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Neurology 2000;54:2039-2044
© 2000 American Academy of Neurology
Special Article

Practice parameter: The role of corticosteroids in the management of acute monosymptomatic optic neuritis

Report of the Quality Standards Subcommittee of the American Academy of Neurology

D. I. Kaufman, DO, J. D. Trobe, MD, E. R. Eggenberger, DO and J. N. Whitaker, MD

From the Department of Neurology and Ophthalmology (Drs. Kaufman and Eggenberger), College of Osteopathic Medicine and College of Human Medicine, Michigan State University, East Lansing, MI; the Departments of Ophthalmology and Neurology (Dr. Trobe), W.K. Kellogg Eye Center, University of Michigan, Ann Arbor; and the Department of Neurology and Center for Neuroimmunology (Dr. Whitaker), University of Alabama at Birmingham and Research and Neurology Services, Birmingham Veterans Medical Center.

Address correspondence and reprint requests to the American Academy of Neurology, 1080 Montreal Ave., St. Paul, MN 55116.


   Introduction
Top.
 Introduction
Evidence review.
 Definitions for the...
 Results.
 Recommendations.
 Recommendations for future...
 Disclaimer.
 Appendix
 References
 
Optic neuritis (ON) is an inflammatory disorder of the optic nerve. Most cases are idiopathic or associated with MS. ON can be associated with a variety of systemic or ocular disorders and is the most common acute optic neuropathy in adults younger than 46 years. Among high-risk populations for MS, the incidence of ON is about 3 per 100,000 population per year, whereas in other areas the incidence is about 1 per 100,000 population per year.1-13

Acute ON often presents as an isolated clinical event without contributory systemic abnormalities (monosymptomatic ON). Clinical features include periocular pain, abnormal visual acuity and fields, reduced color vision, a relative afferent pupillary defect, and abnormal visual evoked potentials. The fundus may appear normal or demonstrate edema of the optic nerve head (papillitis).12-18 MRI white matter abnormalities identical to those seen in MS are found in 50 to 70% of monosymptomatic ON cases.19-22 The visual deficit of ON may worsen over 1 to 2 weeks and usually begins improving over the next month. Lack of improvement in visual function by 30 days is unusual.23 However, most patients have some residual visual function deficit, even if visual acuity improves to 20/20.1-18 Differential diagnosis includes compressive, ischemic, hereditary, toxic, or other inflammatory optic neuropathies (e.g., sarcoid). These conditions usually do not exhibit the same clinical pattern (table 1) or rate of recovery as monosymptomatic ON.1-13


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  		Table 1. Features of acute demyelinating monosymptomatic optic neuritis
 
Treatment of monosymptomatic ON has included oral, retrobulbar, and IV steroids, immunoglobulin, and acupuncture.23-77 Monosymptomatic acute ON is not rare and because the usefulness of oral prednisone in this disorder has recently been questioned,23,78-82 this practice parameter was developed to provide recommendations regarding the management of this common neurologic problem.


   Evidence review.
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 Introduction
 Evidence review.
Definitions for the...
 Results.
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 Disclaimer.
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 References
 
A literature search was conducted using Medline and Healthstar from 1966 to July 1, 1999. ON was cross-referenced with treatment and therapy. Citations earlier than 1966 were searched by cross-referencing techniques and an Index Medicus hand search. A total of 582 different citations dealing with ON and some aspect of therapy were identified and reviewed. Only literature published in well-disseminated journals dealing specifically with MS-related or idiopathic ON involving at least three patients was retained. Both retrospective and prospective data were reviewed. Citations were excluded when they simply described a small number of individual case reports or reviewed "ON" due to diseases such as sarcoid, lupus, anterior ischemic optic neuropathy, trauma, hereditary optic neuropathy, optic nerve compression, or other unrelated optic neuropathy.


   Definitions for the classification of evidence.
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Class I. Evidence provided by well-designed, randomized, controlled clinical trials, including overviews (meta-analyses) of such trials.

Class II. Evidence provided by well-designed observational studies with concurrent controls (e.g., case control and cohort studies).

Class III. Evidence provided by expert opinion, case series, case reports, and studies with historical controls.

All pertinent studies are listed in table 2.


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  		Table 2. Studies of optic neuritis (ON) classified chronologically by level of evidence
 

   Results.
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 Introduction
 Evidence review.
 Definitions for the...
 Results.
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Several studies were identified, the largest of which was the National Eye Institute–sponsored Optic Neuritis Treatment Trial (ONTT).11,12,23,30-33,39,56-59 61-77,83-85 The ONTT enrolled 457 patients with acute ON, age 18 to 46 years, and followed them for 6 months or longer.23 The study subsequently completed 5-year follow-up on a cohort of 388 ON patients with no history of MS.83,85

ONTT patients were randomized into three treatment groups within 8 days of symptoms onset: 1) oral prednisone alone (1 mg/kg every day) for 14 days (oral treatment group); 2) IV methylprednisolone sodium succinate 250 mg four times daily (1000 mg/day) for 3 days in hospital, followed by oral prednisone (1 mg/kg every day) for 11 days as outpatient (IV treatment group or IVMP); or 3) oral placebo for 14 days (placebo group). The prednisone arm of the study was double-masked, whereas the IVMP arm was single-masked. The use of a placebo IV group was not included because study organizers could not justify, ethically or financially, hospitalizing patients for 3 days of sham IV therapy.65,84

The study was designed to determine speed and level of recovery and complications of therapy. Visual acuity, visual fields, contrast sensitivity, and color vision were measured at study entry and at seven follow-up visits during the first 6 months, at 1 year, and then annually for 5 years. MRI was performed in nearly all patients at study entry. Lumbar puncture was optional and performed in 133 of 457 (29.1%) of the cohort.65,84 Two of 457 patients were eventually discovered to have compressive ON.

Oral prednisone at 1 mg/kg/day (previously the most common method of treating ON) failed to demonstrate any statistically significant improvement in the speed or degree of visual recovery compared to placebo.23 The IV treatment group, by contrast, had significantly faster visual recovery than placebo over the first 30 days (p = 0.02 and p = 0.0001 for the respective primary outcomes) but, after 6 months, there were no significant differences in visual acuity in the three treatment groups.23 After 12 months of follow-up, visual acuity in the study eye was better than 20/20 in 69% and 20/200 or worse in only 3%.86 The only predictor of a poor visual outcome was poor visual acuity at study entry. Of 160 eyes starting at 20/200 or worse, only 8 (5%) were still 20/200 or worse at 6 months.12,23,67

Recurrent ON was greater in the group treated with oral prednisone alone than in the other two groups.23,61,62 Also by year 2, 30% of patients in the oral treatment group experienced at least one new attack of ON in either eye compared to 16% in the placebo group and 13% in the IV treatment group.23,71,75 This disparity among treatment groups continued throughout the 5-year follow-up period (41% recurrences in the prednisone treatment group and 25% in the IV and placebo groups; p = 0.004). Also, the ONTT noted that IVMP was associated with reduced risk of developing clinically definite MS in patients with an abnormal brain MRI at study entry and followed for 2 years compared to the two other treatment groups.71,83,87 These relationships between treatment and both recurrent ON and MS remain unexplained and controversial.78-82,88 Herishanu et al.40 suggested that both recurrent ON and ON conversion to MS were greater following the use of IVMP compared to oral prednisone. This study, however, retrospectively evaluated a total of only 26 nonrandomized patients receiving no therapy, oral prednisone or IVMP, and, therefore, provides essentially Class III evidence of any such associations.

In the ONTT the therapeutic effect of the IVMP was no longer significant by the third year of follow-up (table 3).75,83 Among patients with a normal MRI, the 2-year rate of MS was so low that a benefit from IV treatment could not be established (see table 3). 83 The IV treatment arm of the ONTT was single masked.71,89 Patients or neurologists, using a detailed and standardized protocol months or years after therapy, are unlikely to have been biased in reporting attacks of demyelination in the IVMP group or in any of the other treatment groups.76 All patient forms were reviewed without knowledge of the treatment arm by a neurologist experienced in MS.76


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  		Table 3. Cumulative probability of patients with clinically definite MS after specific time intervals by treatment group83
 
Four other Class I and three other Class II corticosteroid treatment trials in ON that were relevant to this practice parameter were identified (see table 2).30-33,39,56-59 All were prospective, randomized, and placebo-controlled studies, although employing sample sizes considerably smaller than the ONTT. Thus, these studies lack the statistical power to exclude a therapeutic benefit to steroid treatment.90 Several of these Class I studies report positive results. For example, Rawson et al. found that the speed of recovery in visual acuity was faster in patients receiving ACTH (40 units IM daily for 30 days; p < 0.01) compared to placebo over the first 30 days, although by 12 months there was no significant difference between groups.30,31 Bowden et al.32 similarly demonstrated that visual acuity was the same at 12 months in patients treated with either ACTH (40 units IM daily for 30 days) or placebo. Kapoor et al. showed no effect of IVMP (1000 mg/d x 3 days) compared to placebo on the visual outcome at 6 months in 66 individuals with ON lesions involving the optic canal.56 Sellebjerg et al. studied 60 patients59 using either 500 mg of oral methylprednisolone daily for 5 days with a 10-day taper or placebo. They reported that there was an increased speed of visual recovery in the treated group (p = 0.008) but no long-term benefit compared to placebo. There was no increase in recurrence of ON at 1 year using oral methylprednisolone; however, they noted that the number of patients was too low to rule out an effect on subsequent disease activity.59

Three Class II studies were noted. Gould et al. found that ON treated with a single dose of retrobulbar triamcinolone (40 mg) was associated with nonsignificant increase in the speed of visual recovery but resulted in no benefit compared to placebo at 12 months.33 In 1999, Wakakura et al. evaluated 66 patients with optic neuritis treated with either 1000 mg IVMP for 3 days or mecobalamin (500 mg/day) and found that IVMP improved the speed of visual recovery in the first several weeks (p < 0.05) but that visual function at 12 weeks and 1 year did not differ between the two groups.13,58 Another oral methylprednisolone study has also been reported. The Tübingen study tested 50 patients,39,57 14 of whom were treated patients with 100 mg of oral methylprednisolone for 3 days, subsequently tapering the dose by 20 mg every 3 days thereafter. At 4 weeks the treated group had a 61% better visual outcome (nearly normal function) compared to placebo (thiamine), although this was not statistically significant. By 12 months, however, no such difference was apparent.

Thirteen Class III studies were also identified (see table 2). These included reports from the early 1950s dealing with glucocorticoid treatment of ON.24,27 All of these studies had serious methodologic flaws related to very low patient numbers,90 retrospective analysis, no randomization, or lack of placebo control.24,27-29,34,35,40-42,44,53-55 In a 1988 publication, Spoor and Rockwell showed rapid recovery of vision (some within 24 hours) in 12 patients given 1 to 2 g of IVMP. This study was neither randomized nor placebo-controlled.41 A study by Alejandro et al. in 1994 looked at eight patients given IVMP versus eight patients treated with oral prednisone and found no difference between groups.55 Other studies are listed in table 2.

There are also several studies reviewing the prognostic value of MRI and CSF in determining the relative risk of developing MS after ON.20,60,83,91 However, an in-depth analysis of that work is beyond the scope of this practice parameter.


   Recommendations.
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 Introduction
 Evidence review.
 Definitions for the...
 Results.
 Recommendations.
Recommendations for future...
 Disclaimer.
 Appendix
 References
 
Definitions for the strength of recommendations were based on the following criteria:

Standard: A principle for patient management that reflects a high degree of clinical certainty (usually this requires Class I evidence that directly addresses the clinical question, or overwhelming Class II evidence when circumstances preclude randomized clinical trials).

Guideline: A recommendation for patient management that reflects moderate clinical certainty (usually this requires Class II evidence or a strong consensus of Class III evidence.

Practice Option: A strategy for patient management for which the clinical utility is uncertain (inconclusive or conflicting evidence or opinion).

Practice Advisory: A practice recommendation for emerging and/or newly approved therapies or technologies based on evidence from at least one Class I study. The evidence may demonstrate only a modest statistical effect or limited (partial) clinical response, or significant cost–benefit questions may exist. Substantial (or potential) disagreement among practitioners or between payers and practitioners may exist.

Acute monosymptomatic ON recommendations. Oral prednisone in doses of 1 mg/kg/day has no demonstrated efficacy in the recovery of visual function in acute monosymptomatic ON, and therefore is of no proven value in treating this disorder. Standard

Higher dose oral or parenteral methylprednisolone or ACTH may hasten the speed and degree of recovery of visual function in persons with acute monosymptomatic ON. There is, however, no evidence of long-term benefit for visual function. The decision to use these medications to speed recovery but not to improve ultimate visual outcome should therefore be based on other non-evidence–based factors such as quality of life, risk to the patient, visual function in the fellow eye, or other factors that the clinician deems appropriate. Guideline


   Recommendations for future research.
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 Introduction
 Evidence review.
 Definitions for the...
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 Appendix
 References
 
Several management issues still lack evidence for specific recommendations: 1) whether corticosteroid treatment is beneficial in patients whose symptom duration is longer than 8 days; 2) whether larger doses of corticosteroids are more effective than lower doses; 3) what the optimal corticosteroid regimen is; 4) whether the observed increased ON recurrence rate associated with oral prednisone is also observed in MS attacks; and 5) whether high-dose methylprednisolone given periodically will improve the prognosis for patients with MS.


   Disclaimer.
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This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.


   Appendix
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 Introduction
 Evidence review.
 Definitions for the...
 Results.
 Recommendations.
 Recommendations for future...
 Disclaimer.
 Appendix
References
 
American Academy of Neurology Quality Standards Subcommittee Members: Gary Franklin, MD, MPH—Co-Chair; Catherine Zahn, MD—Co-Chair; Milton Alter, MD, PhD; Stephen Ashwal, MD; John Calverley, MD; Richard Dubinsky, MD; Jacqueline French, MD; Michael Greenberg, MD; Gary Gronseth, MD; Deborah Hirtz, MD; Robert Miller, MD; James Stevens, MD; and William Weiner, MD.


   Acknowledgments
 
The American Academy of Neurology Quality Standards Subcommittee thanks David I. Kaufman, DO, for his service to the Academy’s membership as the lead author of this practice parameter; Michael Greenberg, MD, and Gary Franklin, MD, MPH, for facilitating this project; Jonathon Trobe, MD, Eric Eggenberger, DO, and John N. Whitaker, MD, for providing their expertise, time, and insight into the development of this document; and Sandy Holliday, for her help in bringing this manuscript to conclusion.

They also thank the numerous individuals, AAN Sections, and organizations that reviewed drafts of this practice parameter, including the American Academy of Ophthalmology, National MS Society, MS Society of Canada, AB Baker Section, Government Services Section, MS Section, Neuro-Ophthalmology/Neuro-Otology Section, Neuroimaging Section, Pain Section, Sleep Section, Spine Section, and the Stroke Section.


   Footnotes
 
Approved by the Quality Standards Subcommittee July 24, 1999. Approved by the Practice Committee January 15, 2000. Approved by the American Academy of Neurology Board of Directors February 26, 2000.


   References
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 Introduction
 Evidence review.
 Definitions for the...
 Results.
 Recommendations.
 Recommendations for future...
 Disclaimer.
 Appendix
 References
 

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Received May 4, 1999. Accepted in final form September 18, 1999.




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