatment? The rate of generalization from OMG to GMG varies widely, from 36% to 83% of OMG patients (2,5). These rates are very important because of the converse question: what percent of patients are we treating with immunosuppressive drugs that will never have the disease we are trying to prevent? With a 36% rate of generalization, almost two-thirds of treated patients would never have the disease for which they are being treated. Given the variable rate of generalization, the success of preventing GMG is difficult to measure. There are no RCTs to answer the question, only small retrospective studies. One such study noted that 13% of OMG patients treated with prednisone (N = 55) developed GMG, whereas 50% of OMG patients treated with pyridostigmine (N = 32) developed GMG (4). In another retrospective study using prednisolone, azathioprine and thymectomy alone or in combination, 12% (N = 50) of patients treated with immunosuppression developed GMG, whereas 64% (N = 28) of patients treated with pyridostigmine alone developed GMG (6). The risks of treatment with prednisone are well known. In a study of 27 patients with OMG and GMG treated with oral prednisone for an average of 5.4 months, new onset glucose intolerance or worsening of diabetes occurred in 67%, weight gain in 42%, hypertension in 21%, and osteoporosis in 20% (30). Finally, is there an advantage to preventing the development of GMG or a disadvantage to waiting to treat when GMG occurs? There is no evidence that treating GMG when it develops, by 3 years in 90% who generalize, puts patients at any disadvantage. Waiting to treat also significantly reduces the number of patients treated unnecessarily who would develop side effects. In Group 3 (negative testing and no response to pyridostigmine), the decision to treat is difficult. Do we start immunosuppressive therapy with a "probable" diagnosis, to borrow from the multiple sclerosis classification scheme, of OMG? In this group, I do not believe the unproven benefit of reduction in generalization, discussed above, should play a factor in the decision to treat. In this fortunately rare group, we are far removed from evidence based medicine and must rely on the art of medicine instead of the science. These patients can be followed without treatment and retested either if there are changes in examination or after additional time. Or, a treatment trial with immunosuppressive agents, taking the patient's medical condition into account, could be undertaken with careful monitoring. In addition, careful neuro- Wong et al: J Neuro-Ophthalmol 2016; 36: 98-102 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point ophthalmic examination to eliminate other causes of diplopia must be performed before a trial of immunosuppressive agents. In Group 4 (negative testing and response to pyridostigmine), we can have a patient with variable ptosis who reports resolution with pyridostigmine. In this case, as in Group 2, symptoms are resolved and the risk of immunosuppressive treatment for an unproven benefit of reduction in generalization is too high. The "probable" diagnosis of MG further changes the risk benefit ratio toward the risk side, eliminating the consideration of using immunosuppressive therapy in this group. Treating patients with OMG with prednisone to reduce the risk of development of GMG would definitely put a significant number of patients at risk of developing side effects for a disease they might never get. The possible reduction in the chance of developing GMG makes no difference in a disease where there is no penalty if treatment is started at a later date when the GMG actually manifests. Rebuttal: Sui H. Wong, MRCP and Gordon T. Plant Dr. Cornblath provides a nice framework that divides patients with ocular myasthenia into 4 groups, in essence combinations of pyridostigmine response (yes/no) and supportive investigations of anti-AChR antibodies or sfEMG (positive/negative). However, the above approach is more "art" than "science," although certainly a practical and systematic one. It is also likely that seropositive patients will have a positive EMG test, that is, seropositivity to anti-AChR may be the main determinant in the above approach. The majority of anti-AChR antibody tests use the radioimmunoassay. In patients with a seronegative result, it is worth considering the cell-based assays, if available. A recent study showed 50% of patients seronegative to radioimmunoassay were seropositive on cell-based assay where acetylcholine receptors are clustered (31). At this time, we have completed our prognostic study (submitted for publication). Our proposed score for the risk of generalization (ROG) revealed that seropositivity contributes one point to the ROG score. This hints that seropositive patients may be in the group that benefits most from early immunosuppression. We share the concerns of the potential risks of corticosteroids or other immunosuppression and eagerly await the results of the EPITOME study. The lack of evidence in this area emphasizes the importance of an RTC of risk-modifying treatment. We propose a paradigm shift in the approach to OMG: to identify high-risk patients early and to move forward with an RCT of early immunosuppression. We calculated that a sample size of at least 304 patients is needed to show a 50% reduction in GMG. In response to Dr. Cornblath's question, what benefit will early immunosuppression or prevention of GMG bring? It would be a theoretical and instinctive one, to reduce the burden of morbidity and mortality, as patients with GMG have weakness of bulbar, respiratory, and/or limb muscles (in addition to the ophthalmoparesis). Rebuttal: Wayne Cornblath, MD Drs. Wong and Plant suggest early immunosuppressive treatment for patients with OMG while noting the weaknesses in the data proving a benefit to early treatment and in the data of side effects of treatment. While I agree "we do not have specific information" on the risk of corticosteroids in this group of patients, I do not think anyone believes that prednisone use has 0% side effects or that the risk would be substantially less than our experience with other patients over the years. I certainly agree that having precise data on prednisone side effects with respect to age, gender, and other medical factors would be enormously helpful along with being able to predict which patient will progress to GMG. I Wong et al: J Neuro-Ophthalmol 2016; 36: 98-102 eagerly await information from the model they are developing to predict progression. In our practice, in patients older than 60 years or with diabetes or preexisting osteoporosis, we will typically start treatment with mycophenolate mofetil knowing that the time to take effect will be longer than corticosteroids, but the morbidity will be significantly lower, again without any RCTs to guide this choice. Finally, and I believe most critically, Drs Wong and Plant do not address what benefit, even if we are treating a "high risk to generalize" group, treatment with corticosteroids before generalization confers. There is no evidence for any harm by delaying treatment until the time of generalization. 101 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point CONCLUSIONS The management of OMG is challenging. The conversion of OMG to GMG transforms what is a bothersome and occasionally visually disabling disease to one which is potentially life threatening, and the ability to potentially alter the disease course through institution of immunosuppressive therapy is tempting. Until better evidence emerges, we must rely on less robust data and clinical judgment when offering treatment to patients. Future RCTs may provide clearer guidance. 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Date | 2016-03 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Collection | Neuro-ophthalmology Virtual Education Library: NOVEL http://NOVEL.utah.edu |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah, 10 N 1900 E SLC, UT 84112-5890 |
Rights Management | © North American Neuro-Ophthalmology Society |
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Reference URL | https://collections.lib.utah.edu/ark:/87278/s6dc1wbn |