Should Oral Corticosteroids Be Used to Treat Demyelinating Optic Neuritis?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Should Oral Corticosteroids Be Used to Treat Demyelinating Optic Neuritis? Mark J. Morrow, MD, Melissa W. Ko, MD Isolated demyelinating optic neuritis is the most common cause of acute optic nerve dysfunction in adults. Although the natural history is one of spontaneous recovery of vision for most patients, treatment with corticosteroids is often offered to speed recovery and relieve pain. The type, dose, route, and duration of administration of corticosteroids vary considerably among providers and there is an ongoing discourse about the role of oral versus intravenous steroid therapy. Two experts debate this topic. For the purposes of this discussion, the authors have adopted the following definitions of steroid dosing: low-dose #100 mg methylprednisolone [MP] or equivalent per day; moderate-dose 101-499 mg MP or equivalent per day; high-dose $500 mg MP or equivalent per day. Pro: Mark Morrow, MD Optic neuritis (ON) is an inflammatory demyelinating condition that can affect the optic nerve anywhere along its length. It may involve one or both nerves and typically manifests as visual loss with pain that is often worsened by eye movement. Its association with multiple sclerosis (MS) is well known; approximately half of patients presenting with ON will ultimately develop MS. Based on brain magnetic resonance imaging (MRI) findings at presentation, many ON patients meet current criteria for MS or demonstrate high risk of conversion (1). At least 25% of patients with MS will suffer a bout of ON at some time in the course of their illness. ON typically leaves evidence of both axonal loss and demyelination, which correlates with often-subtle residual visual loss. Optimal therapy would include rapid relief of symptoms, as well as prevention of tissue damage and persistent visual impairment. I will write in favor of the convenient and inexpensive use of high-dose oral corticosteroids for ON symptom relief in the absence of evidence that any form of steroid treatment induces long-term benefit for ON, whether in the context of MS or not (2). The role of corticosteroids in multiple sclerosis In discussing therapy for MS relapses including ON, it is important to distinguish the short-term goal of symptom relief from the idealized long-term goals of preserving neural function and modifying disease. Any claim of benefit in Department of Neurology (MJM), Harbor-UCLA Medical Center, Torrance, California; and Department of Neurology (MWK), State University of New York (SUNY) Upstate Medical University Syracuse, New York. The authors report no conflicts of interest. Address correspondence to Mark J. Morrow, MD, Department of Neurology, Harbor-UCLA Medical Center, Torrance, CA, 90509; E-mail: [e-mail] 444 preventing future relapses or disability progression should be viewed in the context of the 16 currently available, FDAapproved disease-modifying therapies (DMTs). The evidence-based consensus is that an approved DMT should be started as soon as a diagnosis of relapsing-remitting MS can be made. DMTs should also be offered to patients who have suffered a single attack such as ON and have brain MRI findings that confer MS risk (3-5). Corticosteroids have a wide range of effects that may be beneficial in MS, including receptor-mediated antiinflammatory activity and blood-brain barrier preservation (6). Support for using steroid-related medications for MS relapses has accrued since the first small trials of adrenocorticotropic hormone (ACTH) in the 1950s (7). ACTH and various corticosteroids in a variety of doses and routes of administration have been used for this purpose. Current physician practices in treating MS relapses vary (8). Intramuscular/subcutaneous ACTH remains the only steroidrelated drug that is FDA-approved for the treatment of MS relapse, but the very high cost and long course of daily injections are prohibitive. High-dose MP, used in 3-5 day intravenous (IV) courses, emerged as an ACTH alternative in the 1980s and showed similar or better effects (9,10). The optimal duration and dose of MP have not been determined. One small trial compared 1-day and 5-day courses of IV-MP 1,000 mg/d, showing greater benefit for the longer treatment (11). Another study compared 5-day courses of 500 and 2,000 mg of IV-MP, finding no differences in clinical outcome despite a benefit of the higher dose on MRI findings (12). A small, 3-armed study compared the effects of 14-day courses of IV-MP with high- and lowmaximum doses of 500 and 40 mg/d, respectively, versus dexamethasone at a maximum dose of 8 mg/d (13). LowMorrow and Ko: J Neuro-Ophthalmol 2017; 37: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point dose IV-MP showed less benefit than either of the other treatments. There is little evidence of benefit beyond the first few months after intermittent courses of high-dose steroids in relapsing MS (14). Regularly scheduled pulses of moderateto-high-dose oral or IV corticosteroids, delivered every 1-4 months, have been used in an attempt to modify the course of MS. Results have been mixed. Of 4 large studies of this type (15-18), only one IV trial found a benefit on disability progression (18). Unlike the others, this trial did not include the use of a standard DMT, and treatment was not blinded to examining physicians. The 3 other investigations randomized groups of interferon-treated patients to placebo versus supplementary 3-5 day pulses of oral MP 200 mg (16), oral MP 500 mg (17), or IV-MP 1,000 mg daily (15). In the 2 oral MP studies, improvements were seen in relapse rate and MRI measures in corticosteroid-treated patients. Oral corticosteroids generally have bioavailability of about 80% compared to their IV forms (19). Their use is attractive because of significantly lower cost and greater convenience compared to home or hospital infusion, with similar tolerance (20-23). Many MS experts use oral high-dose corticosteroids in preference to IV delivery for relapses (8). The largest randomized, controlled study comparing high-dose oral and IV corticosteroid therapy in MS relapses was published in 2015 (24). The Corticothérapie Orale dans le traitement des POUssées de SEP (COPOUSEP) trial enrolled 199 patients who were randomly assigned to receive 3 days of MP 1,000 mg in either oral or IV form. There was no difference in outcome between the 2 groups, with 81% and 80%, respectively, reaching the primary outcome of improvement. Secondary endpoints of disease activity also were similar in both groups. These findings are noteworthy in that the use of identical daily doses in both groups put oral therapy at a bioavailability disadvantage. The only statistically significant difference in side effects was slightly higher insomnia in the oral treatment group. Patients with MS who have received highdose oral or IV corticosteroids for a relapse show no difference in relapse rates over the following 2 years (25). A Cochrane review in 2012 suggested no differences in clinical outcomes between high-dose oral and IV corticosteroids based on a meta-analysis of existing studies in MS relapse (26). A randomized trial of MRI outcomes also showed no difference between high-dose oral and IV-MP (27). The role of corticosteroids in optic neuritis The largest study of corticosteroids in ON was the Optic Neuritis Treatment Trial (ONTT), whose results first were published in 1992 (28). Many subsequent publications addressed the ONTT cohort, including a final 15-year followup of over 75% of the original group (29). The ONTT was a double-blind controlled study that entered 457 patients within 8 days of symptom onset; 14% had definite or probable MS at study entry, according to the prevailing clinical criteria Morrow and Ko: J Neuro-Ophthalmol 2017; 37: 444-450 of the time. Patients were randomized to one of 3 treatment arms: 1) IV-MP 250 mg 4 times per day for 3 days followed by an 11-day oral prednisone taper; 2) low-dose oral prednisone alone (1 mg/kg) for 14 days without taper; and, 3) oral placebo alone for 14 days. The initial publication, based on data collected 6 months after therapy, showed faster recovery in the IV-MP group than in the other 2 arms, especially, within the first 2 weeks. At the 6-month mark, IV-treated patients had slightly better visual fields, contrast sensitivity and color vision, but not visual acuity, compared to the other 2 groups. At 1-year follow-up, however, the advantages of IV treatment on visual function were no longer present (30). More recent studies also failed to show benefit for high-dose corticosteroids on clinical or radiographic outcomes (31-33). As with IV-MP in the ONTT, high-dose oral MP produces short-term visual improvement (32). An interesting and somewhat unexpected finding of the ONTT was that patients who had received low-dose oral prednisone alone had higher rates of recurrent optic neuritis than in the other 2 groups, including events in initially affected and unaffected eyes (34). By the 15-year follow-up mark, 50% of the identifiable ONTT patients who did not have clinically definite MS at study entry had developed this diagnosis (29). Risk was heavily dependent upon MRI findings at study entry. For those patients with a normal brain MRI, 15-year MS risk was 25%. In contrast, those with one or more MRI lesions consistent with demyelination had a 72% risk, with higher lesion count conferring greater risk. At the 2-year mark, IV corticosteroid-treated ONTT patients demonstrated a significantly lower conversion rate to clinically definite MS (8%) than those in the other 2 groups (15%-17%) (34). This apparent benefit dissipated over time such that there was no difference in MS conversion between the 3 treatment arms at 5 years (approximately 30% in all groups) (35). The suggestion of benefit of single-course, high-dose steroids upon MS conversion rates is supported by one small study (13). One large trial actually suggested a higher conversion rate in IV-MP-treated patients, although first attack severity may have explained this effect (36). Practical questions in applying the regimen employed in the ONTT include the inconvenience of 4 times per day IV administration and the use of a low-dose oral steroid taper after high-dose therapy. Most current MS trials with highdose corticosteroid treatment have included once-daily administration for 3-5 days with no low-dose oral taper. Although they prolong the risk of steroid side effects, there is no evidence of clinical benefit of a steroid taper after highdose therapy in MS relapse (37). Other acute therapies in optic neuritis It is clear that high-dose corticosteroids offer only partial benefit for ON and do so with a modicum of side effects. Some patients do not experience short-term symptomatic improvement or even worsen while on therapy. For such 445 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point patients, plasma exchange has shown benefit as salvage therapy (38). Although most patients recover reasonable visual function after an episode of ON, almost all are left with evidence of axonal loss and demyelination. Although corticosteroids do not induce a measureable neuroprotective effect, treatments that may prevent damage or restore function in chronic optic neuropathy are much needed (39). Summary The available data support clinical and biological equivalence of high-dose oral and IV corticosteroids for symptomatic relief of optic neuritis, whether or not it is associated with MS. The advantage of oral therapy in terms of cost and patient convenience makes it a viable, evidence-based choice in this condition. There is no clear benefit of a steroid taper after high-dose corticosteroids, although it may prolong side effects. Salvage therapies like plasma exchange can be used in cases of treatment failure after a high-dose corticosteroid regimen. The use of an FDA-approved DMT should not be withheld in definite MS or high-risk clinically isolated syndrome, regardless of any potential benefit of high-dose corticosteroids on disease course. Low-dose oral steroids are not recommended for idiopathic or MS-associated optic neuritis. Con: Melissa Ko, MD George Bernard Shaw's comment that "Nothing is worth doing unless the consequences may be serious" essentially summarizes my perspective to not use low-to-moderate doses of oral corticosteroids in treating demyelinating ON. Let us step into the clinical trials time machine and return to February 1992, when the ONTT results were first published in the New England Journal of Medicine (28). We are all familiar with this multicenter, randomized, placebo-controlled trial of corticosteroids in the treatment of acute optic neuritis. Of those subjects who received low dose of oral prednisone alone (1 mg/kg), there was no benefit in terms of their rate of visual recovery or outcome at the 6month mark. In addition, the subjects in the oral prednisone group were noted to have an approximately 2-fold higher rate of new attacks of optic neuritis in the initially affected and fellow eyes during the follow-up interval of 6-24 months (27%) than the patients who received placebo (13%) or IVMP followed by oral prednisone (15%). With these findings of lack of benefit and potential harm of using oral prednisone in low doses in patients with acute optic neuritis, the ONTT set the standard of care for the last 2 decades-we simply do not offer these patients oral corticosteroids in conventional doses. Furthermore, at 1-year follow-up, even the previously noted visual benefit in the IV group compared to the oral group was no longer present and there was no significant difference for all measures of visual outcome between the 2 groups (30). In fact, the higher relative risk of a new attack of ON in either eye in the oral prednisone group compared to IV and placebo groups persisted beyond 1 year. The higher risk of recurrence was noted at the 4- and 10-year follow-up mark (30,40). A recent Cochrane meta-analysis of corticosteroids for treating optic neuritis reiterated the findings above and stated "there is no conclusive evidence of benefit in terms of recovery to normal visual acuity, visual field, or contrast sensitivity after initiation with either IV or oral corticosteroids at the doses evaluated in the trials included in this review" (2). Compounded with that lack of benefit to vision, corticosteroids are not without adverse side effects. In the 446 ONTT study, subjects experienced sleep disturbance, mood changes, stomach upset, facial flushing, and weight gain at a rate that significantly exceeded what occurred in the placebo group subjects (41). What about risk of MS after ON in patients treated with oral corticosteroids? We are familiar with the ONTT data demonstrating that at 2-year follow-up, high-dose IV-MP reduced the rate of developing MS compared to placebo and oral-prednisone-treated patients (34). This "protective effect" of IV corticosteroids abated by year 3 and was not present by year 5 of follow-up (35). There were no significant differences among treatment groups in their rate of development of MS or the degree of neurologic disability in those who had MS at the end of 5 years of follow-up. Definite MS developed in the first 2 years in 7.5% of the IV corticosteroid group, 14.7% of the oral prednisone group, and 16.7% of the placebo group. The adjusted rate ratio for the developmental of definite MS (defined through Poser Criteria) in the IV-MP group as compared to the placebo group was 0.34, in the IV-MP group as compared to the prednisone group was 0.38, and in the oralprednisone group as compared to the placebo group was 0.9. Translation: during the first 2 years after treatment, patients with acute optic neuritis who were treated with IV-MP had 0.34 times the rate of developing definite MS compared to patients who received placebo and 0.38 times the rate of developing definite MS compared to patients who received oral prednisone. By 5-year follow-up, treatment showed no significant effect on the development of definite MS (35). What about the role of high-dose oral corticosteroids? Although the ONTT showed no benefit or role for oral prednisone dosed at low doses of 1 mg/kg, some have postulated that perhaps there would be a greater benefit if prednisone is administered at higher doses (32,42). This hypothesis is based on studies mainly emerging out of the rheumatologic literature over the last 15 years, differentiating the genomic and nongenomic effects of corticosteroids, which is dependent on the prednisone equivalent dose (43). Morrow and Ko: J Neuro-Ophthalmol 2017; 37: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point In brief, genomic actions involve binding to cytosolic glucocorticoid receptors, occur at any therapeutically relevant dosage, and are seen no earlier than 30 minutes after receptor binding. Nongenomic effects are both specific, mediated by steroid-selected membrane receptors, and nonspecific. The nongenomic effects occur at higher glucocorticoid concentrations ($100 mg oral prednisone/ day) and occur within seconds or minutes. What does this mean clinically? During exacerbations of most immunologically mediated disorders, pulse therapy with MP is generally preferred over prednisone. In clinical practice, we intuitively know this and select IV corticosteroids empirically to treat a variety of neuroophthalmic conditions, but why? After all, the 2 medications have similar genomic potency; however, in very high/pulse doses, the nongenomic actions of MP take effect, making it 3-fold stronger than prednisone (43). The oral prednisone doses administered in the ONTT (#100 mg prednisone/day) fall in the low range compared with high doses of MP. However, there have been some studies examining treating optic neuritis with high-dose oral cortico- steroids. In a single-center, randomized, placebo-controlled study, 60 patients were randomized to oral MP (500 mg daily for 5 days with 10-day taper) compared to placebo. Although patients in the high dose oral MP group had improved visual recovery from ON at 1 and 3 weeks, no effect was noted at 8 weeks or on subsequent attack frequency (32). A retrospective single-center study looked at which risk factors in Chinese patients with demyelinating ON lead to recurrence and noted that those treated with the equivalent of #100 mg prednisone/day, had a higher rate of recurrence of ON compared with those treated with .100 mg/d (42% vs 25%, P = 0.045) (42). Summary Based on the body of data published over nearly 30 years, what we can agree on is that there is still no role for lowto-moderate doses of oral corticosteroids in the treatment of acute demyelinating optic neuritis. What stands true is still to "first, do no harm" and a thoughtful discussion with the patient will guide the clinician to the optimal treatment. Rebuttal: Mark Morrow, MD Dr. Ko and I are in fundamental agreement, so my "rebuttal" will be brief. First, my "pro" argument is limited to high-dose oral corticosteroids. We both agree that there is no evidence of benefit and some evidence of risk in treating optic neuritis with lower-dose corticosteroids. I have presented data suggesting bioequivalence for similar doses of oral and IV corticosteroids, including clinical data that imply comparable effects in ameliorating MS relapse symptoms. A recent study in 46 ON patients showed noninferiority for oral prednisone 1,250 mg versus IV-MP 1,000 mg on visual acuity and evoked potential outcomes at 6 months (44). There is no evidence of benefit of any form of corticosteroids on long-term visual outcome. The ONTT implied a medium-term benefit of high-dose IV corticosteroids on conversion to clinically definite MS in patients with high-risk MRI findings. However, this effect has not been confirmed in other MS trials and might be expected to be similar with high-dose oral administration if it is genuine. Moreover, current evidence-based consensus calls for patients to be offered approved, nonsteroid disease-modifying medications in the settings of MRIdefined high-risk clinically isolated syndrome or definite MS. I personally use and suggest the following as a safe, effective, and much less expensive alternative to high-dose IV corticosteroid therapy for idiopathic or MS-associated optic neuritis within 1-2 weeks of onset: • Prednisone 1,250 mg or MP 1,000 mg or dexamethasone 200 mg daily, given in 2-3 divided oral doses over 3 days. Of these corticosteroids, prednisone in 20 mg tablet form is generally the most available and least expensive alternative in the US. • No oral taper unless patient has previously rebounded soon after bolus dosing • Gastric protection (eg, ranitidine 150 mg twice daily) • Consider as-needed medications for anxiety (eg, alprazolam 0.25-0.5 mg every 8 hours) and insomnia (eg, zolpidem 10 mg QHS) Patients who do not respond to high-dose oral corticosteroids can be considered for follow-up treatment with IV corticosteroids or plasma exchange. Rebuttal: Melissa Ko, MD Dr. Morrow does a fantastic job summarizing the existing clinical trials that have compared oral and/or IV corticosteroids use in the setting of MS relapses or acute optic neuritis. Morrow and Ko: J Neuro-Ophthalmol 2017; 37: 444-450 Although many of these trials were well designed, they all had their limitations. In the largest randomized, controlled trial comparing high-dose oral versus IV-MP therapy in patients with MS relapses (COPOUSEP trial) 447 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point (24), Dr. Morrow highlights that the investigators did not use a bioequivalent dose of oral corticosteroids compared to IV-MP. This is a critical point because the difference in bioavailability is greater in IV-MP compared with an equal oral dose of MP, with oral having only 82% bioavailability compared to the IV dose (19,45). Although the study results suggest that this nonequivalent oral steroid dose is noninferior to high dose IV-MP, it is worth highlighting that the study was not designed to provide the clinician information regarding a direct apples-to-apples dose comparison of oral to IV-MP in acute ON. Furthermore, in the COPOUSEP trial, of the 199 subjects enrolled, only 13% were categorized as having "vision problems"-the study did not provide specifics regarding what these vision problems entailed, with no mention of optic neuritis as the condition being treated. In fact, the overwhelming majority of subjects enrolled (nearly 60%) were categorized as being treated for sensory or extrapyramidal symptoms as their MS relapse making it challenging for the clinician to directly apply the study results to patients with ON. In addition, although the trial looked at outcome measures of an improvement of 1 point on the Kurtzke Functional System Scale, the study did not break down or provide specifics regarding visual function improvement. Placing these limitations aside, other interesting findings from COPOUSEP include that the median time to total recovery was slightly longer in the patients treated with oral versus IV corticosteroids, the absolute number of relapses at 6-month followup were fewer in IV-treated patients versus oral, and the percentage of relapse-free patients at 6-month follow-up were greater in the IV-treated patients versus oral. Although these differences did not reach statistical significance, it again highlights that oral treatment is certainly not superior to IV corticosteroids and continues to cast a lingering shadow of doubt such that I would not universally and preferentially select oral corticosteroids over IV. In the only published study where bioequivalent doses of oral-MP and IV-MP were compared, limitations include that patients with optic neuritis were not the specific group being studied; rather, all-comers with MS relapses were enrolled and relapse types were not specified (46). Furthermore, enrollment was small (24 subjects in each treatment group), the duration of follow-up was short (4 weeks), and visual testing was not used for primary or secondary outcomes. It remains unclear as how to interpret or extrapolate these trials to our present question. You might suppose, I am asking for too much: a welldesigned clinical trial enrolling only patients with acute demyelinating optic neuritis using bioequivalent doses of oral corticosteroids compared to IV with visual function as its primary and secondary outcomes. Well, one fairly close to that description does, in fact, exist. Sarah Morrow et al (44) randomized 46 patients with acute optic neuritis and no history of ON in the same eye to receive bioequivalent doses of either 1,000 mg of IV-MP (23 patients) or 1,250 mg of oral prednisone (27 patients) for 3 days. Subjects were not blinded to their treatment. Primary outcome was recovery of P100 visual evoked potential (VEP) latency signal at 6 months. Secondary outcomes included P100 VEP signal at 1 month and visual acuity at 1 and 6 months. The study results showed that oral corticosteroids were not inferior to bioequivalent doses of IV-MP in the treatment of acute ON. Although this trial is not perfect, it gives the clinician helpful data when addressing treatment options with their patients. So here is where Dr. Mark Morrow and I agree. To the best of our knowledge, high-dose oral corticosteroids (at least 1,000 mg prednisone equivalents) is noninferior to IV-MP (1,000 mg) in the setting of acute demyelinating optic neuritis. Oral corticosteroids have never demonstrated superiority to IV-MP at nonequivalent or even bioequivalent doses. In settings where patients have limitations to receive IV-MP because of barriers of access or cost, bioequivalent or near bioequivalent high doses of oral corticosteroids can be offered as a reasonable alternative. Conclusion: Andrew G. Lee, MD, and Greg Van Stavern, MD There is good evidence arguing against the use of low- or intermediate-dose corticosteroids for the treatment of isolated demyelinating optic neuritis. As the experts note, all of the studies addressing this question have limitations. For some patients, high-dose IV-MP in a hospital setting REFERENCES 1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302. 2. Gal RL, Vedula SS, Beck R. Corticosteroids for treating optic neuritis. Cochrane Database Syst Rev. 2015: CD001430. 448 may be preferred (closer monitoring for steroid-related complications, expedited neuroimaging and further workup, and compliance issues). Based on the available data, it is reasonable to offer high-dose oral prednisone to patients with isolated ON as an alternative to IV-MP. 3. 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A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS. Mult Scler. 2014;20:717-725. Images in Neuro-Ophthalmology Ocular neurosyphilis. A 42-year-old woman, with a 2-week history of vision loss in both eyes, was found to have bilateral optic disc edema (A), patchy hair loss (B), and a macular rash on the palmar surfaces of both hands (C). Results of rapid plasma regain and enzyme immunoassay were positive for syphilis. The patient responded to treatment with intravenous penicillin and oral corticosteroids. (Courtesy of Shaun R. Parsons and Anthony J Hall. Melbourne, Australia) 450 Morrow and Ko: J Neuro-Ophthalmol 2017; 37: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.