• Nov 2013
    AAO PPP Committee, Secretary for Quality of Care, Hoskins Center for Quality Eye Care
    Neuro-Ophthalmology/Orbit
    Compendium Type: I

    Clinical Question

    What is the evidence that corticosteroids are more or less effective treatments than placebo or “no treatment” conditions for patients with acute optic neuritis?

    Literature Search

    The literature search for the Cochrane Review was last updated in February 2012. To present this Clinical Question, an additional literature search was undertaken in April 2013. 

    Literature search details

    Systematic Review

    Gal RL, Vedula SS, Beck R. Corticosteroids for treating optic neuritis. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No. CD001430. DOI: 10.1002/14651858.CD001430.pub3.

    Methods and Key to Ratings

    Preferred Practice Pattern Clinical Questions should be clinically relevant and specific enough to provide useful information to practitioners. Where evidence exists to support a recommendation for care, the recommendation should be given an explicit rating that shows the strength of evidence. To accomplish these aims, methods from the Scottish Intercollegiate Guideline Network (SIGN)1 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE)2 group are used. All studies used to form a recommendation for care are graded for strength of evidence individually. To rate individual studies, a scale based on SIGN1 is used. GRADE is a systematic approach to grading the strength of the total body of evidence that is available to support recommendations on a specific clinical management issue. Organizations that have adopted GRADE include SIGN, the World Health Organization, the Agency for Healthcare Research and Policy, and the American College of Physicians.3

    SIGN1 Study Rating Scale

    I++

    High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias

    I+

    Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

    I-

    Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias

    II++

    High-quality systematic reviews of case-control or cohort studies

    High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

    II+

    Well-conducted case-control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

    II-

    Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

    III

    Nonanalytic studies (e.g., case reports, case series)

    GRADE2 Quality Ratings

    Good quality

    Further research is very unlikely to change our confidence in the estimate of effect

    Moderate quality

    Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

    Insufficient quality

    Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate

    Any estimate of effect is very uncertain

    GRADE2 Key Recommendations for Care

    Strong recommendation

    Used when the desirable effects of an intervention clearly outweigh the undesirable effects or clearly do not

    Discretionary recommendation

    Used when the trade-offs are less certain-either because of low-quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced

    Recommendations for Care

    Summary

    Optic neuritis is an inflammatory demyelination of the optic nerve, occurring more commonly in women than in men. Multiple sclerosis (MS) is almost always the suspected cause. Optic neuritis is typically characterized by a sudden vision loss over several hours or days. However, 95% of patients experience an improvement in visual acuity (VA) to 20/40 or better at 12 months.

    While the VA symptoms associated with optic neuritis should never be treated in isolation, this review focuses predominantly on the effectiveness of oral or intravenous (IV) corticosteroid treatment to address these symptoms. Because corticosteroids are commonly used, in part, to treat optic neuritis, and their effectiveness in the treatment of optic neuritis has historically (i.e., since the 1950s) remained in question, the Cochrane Collaboration conducted a review focused exclusively on the treatment of acute optic neuritis and the outcome of VA recovery, with corticosteroids. The AAO emphasizes, however, that it is the role of the attending ophthalmologist to treat the entire person, and not just the limited symptoms discussed in this review.

    The Cochrane Review authors systematically reviewed the evidence for the use of corticosteroid therapy in any form or dosage with the intention to treat or reduce the symptoms of acute optic neuritis, compared with placebo or no treatment conditions. Studies included in their review were randomized controlled trials (RCTs) where 1) study participants had acute optic neuritis; 2) the proportion of patients achieving normal VA, normal contrast sensitivity, or normal visual field at six months or more were reported; and 3) secondary outcomes, defined as immediate response (rate of recovery) for the same visual outcomes, were measured one month after treatment.

    The authors of the Cochrane Review identified six RCTs meeting these criteria. A total of 750 patients were included in these trials. However, 457 patients constituted one large RCT (the Optic Neuritis Treatment Trial [ONTT]),4 and the remaining trials were small (i.e., less than 70 total patients). These studies varied considerably in terms of the corticosteroid regimens studied and patient populations sampled. For instance, different studies required various durations of symptoms for inclusion and one trial did not exclude patients with corticosteroid treatment histories.

    The objective of this review was to assess the effectiveness of corticosteroids for acute optic neuritis. There is conclusive evidence that high-dose corticosteroids—either oral or IV corticosteroids—produce a more rapid recovery of vision in the short-term, but do not provide a long-term visual benefit. There is also a delay in the onset of subsequent demyelination, and a decrease in the rate of subsequent demyelination events,5 in those with higher risk MRI findings for 2-3 years with high dose corticosteroids as compared to those not treated with high dose corticosteroids.

    (Study Rating Scale I+, Moderate Quality, Discretionary Recommendation)

    Discussion

    Oral Corticosteroids vs. Placebo

    None of the trials found evidence of a statistically significant benefit of oral corticosteroid treatment (generally low-dose prednisolone), compared to placebo, as measured by the proportion of patients achieving normal VA, normal contrast sensitivity, or normal visual field at one month, six months, or one year. Trials evaluating the oral corticosteroids used varying dosages of the medication. The ONTT found that there was no difference between the proportion of patients achieving normal VA and contrast sensitivity at one year in comparison to the placebo group (Risk Ratio (RR): 0.93; 95% Confidence Interval (CI): 0.86–1.00), the VA between the three groups was similar. (There was an oral prednisone group, an intravenous methylprednisone group, and a placebo group.) Also, oral corticosteroid therapy at a specific dose of 1 mg/kg prednisone was associated with an increase in rate of new episodes of optic neuritis as suggested by the analyses reported in the ONTT.

    Intravenous Corticosteroids vs. Placebo

    None of the trials found evidence of a statistically significant benefit of IV corticosteroids (dexamethasone or methylprednisolone (>3,000 mg total dose)), compared to placebo, as measured by the proportion of patients achieving normal VA at one month, six months, or one year. No trials found evidence of a benefit as measured by the proportion of patients achieving normal contrast sensitivity at one month or six months. One small RCT6 found that IV corticosteroids were associated with a significantly higher proportion of patients achieving normal contrast sensitivity at one year (RR: 1.33; 95% CI: 1.02–1.72). However, this association was both of marginal significance and not replicated in the ONTT. In fact, the ONTT found no benefit for contrast sensitivity using corticosteroids at one year (RR: 0.99; 95% CI: 0.93–1.06). A life-table analysis reported in the ONTT found that the rate of return of vision to normal was faster with IV corticosteroids compared with placebo (P=0.09 for VA, 0.02 for contrast sensitivity, and 0.00001 for visual field), yet this outcome was not sustained over time.

    None of the trials found a benefit as measured by the proportion of patients achieving a normal visual field by six months or one year. The ONTT found evidence of a benefit using this measure at one month (RR: 1.36; 95% CI 1.05–1.75), but the effect was not maintained over time. At six months, the RR associated with corticosteroids was 1.07 (95% CI: 0.95–1.21), and at one year, the RR was 1.00 (95% CI: 0.85–1.18).

    Conclusion

    A systematic review of one large RCT and five smaller RCTs found that high-dose IV corticosteroids produce a more rapid recovery of vision among patients with acute optic neuritis in the short-term, but do not provide a long-term visual benefit overall. Although high-dose IV corticosteroid treatment does lead to a more rapid recovery of vision, there were no consistent improvements as measured by patient recovery to normal VA, normal contrast sensitivity, or normal visual field. High dose corticosteroid treatment does, however, delay the onset of subsequent demyelination5 events for 2-3 years for patients with MS. Comparisons among the trials are limited by heterogeneity across the patients sampled, the corticosteroid regimens studied, and small treatment effects.

    From a clinician’s perspective, treatment with high-dose IV corticosteroids followed by oral corticosteroids may be appropriate, in terms of helping patients achieve faster recovery to normal vision; no treatment for these symptoms may also be an appropriate course of action. We emphasize that patients with acute optic neuritis are often afflicted with MS or other underlying conditions. Appropriate care for these patients must not focus solely on the visual symptoms in exclusion of potential neurological implications. Neural damage occurs with the great majority of patients even though VA returns to normal. Going forward there is a clear need for future research for improved pharmacologic therapy.

    References

    1. Scottish Intercollegiate Guidelines Network. SIGN 50: A Guideline Developer's Handbook. Available at: www.sign.ac.uk/methodology/index.html. Accessed May 25, 2013.

    2. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6.

    3. GRADE Working Group. Organizations that have endorsed or that are using GRADE. Available at: www.gradeworkinggroup.org/society/index.htm. Accessed July 22, 2013.

    4. Beck RW, Cleary PA, Anderson MM, Jr., et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 1992;326(9):581-8.

    5. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med 1993;329:1764-9.

    6. Wakakura M, Mashimo K, Oono S, et al. Multicenter clinical trial for evaluating methlprednisolone pulse treatment of idiopathic optic neuritis in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative Research Group (ONMRG). Jpn J Ophthalmol 1999;43:133-8.

    Reviewers

    Roy W. Beck, MD, PhD

    David Kaufman, DO

    North American Neuro-Ophthalmology Society (NANOS) Panel Members

    Eric Eggenberger, DO

    Jonathan Trobe, MD

    Leah Levi, MBBS

    Preferred Practice Pattern Committee Members

    Stephen D. McLeod, MD, Chair

    David F. Chang, MD

    Robert S. Feder, MD

    Timothy W. Olsen, MD

    Bruce E. Prum, Jr., MD

    C. Gail Summers, MD

    David C. Musch, PhD, MPH, Methodologist

    Secretary for Quality of Care

    Anne L. Coleman, MD, PhD - Director, H. Dunbar Hoskins Jr., MD Center for Quality Eye Care

    Academy Staff

    Jennifer K. Harris, MS

    Nicholas P. Emptage, MAE

    Flora C. Lum, MD

    Approved by:

    Board of Trustees

    November 15, 2013

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    Disclosures

    In compliance with the Council of Medical Specialty Societies' Code for Interactions with Companies, relevant relationships with industry occurring from May to October 2013 are listed. The Academy complies with the Code in developing PPP Clinical Questions by following the Preferred Practice Patterns and Ophthalmic Technology Assessments: New Relationship with Industry Procedures.

    Roy W. Beck, MD, PhD: No financial relationships to disclose

    David F. Chang, MD: No financial relationships to disclose

    Anne L. Coleman, MD, PhD: No financial relationships to disclose

    Eric Eggenberger, DO: No financial relationships to disclose

    Robert S. Feder, MD: No financial relationships to disclose

    David Kaufman, DO: No financial relationships to disclose

    Leah Levi, MBBS: No financial relationships to disclose

    Stephen D. McLeod, MD: No financial relationships to disclose

    David C. Musch, PhD, MPH: No financial relationships to disclose

    Timothy W. Olsen, MD: No financial relationships to disclose

    Bruce E. Prum, Jr., MD: No financial relationships to disclose

    C. Gail Summers, MD: No financial relationships to disclose

    Jonathan Trobe, MD: No financial relationships to disclose

    Academy Staff: No financial relationships to disclose