Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Methylprednisolone plus prednisone reduced subsequent development of multiple sclerosis in patients with optic neuritis

ACP J Club. 1994 May-June;120:61. doi:10.7326/ACPJC-1994-120-3-061


Source Citation

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


Abstract

Objective

To compare the development of multiple sclerosis (MS) in adults after treatment of optic neuritis with methylprednisolone and prednisone, prednisone alone, or placebo.

Design

2-year follow-up of a 14-day randomized controlled trial.

Setting

15 clinical centers.

Patients

389 adults (mean age 32 y, 85% white, 77% women) who had acute unilateral optic neuritis with visual symptoms of ≤ 8 days with no history of optic neuritis or optic atrophy in the affected eye, evidence of systemic disease associated with optic neuritis, or previous treatment with corticosteroids for optic neuritis in the other eye. Patients with clinically definite or probable MS were excluded.

Intervention

Patients were allocated to receive intravenous methylprednisolone, 250 mg every 6 hours for 3 days, and then oral prednisone, 1 mg/kg body weight for 11 days (n = 134); oral prednisone, 1 mg/kg for 14 days (n = 129); or placebo for 14 days (n = 126). Follow-up was 91%.

Main outcome measure

Development of definite MS based on clinical criteria. Definite MS was defined as a confirmed second demyelinating attack with a new neurologic abnormality.

Main results

50 patients developed definite MS. Compared with patients in the placebo group, patients in the methylprednisolone group, but not those in the prednisone group, had a lower rate of definite MS at 2 years (P = 0.03) (Table). New optic neuritis occurred more often in the prednisone group than in the methylprednisolone group (P = 0.002) or in the placebo group (P = 0.24).

Conclusion

In patients with optic neuritis, treatment with intravenous methylprednisolone and prednisone, compared with prednisone alone or with placebo, reduced the rate of development of definite multiple sclerosis over 2 years.

Source of funding: National Eye Institute.

For article reprint: Dr. R.W. Beck, The Jaeb Center for Health Research, 3010 East 138 Avenue, Suite 9, Tampa, FL 33613, USA. FAX 813-975-8761.


Table. Methylprednisolone or prednisone vs placebo for the development of definite multiple sclerosis at 2 years*

Intervention type Intervention Placebo RRR (95% CI) NNT (CI)
Methylprednisolone 7% 17% 55% (10 to 78) 11 (6 to 74)
Prednisone 15% 17% 11% (-55 to 50) Not significant

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Inflammatory optic neuritis and the isolated brainstem and acute partial myelopathy syndromes are related to MS. Their cause is unknown, and their clinical courses vary greatly. Many patients recover fully, but others relapse or develop MS. Recurrence cannot be predicted or prevented. This second major report from the Optic Neuritis Treatment Trial (ONTT) suggests that treating acute optic neuritis with a short course of methylprednisolone and prednisone may delay the development of clinically definite MS for up to 2 years. Prednisone alone was not protective. This finding, if confirmed, would change clinical practice and provide important insights into the pathogenesis of these common but poorly understood syndromes.

Clinical experience and several imperfectly designed treatment trials have suggested that corticosteroids have only a transient clinical benefit in MS and a short-lived effect on magnetic resonance imaging (MRI) evidence of blood-brain barrier disruption. The ONTT was not primarily designed to determine whether corticosteroids have a prolonged, protective effect after acute optic neuritis. MRI evidence of reduced ongoing disease activity after treatment with methylprednisolone would have greatly strengthened the clinical observation, but serial MRIs were not done. As a word of caution, "censoring" (failure to complete the 2-y follow-up) occurred most frequently in the methylprednisolone group. If these censored patients did less well than those followed regularly, the protective effect from methylprednisolone may have been more apparent than real (false positive finding, type 1 error).

No evidence shows that prednisone should be used in acute optic neuritis. Methylprednisolone did not enhance visual recovery at 1 year, yet it will probably be administered to some patients with severe, painful, recurrent, or bilateral optic neuritis. Natural history studies suggest that frequent attacks early in the course of MS increase long-term disability. As such, delaying the development of clinically definite MS should be a worthwhile aim, particularly if it can be done with little risk. This study's promising findings must be confirmed before we can be certain that we can delay the onset of MS in patients with acute optic neuritis.

In the 5 years since the publication of the paper by Beck and colleagues, studies have supported the findings that patients with isolated, presumed inflammatory-demyelinating optic neuritis will develop clinically definite MS (1-4). The findings are consistent across these studies and indicate that cranial MRI changes consistent with subclinical inflammatory demyelination at the time of clinical presentation with optic neuritis markedly increase the risk that further clinical episodes may arise within 5 to 10 years. Both the risk for developing clincially definite MS and the risk for substantial short-term disability from MS is determined, in part, by the degree of abnormality on this test (e.g., the number and cross-sectional area of MRI signal changes). The risk for further clinical events during this relatively short time span is reduced, but not eliminated, if the baseline MRI study is normal. The presence of cerebrospinal oligoclonal bands slightly increases the risk for MS for patients with a normal MRI and the absence of this finding may reduce the chances of recurrence. Children with optic neuritis have not been adequately studied with MRI, and long-term follow-up to determine whether these observations apply to this age group is needed. The Mayo Clinic experience provides useful prognostic information based on clinical findings present at onset for patients with childhood optic neuritis. Physicians need to use care in presenting this prognostic information to patients with their first episodes of optic neuritis to avoid falsely increasing hopes or adding to the concerns brought on by the frightening visual loss.

John Noseworthy, MD
Mayo Clinic and Mayo Medical SchoolRochester, Minnesota, USA


References

1. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis. Experience of the optic neuritis treatment trial. Neurology. 1997 Nov;49:1404-13.

2. The Optic Neuritis Study Group. Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1997;115:1545-52.

3. O'Riordan JI, Thompson AJ, Kinsgley DP, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain. 1998 Mar;121:495-503.

4. Cole SR, Beck RW, Moke PS, Kaufman DI, Tourtellotte WW. The predictive value of CSF oligoclona banding for MS 5 years after optic neuritis. Optic Neuritis Study Group. Neurology. 1998 Sep;51:885-7.