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Show Safety of Prednisone for Ocular Myasthenia Gravis Beau B. Bruce, MD, MS, Mark J. Kupersmith, MD Background: Treatment with chronic corticosteroids has been associated with frequent significant adverse effects. We hypothesized that a long-term low-dose prednisone regimen for ocular myasthenia gravis (OMG) would have a low rate of major side effects. Methods: Consecutive OMG patients from a single institu-tion over a 16-year period and treated with $1 month of daily prednisone were included. Steroid-related complica-tions were defined as the development/worsening of con-ditions requiring alteration to medical therapy. Serious complications included conditions requiring emergency care, hospitalization, or surgery. Results: Eighty-three patients with follow-up period ranging from 1 to 271 months (median, 58 months) were included. Fifty-eight (70%) patients had follow-up period of $24 months. The maximum prednisone dose ranged from 10 to 60 mg. Tapering to #10 mg/d required #4 months for all but 2 patients. Median average daily dose following the initial course was 5 mg daily (interquartile range, 4-7.5 mg). During the first 2 years, there were 24.5 complications per 100 per-son- years. Only one patient had a serious complication within the first 2 years (2-year cumulative risk, 1%), but this individ-ual was not following the recommended regimen. Conclusions: Low-dose prednisone for OMG has an accept-able side-effect profile and causes few serious complica-tions (2-year risk,w1%). However, patients need monitoring to detect the relatively common, but less serious, compli-cations (2-year risk, w39%) to adjust medical therapy in a timely fashion. Journal of Neuro-Ophthalmology 2012;32:212-215 doi: 10.1097/WNO.0b013e3182536558 © 2012 by North American Neuro-Ophthalmology Society The use of corticosteroids in the immunologic treatment of ocular myasthenia gravis (OMG) is controversial primarily because of the potential for significant side effects (1). Some have suggested that steroids should be used only "when absolutely necessary" in the treatment of myasthenia gravis (2), whereas others have shown favorable outcomes with long-term low-dose regimens of prednisone (3). In addition, prednisone appears to reduce conversion from OMG to the generalized form (GMG) (4). The combina-tion of prednisone with other therapies, such as azathio-prine, may allow for lower dosing of prednisone, but it remains unclear whether these therapies are equivalent or superior to prednisone when used alone and whether they offer improved outcomes when used in combination with prednisone (5-11). Unlike corticosteroids, which are effec-tive within weeks, these other immunosuppressive therapies often achieve their benefit only after several months. We hypothesized that the systemic hypertension, diabetes mellitus, osteoporosis, gastrointestinal disorders, and infections that typically occur with long-term moderate-to-high-dose therapy (3) may be minimized with long-term low-dose ther-apy (prednisone ,10 mg daily), especially if co-interventions are utilized (11,12). Our goal was to determine the side-effect profile of a low-dose regimen for the treatment of OMG and to determine the safety of systemic corticosteroid use in OMG. METHODS Consecutive patients with OMG evaluated and managed at the Institute for Neurology and Neurosurgery at Roosevelt Hospital and New York Eye and Ear Infirmary by one of the investigators (M.J.K.) were considered for inclusion. The study was approved by the Institutional Review Board at St. Luke's Roosevelt Hospital. Patients who were begun on prednisone between October 1984 and December 2010 and treated with a minimum of 1 month of daily prednisone were included. OMG was diagnosed on the basis of having ptosis, binocular diplopia, or extraocular motility limitation con-firmed by ice test, edrophonium test, repetitive nerve stimu-lation electromyography, single-fiber electromyography, or positive acetylcholine receptor antibody testing (13,14). Departments of Ophthalmology and Neurology (BBB), Emory Uni-versity, Atlanta, Georgia; and Neuro-Ophthalmology Unit (MJK), INN at Roosevelt Hospital and Albert Einstein School of Medicine, New York, New York. The authors report no conflicts of interest. Supported in part by an unrestricted departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, and by National Institutes of Health/National Eye Institute core grant P30-EY06360 (Department of Ophthalmology). Dr Bruce receives research support from the National Institutes of Health/ National Eye Institute (K23-EY019341). The authors have no relevant financial disclosure. Address correspondence to Mark J. Kupersmith, MD, Neuro- Ophthalmology Unit, Roosevelt Hospital, 1000, 10th Avenue, New York, NY 10019; E-mail: mkuper@chpnet.org 212 Bruce and Kupersmith: J Neuro-Ophthalmol 2012; 32: 212-215 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Patients had their last clinical assessment between August 1996 and June 2011. In general, patients were evaluated monthly for the first 3 months and thereafter every 6 months. Patients were not randomized to therapy. Those with diplopia or with ptosis that blocked the visual axis and were unresponsive to pyridostigmine were treated with predni-sone. Patients were not given corticosteroids if they refused or had a contraindication, including active infection, gastro-intestinal ulcer, history of tuberculosis, diabetes mellitus that was difficult to control, severe hypertension, or con-gestive heart failure. Patients with a history of a positive purified protein derivative or one or more calcified lesions, suggestive of healed tuberculosis, on the chest CT received 300 mg of isoniazid and 50 mg of pyridoxine concomitantly with prednisone. Patients were prescribed a daily H2 blocker (ranitidine hydrochloride, nizatidine, or famotidine) and 1000-1500 mg of calcium daily as long as they took prednisone. If baseline bone mineral density (not done in all patients) showed osteopenia of the lumbar spine or hips, biphosphonate therapy was also prescribed. Complications of steroids were defined as the development of or worsening of any of the following conditions that required a change in management (e.g., addition of a medi-cation): osteopenia, osteoporosis, bone fracture, hypertension, diabetes mellitus, gastrointestinal disturbance, psychosis, depression, dementia, infection (other than viral upper res-piratory infection), elevated intraocular pressure, glaucoma, or cataract. Serious complications included conditions requiring emergency care, hospitalization, or surgery. Statistical analysis was performed using R: a language and environment for statistical computing (R Foundation for Statistical Computing, http://www.r-project.org). We performed univariate analyses to produce summary meas-ures for continuous measures (medians, interquartile ranges, and ranges) and proportions. Significance was defined as the 0.05 level. Person-time for incidence rates was determined using time of prednisone initiation as the start of follow-up and using either the number of weeks to last follow-up (censored) or the development of the first complication (event) as the end of person-time. Kaplan-Meier plots were used for graphical presentation of the survival curves. Con-fidence limits were calculated using the normal approxima-tion of the Poisson distribution. RESULTS Eighty-three patients with confirmed OMG were included. Median age at diagnosis was 61 years (interquartile range, 46.5-73 years; range, 16-87 years). Sixty (72%) patients were men. Follow-up period ranged from 1 to 271 months with a median of 58 months. Fifty-eight (70%) patients had follow-up of at least 24 months. Patients were on a maxi-mum daily dose of prednisone ranging from 10 to 60 mg (all but 3 patients were on a maximum dose of 40-60 mg). Tapering from this dose to 10 mg/d required 4 months or less for all but 2 of the patients and a significant majority of the patients (58/83, 70%) required exactly 3 months to taper to 10 mg. The median average daily dose following the initial course was 5 mg daily (interquartile range, 4-7.5 mg). Twenty-nine (35%) patients developed a complication (Table 1) that could potentially be related to steroid use within the total period of follow-up (439 person-years) cor-responding to a rate of 6.6 complications per 100 person-years (95% confidence interval [CI], 4.2-9.0; Fig. 1A). Nine (31%) of these 29 patients developed more than 1 complication during the total period of follow-up. Within the first 2 years, the complication rate was 24.5 per 100 person-years (26 complications during the 106 person-years accumulated during the first 2 years of study; 95% CI, 15.0-33.9; Fig. 1A, inset). There were 10 complications in the first year (1-year cumulative risk, 12%), and 3 during the second year (2-year cumulative risk, 16%). Three patients had serious complications during the total period of follow-up corresponding to a rate of 0.7 serious complications per 100 person-years (95% CI, 0.0-1.5; Fig. 1B). None occurred during the first year (1-year cumulative risk, 0%) and only one occurred during the second year (2-year cumulative risk, 1%). The rate within the first 2 years was 2.2 serious complications per 100 person-years (95% CI, 0.0-4.7; Fig. 1B, inset). The one patient who had a serious complication during this period developed severe hyperten-sion complicated by myocardial infarction during month 12. However, this patient was not following the recommended prednisone regimen, instead taking 20-40 mg daily through-out the time prior to his associated complication by obtaining prednisone from multiple practitioners. DISCUSSION Our retrospective study demonstrated a low rate of serious complications related to a low-dose steroid regimen for OMG. Seventy percent of our patients had more than 2 years of follow-up. Assuming a constant rate of 2.2 serious complications per 100 person-years during a 2-year study, we have extrapolated our results to a larger patient cohort. If we assume a sample size of 231 patients, we would expect 4.3% (10/231; 95% CI, 0%-9%) of the patient treated with steroids to develop a serious complication that could be related to steroids. However, because the one patient in our study with a serious complication during the first 2 years was not following the low-dose regimen, we believe that the lower rate of 0.7 serious complications per 100 person-years seen over the entire study period represents a more accurate estimate. Given these assump-tions, we would expect only 1.4% (3/231) of subjects to develop a serious complication. Our data suggest that the use of a low-dose corticosteroid regimen has an acceptable side-effect profile for the treatment of OMG. This is in contrast to the frequent adverse effects seen with the relatively long-term high-dose Bruce and Kupersmith: J Neuro-Ophthalmol 2012; 32: 212-215 213 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. corticosteroid regimens (15,16). Many clinicians are wary of the adverse effects of chronic corticosteroid use and fre-quently prescribe only pyridostigmine. Although this can be helpful for ptosis, it is rarely completely successful in relieving diplopia and fails to alter the underlying autoim-mune process that leads to GMG in patients who first present with OMG (6,17). Our study was limited because it was retrospective and represented a single center's experience. There may have been patient selection bias, although we included patients without regard to having detectable acetylcholine receptor-binding antibody. Finally, the use of retrospective data from standard office visits, rather than systematic data collection, limits our ability to detect all other adverse effects of prednisone. In conclusion, it appears that a low-dose prednisone regimen for the treatment of OMG causes few serious complications. Patients need monitoring for relatively com-mon, but less serious, complications to ensure that these issues are detected early and allow for timely adjustment of medical therapy. TABLE 1. Summary of complications possibly related to predinsone Patient No. Onset (mo) Comments Osteopenia 10 120 22 18 26 10 28 9 Rx alendronate 30 125 Rx calcium + vitamin D 43 30 Rx risedronate 44* 12 49 24 69* 42 Rx alendronate 70 18 Osteoporosis 3* 11 Rx alendronate 25 24 Rx calcium + vitamin D (improved later) 38 25 Rx alendronate 53* 72 Rx risedronate 76 70 Baseline osteoporosis, on alendronate, complicated by fracture 80* 23 Rx alendronate Diabetes mellitus 2 60 2 years after stopping prednisone 3* 50 Rx pioglitazone 15 120 Rx metformin + insulin 19 48 Rx 4 oral agents 44* 1 Transient, no Rx 60 48 Rx oral agent (4 oral agents by year 8) 61 4 Rx metformin + pioglitazone 62* 12 Rx glyburide + insulin Hypertension 4 1 Rx 2 agents 27* 36 Rx additional oral agent 35 1 Increased propranolol 62* 1 Rx metoprolol + captopril, complicated by myocardial infarction 63 1 Rx lisinopril 78* 1 Rx valsartan 80* 24 Rx oral agent Psychological 78* 1 Agitation, no Rx Cataract 53* 65 Nuclear sclerosis only 69* 72 Nuclear sclerosis only Intraocular pressure 27* 36 Ocular hypertension 69* 48 Ocular hypertension Infection 12 54 Lid cellulitis requiring hospitalization Serious complications are indicated in bold. *Patients with $2 complications. 214 Bruce and Kupersmith: J Neuro-Ophthalmol 2012; 32: 212-215 Original Contribution Copyright © North American Neuro-Ophthalmology Society. 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Kaplan-Meier survival curves for all (A) and major (B) complications (solid lines) during the study, with 95% confidence intervals (dashed lines). Hashes on solid line represent censored observations. Inset: complications during first 2 years. Bruce and Kupersmith: J Neuro-Ophthalmol 2012; 32: 212-215 215 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
