Effect of Initial Prednisone Dosing on Ocular Myasthenia Gravis Control

Ocular myasthenia is an autoimmune condition that results in double vision or ptosis. It often requires treatment with prednisone for immunosuppression, but there have been no prospective trials to help clinicians determine ideal dosing.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Effect of Initial Prednisone Dosing on Ocular Myasthenia Gravis Control Yesha S. Shah, BBA, BSA, Amanda D. Henderson, MD, Andrew R. Carey, MD, Background: Ocular myasthenia is an autoimmune condition that results in double vision or ptosis. It often requires treatment with prednisone for immunosuppression, but there have been no prospective trials to help clinicians determine ideal dosing. Methods: This was a retrospective study comparing myasthenia symptom control at 1 month between patients treated with a maximum daily equivalent dose of prednisone less than 20 mg (low-dose group) vs 20 mg or more (medium-dose group). Results: Thirty-nine patients were identified: 19 patients in the low-dose group with mean maximum daily dose of 10 mg and 20 patients in the medium-dose group with a mean maximum daily dose of 29 mg. The low-dose group had 75% controlled or significantly improved at 1 month, and the medium-dose group had 74% controlled or significantly improved at 1 month, P = 0.94. The overall seropositivity rate was 64%, with 84% of the antibody-positive group being controlled or significantly improved at 1 month and 57% of the antibody-negative group being controlled or significantly improved at 1 month, P = 0.07, and no difference in prednisone dosing between the 2 groups. Conclusion: Based on the results of this small retrospective study, it seems initial treatment for ocular myasthenia gravis with a mean maximum daily prednisone dose of 10 mg is similarly effective compared with mean maximum daily dose of 29 mg for control at 1 month. Journal of Neuro-Ophthalmology 2021;41:e622–e626 doi: 10.1097/WNO.0000000000001058 © 2020 by North American Neuro-Ophthalmology Society M yasthenia gravis (MG) is the most common autoimmune disease involving the neuromuscular junction (NMJ) and clinically presents with muscle fatiguability. Disease manifestations may be either ocular, including ptosis Johns Hopkins University School of Medicine (YSS), Baltimore, Maryland; and Division of Neuro-Ophthalmology (ADH, ARC), Department of Ophthalmology, Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, Maryland. A. D. Henderson: expert witness fees. A. R. Carey: expert witness fees and consulting for US Nutraceuticals (not conflicting with this manuscript). The remaining author has no conflicts of interest. Address correspondence to Andrew R. Carey, MD, 600 N. Wolfe Street, Wilmer Eye Institute Woods 459A, Baltimore, MD 21287; E-mail: [e-mail] e622 and diplopia, or generalized, with symptoms including bulbar weakness, respiratory muscle weakness, and proximal weakness. Ocular symptoms are the presenting features in 85% of patients with MG (1), and rates of conversion from ocular to generalized MG have been shown to be as low as 15%–21% (2,3). Therefore, treatment in these cases may be aimed at controlling ocular symptoms. Ten–fifteen percent of patients will have only ocular symptoms throughout their disease course (4,5). The pathophysiology of MG classically involves an autoantibody to the skeletal muscle nicotinic acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase receptor (MuSK) (6), which interferes with neuromuscular action potential transmission, leading to the clinical signs and symptoms of muscle fatiguability. Recently, autoantibodies also have been shown to activate and amplify complement cascades, leading to the formation of membrane attack complexes and destruction of the NMJ (7). However, up to 50% of patients with ocular MG will be double seronegative for AChR and MuSK (8), thus, complicating the diagnosis and treatment of these patients. Various medical treatment options are used for ocular MG. Pyridostigmine may be tried initially, but if a patient fails this, oral immunosuppressive therapy is the next option. Although there are no randomized clinical trials evaluating the effectiveness of common immunosuppressive therapies, retrospective series and clinical experience support their use. Corticosteroids are the first line immunosuppressive treatment; however, no guidelines exist for initial dosing. Previous retrospective reports have suggested initial doses of 40–80 mg daily to control symptoms (9) but have also demonstrated success at 10 mg daily (10,11). High dosages of corticosteroids have been shown to be detrimental because of side effects including Cushing syndrome, weight gain, diabetes, hypertension, cataracts, and osteoporosis (12). Corticosteroids are relatively contraindicated for patients with pre-existing diabetes mellitus, hypertension, and osteoporosis because they may exacerbate these conditions. On the other hand, low-dose steroid treatment for ocular MG has been shown to have a low rate of major side effects (13). Shah et al: J Neuro-Ophthalmol 2021; 41: e622-e626 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution This study aims to determine the effect of initial prednisone dosing on symptom control. Prednisone is not FDA approved for treatment of ocular myasthenia. METHODS This study was approved by the institutional review board, and requirement for informed consent was waived given its retrospective design. Charts were identified among patients seen by 2 neuro-ophthalmologists with different prescribing practices for initial prednisone dosing for ocular MG. Standard prescribing practice for one doctor was low-dose corticosteroids (20 mg every other day for 5 weeks) and for the other doctor, medium-dose corticosteroids (10 mg daily for 1 week, 20 mg daily for 1 week, and 30 mg daily until clinical response), although patients were included if they were prescribed or took a different regimen. Patients were separated into 2 groups: maximum equivalent daily dose of less than 20 mg in the 5 weeks of treatment vs 20 mg or greater based on their actual regimen rather than the prescribed regimen; 2 patients in the low-dose group were initially treated by the physician who typically prescribes the medium-dose regimen, and 1 patient in the medium-dose group was treated by the physician who usually prescribes the low-dose regimen. The inclusion criteria included an ICD-10 diagnosis of double vision, MG, or ptosis with a prescription for corticosteroids and age 18 years or older. Patients were allowed to have been on previous or concurrent pyridostigmine and to have mild bulbar or systemic symptoms. Patients were excluded if chart review showed an alternative cause for double vision or ptosis, incomplete records, a nonMG indication for immunosuppression, severe MG requiring early nonsteroid immunosuppression before completing 5 weeks of corticosteroid therapy, previous immunosuppressive therapy, or less than 5 weeks of follow-up. The primary outcome was the rate of control after 5 weeks of prednisone. The control was defined as no symptoms or signs, or no symptoms with minimal signs (Cogan lid twitch or orbicularis weakness), or blurred vision lasting seconds but no diplopia. The fisher exact test was used to compare low-dose with medium-dose prednisone groups and to compare control rates between antibody positive and negative groups. Baseline factors were evaluated for age at diagnosis, duration of symptoms at diagnosis, severity of symptoms at baseline (severe defined as constant or interfering with daily activities, moderate defined as intermittent and daily lasting hours, and mild defined as intermittent lasting seconds to minutes or less than daily), gender, diplopia at diagnosis, ptosis at diagnosis, both diplopia and ptosis at diagnosis, isolated ptosis at diagnosis, isolated diplopia at diagnosis, and simultaneous use of pyridostigmine. Secondary outcomes included improvement but not total resolution of symptoms, defined as significant reducShah et al: J Neuro-Ophthalmol 2021; 41: e622-e626 tion in frequency or duration of symptoms noticed by the patient and judged clinically as not warranting dose escalation (i.e., constant symptoms improved to intermittent, resolution of one intermittent symptom but not all symptoms, or complete ptosis improved to partial ptosis, a reduction in amplitude of ocular deviation alone did not count), mean time to control, dose at relapse, control at 6 months (to determine if initial lower dose increased the risk of poor control later), dose at 6 months, effect of combination prednisone and pyridostigmine compared with prednisone alone, and need for steroid-sparing immunotherapy. The Fisher exact test was used for nonbinary categorical tests; the student t test was used for binary tests. RESULTS One hundred forty-one patients were identified by ICD-10 code and use of prednisone. Seventy-two patients were excluded for having an alternate condition causing diplopia. Eleven patients were excluded for previous immunosuppressive treatments for myasthenia or incomplete records. Six patients were excluded for myasthenia in the setting of other systemic inflammatory diseases requiring immunosuppression (neuromyelitis optica in 3 patients; and Graves disease, scleroderma, and multiple sclerosis in 1 patient each). Sixteen patients were excluded for lack of follow-up, and 2 patients were excluded for severe systemic myasthenia requiring urgent hospitalization. Thirty-nine patients were included in the final analysis with 19 in the low-dose group (49%) and 20 in the medium-dose group. Sixty-four percent of patients had their diagnosis confirmed with positive antibodies. All patients had antibody testing with a minimum of AChR binding antibodies. In the antibody negative group, 6 patients had their diagnosis confirmed with single-fiber electromyogram (4 definite and 2 suggestive), and 8 patients had a clinical diagnosis (6 with documented variable motility, 1 with documented fatigable ptosis, and 1 with documented alternating ptosis who had a negative single-fiber electromyogram while having ptosis). The baseline characteristics are displayed in Table 1. All patients had negative chest imaging for thymoma. Four patients had previously been treated with pyridostigmine with no significant difference between the low-dose and medium-dose groups and no effect on symptoms. The only significant difference between the 2 groups at baseline was that the medium-dose group had a higher percentage of patients with concurrent pyridostigmine use, which was reflective of prescribing practices of the treating neuroophthalmologist. The low-dose group had a mean maximum daily dose of prednisone of 10 ± 2 mg (median 10 mg) and cumulative dose of 354 mg in the first 5 weeks, whereas the mediumdose group had a mean maximum daily dose of 29 ± 4 mg (median 30 mg) and cumulative dose 820 mg in the first 5 e623 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Baseline characteristics of low-dose and medium-dose prednisone groups Characteristic N Age Female Duration Severity (severe, moderate, and mild) Bulbar/systemic Diplopia Ptosis Diplopia and ptosis Diplopia alone Ptosis alone Prior pyridostigmine Concurrent pyridostigmine Seropositivity Low-Dose Medium-Dose P 19 (49%) 68 ± 10 (70) 35% 8.5 ± 21 (2) 74%, 16%, 11% 25% 95% 65% 60% 35% 5% 5% 20% 65% 20 (51%) 67 ± 14 (69) 53% 13 ± 17 (7) 65%, 20%, 15% 21% 90% 68% 58% 32% 10% 16% 63% 63% 0.7 0.3 0.5 0.9 1 1 1 1 1 0.6 0.3 ,0.01* 1 Age in years at the start of prednisone with mean ± SD (median). Duration = duration of symptoms before starting prednisone in months with mean ± SD (median). *Statistically significant with P , 0.05. weeks (P , 0.0001 for both). The mean dose at control in the low-dose group was 21 ± 10 mg (median 20 mg) and in the medium-dose group was 31 ± 10 mg (median 30 mg) (P = 0.02). Table 2 summarizes rates of controlled, significantly improved, and unimproved patients at 5 weeks. In the low-dose group, 35% of patients were controlled compared with 37% in the medium-dose group, P = 1. Seventy-five percent of patients were either controlled or substantially improved in the low-dose group vs 74% in the mediumdose group. Subanalyses were performed for response at 5 weeks for diplopia, ptosis, combined ptosis and diplopia, isolated diplopia, and isolated ptosis, and the results are shown in Table 3. There was no significant difference between response to low and medium doses or across mutually exclusive groups in the total set. In addition, the 5-week outcome for patients with severe symptoms at baseline was similar between the low-dose and medium-dose groups, P = 0.5. At 6 months, data were available for fewer patients (17 in low-dose group and 13 in the medium-dose group). Fortyone percent and 50% of patients were controlled in the lowdose and medium-dose groups, respectively; 29% and 25% TABLE 2. Five-week rates of controlled, improved, and unimproved patients on low-dose and medium-dose corticosteroid therapy Low-Dose (n = 20) Medium-Dose (n = 19) Symptom status Controlled Improved Unimproved Fisher exact P e624 35% 40% 25% 37% 37% 26% 1 of patients were improved in the low-dose and mediumdose groups, respectively; and 29% and 25% of patients were unimproved in the low-dose and medium-dose groups, respectively, P = 0.8. There were no significant differences between groups in a number of other variables. The mean time to control of MG was 97 ± 95 days (median 63 days, n = 15) in the lowdose group and 69 ± 42 days (median 46 days, n = 12) in the medium-dose group (P = 0.3). The equivalent daily dose at relapse, after attaining initial control, for the lowTABLE 3. Five-week rates of controlled, improved, and unimproved patients by symptoms n A: Low dose Diplopia Ptosis Both Diplopia alone Ptosis alone B: Medium dose Diplopia Ptosis Both Diplopia alone Ptosis alone C: All Diplopia Ptosis Both Diplopia alone Ptosis alone Controlled Improved Unimproved 18 13 12 6 1 44% 46% 33% 50% 0% 33% 31% 42% 33% 0% 22% 23% 25% 17% 100% 18 13 11 7 2 28% 46% 27% 57% 0% 33% 23% 55% 14% 50% 22% 31% 18% 29% 50% 36 26 23 13 3 36% 46% 30% 54% 0% 33% 27% 48% 23% 33% 22% 27% 22% 23% 67% A. Diplopia and ptosis responses in the low-dose group. B. Diplopia and ptosis responses in the medium-dose group. C. Diplopia and ptosis responses in the entire cohort. Shah et al: J Neuro-Ophthalmol 2021; 41: e622-e626 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution dose group was 4 ± 3 mg (median 4 mg, n = 7) and in the medium-dose group was 5 ± 4 mg (median 5 mg, n = 6) (P = 0.6). Steroid-sparing therapy was used in 50% and 37% of patients in the low-dose and medium-dose groups, respectively (P = 0.5), and time to steroid-sparing therapy was a mean of 4 ± 3 months (median 4) in the low-dose group and 7 ± 3 months (median 6) in the medium-dose group (P = 0.13). At 6 months in the low-dose group, the mean daily dose was 14 ± 16 mg (median 10) (n = 15) and in the medium-dose group was 17 ± 11 mg (median 20) (n = 13) (P = 0.5). Of patients tested for MuSK, none were found to be positive. At 5 weeks, in the antibody negative group, 14% of patients were controlled whereas 48% of patients were controlled in the antibody positive group; 43% significantly improved in the antibody negative group vs 36% in the antibody positive group; and 43% were unimproved in the antibody negative group compared with 16% in the antibody positive group, P = 0.07. The mean maximum daily dose of prednisone was 20 ± 9 mg (median 20) for the antibody negative group and 19 ± 10 mg (median 10) for the antibody positive group (P = 0.8). The cumulative prednisone dose for the first 5 weeks was 616 and 580 mg for antibody negative and positive groups, respectively (P = 1). The mean dose at control was 33 mg and 23 mg for antibody negative and positive groups, respectively (P = 0.22), and the time to control was 126 and 51 days, respectively (P = 0.1). Twenty-three percent of patients had bulbar or systemic symptoms (3 with mild weakness or fatigue and 9 with mild bulbar symptoms). Patients with bulbar or systemic symptoms were more likely to be treated with concurrent pyridostigmine and prednisone rather than prednisone alone (75% vs 15% for those with pure ocular myasthenia, P = 0.0006). Patients treated with combination therapy had a mean equivalent daily maximum prednisone dose of 24 ± 10 mg (median 30) compared with prednisone only group with a mean equivalent daily maximum prednisone dose of 17 ± 8 mg (median 10), P = 0.04. Patients treated with combination concurrent pyridostigmine and prednisone compared with prednisone alone had no difference in the control rate at 5 weeks, P = 1. CONCLUSIONS The mean initial prednisone dosing of 10 mg/day (dosed 20 mg every other day) resulted in control or improvement in 75% of patients with ocular MG at 5 weeks, with no additional benefit detected from the higher dose of 30 mg/ day in control at 5 weeks or control at 6 months, time to control, dose at relapse, dose at 6 months, or proportion needing steroid-sparing therapy. There was a trend toward faster control with medium-dose than low-dose steroid treatment, but this finding was not statistically significant. Overall, these findings suggest that low-dose corticosteroids Shah et al: J Neuro-Ophthalmol 2021; 41: e622-e626 may be appropriate for initial dosing of ocular MG. Because higher doses of corticosteroids can lead to adverse effects, starting patients on lower doses may decrease side effects without compromising effectiveness. The only confounding factor identified was a higher percentage of combination pyridostigmine and prednisone in the medium-dose group. Because this finding would be expected to bias results in favor of the medium-dose group, it likely does not affect our conclusions. Although the antibody status did not have any statistical effect on the treatment outcome, there was a trend toward the improved status at 5 weeks, faster time to control, and lower dose needed for control for seropositive patients with no difference in initial prednisone dosing in the first 5 weeks. In the authors’ experience, pyridostigmine rarely improves diplopia, and in this study, its use did not demonstrate any additional benefit compared with prednisone alone. This study also found that 23% of patients presenting to ophthalmologists for predominantly ocular myasthenia symptoms may also have bulbar or systemic symptoms; therefore, it is crucial for ophthalmologists to ask about symptoms which may worsen without proper treatment and require monitoring often in coordination with a neurologist. Benatar, et al attempted a randomized controlled trial with slow titration of prednisone starting at 10 mg every other day and increasing to 40 mg/day; however, they could not meet their prespecified enrollment numbers. They reported a mean time to control of 14 weeks and a mean dose at control of 15 mg/day, with relapse at doses under 10 mg/day (11). In the current study, similar results were obtained with a lower dose of prednisone. These results suggest that clinicians should be cautious when tapering prednisone below 10 mg and particularly cautious below 5 mg per day, although some of our patients were able to taper off prednisone without recurrence. By contrast, Kupersmith has advocated rapid titration to 50–60 mg/day within the first 1–2 weeks, followed by slow taper to 10 mg over a period of 3 months (9,13). Based on the results of our study, these higher doses of prednisone may not be necessary. This study has a number of limitations, namely, the small sample size of patients, thus limiting the detection of small effects, and the retrospective nature, which prevents accounting for all confounding factors. For instance, obstructive sleep apnea (14) is known to contribute to myasthenia severity; however, these data were not available for all patients. In addition, because all identified patients were from a tertiary referral hospital, the results may not be applicable to those with milder disease. This study also does not address questions regarding the effect of different steroid dosing regimens on risk of generalization, optimal tapering schedules, duration of steroid treatment once patients reach symptom control, risk of recurrence or e625 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution generalization, or necessary prednisone dose to reduce risk of recurrence or generalization. A prospective, masked, randomized controlled trial could help to confirm these findings and clarify these other questions. In summary, we report that low-dose corticosteroids seem to be similarly effective to medium dose for control of ocular myasthenia, and we hope these results can help guide clinicians in management of ocular myasthenia. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Henderson and Y. Shah; b. Acquisition of data: Y. Shah; c. Analysis and interpretation of data: A. 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