Optic Neuritis Treatment Trial

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Beck R, et al. "A Randomized, Controlled Trial of Corticosteroids in the Treatment of Acute Optic Neuritis". The New England Journal of Medicine. 1992. 326(9):581-588.
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Clinical Question

In patients with an initial acute presentation of optic neuritis, does IV or oral steroids improve visual recovery compared to placebo?

Bottom Line

In patients with an initial acute presentation of optic neuritis, three days of high dose IV methylprednisolone followed by oral steroids for 11 days led to faster visual recovery compared to placebo but no difference in visual acuity at 6 months. There were no differences in visual recovery between patients treated with oral prednisone for 12 days and placebo. The rate of recurrent optic neuritis appears to be higher in those given oral prednisone compared to IV prednisolone or placebo at 2 year follow up.

Major Points

Optic neuritis (ON) is an inflammatory demyelinating condition affecting the optic nerve which may be idiopathic or a presenting symptom of broader demyelinating conditions such as multiple sclerosis (MS) or neuromyelitis optica (NMO). Much of what we know about the prognosis and treatment of ON is from the cohort of patients studied in the Optic Neuritis Treatment Trial. The paper reviewed here addresses initial treatment of optic neuritis and subsequent papers address long term prognosis with regards to visual recovery, prevalence of fellow eye abnormalities, types of visual field defects and prevalence of conversion to MS [1].

The results of this initial study has guided acute treatment of optic neuritis ever since its publication. IV methylprednisolone is the agent of choice for severe or bilateral optic neuritis as it hastens visual recovery but it is not always warranted for less severe cases as it does not seem to impact the degree of visual acuity recovery. The fact that high dose steroids speed up recovery but does not alter long-term outcomes of ON has been independently verified by subsequent trials [2] [3]. Use of oral prednisone alone at the dose used in the trial has been avoided as more patients had recurrence of their optic neuritis compared to IV methylprednisolone and placebo. There remains a paucity of evidence for treatment of non-steroid responsive ON, with some mixed evidence regarding the efficacy of IVIG [4] [5] [6] and PLEX for ON [7].

From the final 15-year follow up of this cohort, the risk of progression from ON to MS was 50%. For those with normal baseline MRIs, this risk was significantly lower at 25% compared to 72% if the patient had 1 or more lesions on their MRI. Many patients at 15 years had good visual outcomes with 72% of affected eyes having visual acuity of 20/20 or better. Of the patients with the most severe baseline impairments (finger counting to no light perception), 49% had 20/20 acuity or better and 78% had 20/40 acuity or better[8].

Guidelines

2012 American Academy of Ophthalmology Compendium

  • Acute treatment options: high dose corticosteroids (e.g., intravenous methylprednisolone) or no treatment depending upon individual risk-benefit ratio
    • Optic Neuritis Treatment Trial protocol: methylprednisolone 250 mg iv q 6 hours x 3 days, then prednisone 1 mg/kg/day po qd x 11 days, then 20 mg po on day 15 and 10 mg on days 16 and 18 then discontinue prednisone; many centers now administer methylprednisolone 1000 mg iv q day x 3 days for outpatient convenience with or without corticosteroid taper. Chronic treatment options: referral to a multiple sclerosis specialist for management and consideration of MS immunomodulatory therapy if abnormal MRI scan or other neurological abnormalities are suggested by examination or history
    • Oral prednisone 1 mg/kg/day alone contraindicated due to increased risk of recurrent optic neuritis (and no more effective than placebo concerning visual function)

Design

  • Multicenter, prospective cohort study
  • N=457
    • Placebo: 150
    • IV methylprednisolone: 151
    • Oral Prednisone: 156
  • Setting: 15 centers in the United States
  • Enrollment: July 1, 1988-June 30, 1991
  • Follow-up: 2 years at this publication (15 years in total)
  • Primary outcome: Visual field and contrast sensitivity
  • Secondary outcomes: Visual acuity and color vision

Population

Inclusion Criteria

  • Age 18-46 years
  • Acute unilateral optic neuritis with visual symptoms for 8 days or less
  • A relative afferent pupillary defect and a visual field defect in the affected eye
  • Ability to provide written informed consent

Exclusion Criteria

  • Previous episodes of optic neuritis in the affected eye
  • No previous corticosteroid treatment for optic neuritis or multiple sclerosis
  • Systemic disease other than multiple sclerosis that might be the cause of the optic neuritis

Baseline Characteristics

Given for all patients (all three groups similar)

  • Gender (% female):77%
  • Race (% white): 85%
  • Mean Age (years): 32 +/- 6.7
  • Weight in kg (median, range): 70 (42-182)
  • Duration of symptoms before entry (days): 5 +/- 1.6
  • Ocular pain present: 92%
  • Optic disk swollen: 35%
  • Existing diagnosis of Multiple Sclerosis: 6%
  • Visual acuity (n of patients):
    • 20/40 or better: 162
    • 20/50-20/190: 129
    • 20/200 or worse: 166

Interventions

  • Randomization to one of three groups in equal numbers:
    • Intravenous methylprednisolone (Solu-Medrol, 250 mg every 6 hours for 3 days) with hospitalization followed by oral prednisone (Deltasone, 1 mg per kilogram of body weight per day [rounded to the nearest 10 mg] for 11 days)
    • oral prednisone (1 mg per kilogram per day for 14 days) given as a single morning dose
    • oral placebo given as a single morning dose

Oral dose was tapered, to 20 mg on day 15 and to 10 mg on days 16 and 18.

Outcomes

Number of patients not achieving normal visual acuity, normal visual fields and normal contrast sensitivity are given at 4, 15, 30, 49, 91, 133, 180 days in the paper. Outcomes are given placebo vs. IV methylprednisolone vs. oral prednisone.

Primary Outcomes

  • Normal contrast sensitivity at 6 months: 54.7% vs. 62.3% (RR 1.17, 95% CI 0.98-1.41) vs. 55.8% (RR 1.05, 95% CI 0.86-1.26)
  • Normal visual fields at 6 months: 74.7% vs. 80.1% (RR 1.09, 95% CI 0.97-1.23) vs. 74.4% (RR 1.01, 95% CI 0.89-1.14)

Secondary Outcomes

  • Normal visual acuity at 6 months: 58.7% vs. 60.9% (RR 1.07, 95% CI 0.90-1.28) vs. 54.5% (RR 0.96, 95% CI 0.80-1.15)
  • Normal color vision at 6 months: 56.7% vs. 66.9% (RR 1.21, 95% CI 1.02, 1.44) vs. 56.4% (RR 1.01, 95% CI 0.84-1.23)
  • New diagnosis of MS within 2 year follow up: 20% vs. 14% (RR 0.65, 95% CI 0.37-1.16) vs. 24% (RR 1.17, 95% CI 0.71-1.93)
  • Recurrence of ON in either eye within 2 year follow up: 24% vs. 13% (RR 0.81, 95% CI 0.45-1.47) vs. 27% (RR 1.79, 95% CI 1.08-2.95)
  • Recurrence of ON in the previously affected eye within 2 year follow up: 10% vs. 9% (RR 0.86, 95% CI 0.42-1.76) vs. 15% (RR 1.40, 95% CI 0.74-2.65)

Subgroup Analysis

  • For contrast sensitivity, visual field, visual acuity and color vision, % recovery to normal was highest among patients whose vision was 20/40 or better at base line, lower among those whose vision ranged from 20/50 to 20/190, and lowest among those whose vision was 20/200 or worse
  • RR of recovery with treatment with both IV and oral steroids was lowest among patients whose vision was 20/40 or better at base line, higher among those whose vision ranged from 20/50 to 20/190, and highest among those whose vision was 20/200 or worse suggesting increased benefit for those with more severe ON at baseline (keeping in mind all 95% CI of these subgroups crossed zero)
  • No interaction analysis between treatment type and severity at baseline was carried out by the authors

Adverse Events

  • Two serious adverse side effects in IV methylprednisolone group: an acute transient depression that required psychotropic drugs, and acute pancreatitis
  • Steroid groups had more sleep disturbance, mild mood change, stomach upset, facial flushing and greater weight gain than placebo patients (P<0.001 for each comparison).

Criticisms

  • IV methylprednisolone arm patients not blinded to treatment (only oral placebo available) and were hospitalized unlike the two other arms
  • Oral prednisone dose was not equivalent to IV methylpredisolone dose (an equivalent prednisone oral dose would be 1250 Mg daily) so unsure if route or dosage accounts for difference in steroid arms. A subsequent trial has shown oral methylprednisolone 500 MG daily to be beneficial in acute treatment of ON [9]
  • The authors concluded that at six months, the distributions for contrast sensitivity (P = 0.026), visual field (P = 0.054), and color vision (P = 0.033) were still significantly different between IV methylprednisolone and placebo, although those for visual acuity were not (P = 0.66) based on testing using the Wilcoxon rank-sum but no mentions of correcting for multiple testing were made in the paper. When looking at RR of returning to normal on these visual measures, only color vision had a 95% CI that did not cross 1 when IV methylprednisolone was compared to placebo at 6 months.

Funding

  • National Eye Institute of the National Institutes of Health
  • Upjohn Company provided medications for the study

Further Reading

  1. Volpe NJ & The optic neuritis treatment trial: a definitive answer and profound impact with unexpected results. Arch. Ophthalmol. 2008. 126:996-9.
  2. Sellebjerg F et al. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999. 52:1479-84.
  3. Wakakura M et al. Multicenter clinical trial for evaluating methylprednisolone pulse treatment of idiopathic optic neuritis in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative Research Group (ONMRG). Jpn. J. Ophthalmol. 1999. 43:133-8.
  4. Noseworthy JH et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001. 56:1514-22.
  5. Roed HG et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 2005. 64:804-10.
  6. Tselis A et al. Treatment of corticosteroid refractory optic neuritis in multiple sclerosis patients with intravenous immunoglobulin. Eur. J. Neurol. 2008. 15:1163-7.
  7. Ruprecht K et al. Plasma exchange for severe optic neuritis: treatment of 10 patients. Neurology 2004. 63:1081-3.
  8. Optic Neuritis Study Group Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch. Neurol. 2008. 65:727-32.
  9. Sellebjerg F et al. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999. 52:1479-84.