The treatment of optic neuritis has been explored in several randomized clinical trials (RCTs).^{1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20} In the Optic Neuritis Treatment Trial (ONTT),^{1,2,3,4,5,6,7,8,9,10} the largest trial to date, high-dose intravenous methylprednisolone (IV MP) treatment accelerated visual recovery but had no impact on final visual outcome. Three smaller RCTs of optic neuritis^11,12,13 found similar results. Two RCTs of intravenous immunoglobulin (IVIG), one in acute optic neuritis¹⁴ and the other in chronic residual optic neuropathy following optic neuritis,¹⁵ failed to demonstrate any treatment benefit. A study of IVIGs in corticosteroid (CS)-refractory optic neuritis demonstrated a beneficial effect on visual outcome.¹⁶ The ONTT also found that high-dose IV MP treatment temporarily retarded the development of clinically definite multiple sclerosis (CDMS).^2,3,4,10 Four RCTs of interferon beta 1a,^17,18 interferon beta 1b,¹⁹ and glatiramer acetate²⁰ in the treatment of acute optic neuritis and other “clinically isolated” neurologic syndromes that predict MS found that this treatment significantly reduced the development of CDMS and the accumulation of magnetic resonance imaging (MRI) abnormalities typical of MS.

The major findings of these trials are as follows: (1) neither CS nor IVIG treatment appears to have a meaningful effect on visual outcome and CS treatment has no long-term impact on neurologic outcome; (2) continuous interferon beta 1a, beta 1b, and glatiramer acetate treatment of acute optic neuritis reduces the development of new MS-like neurologic manifestations and accumulation of MS-like MRI abnormalities, but there is no evidence that it reduces long-term neurologic disability; and (3) acute optic neuritis, even if untreated, has a relatively benign neurologic course as compared to other clinically isolated neurologic syndromes (spinal cord and brain stem lesions causing weakness, diplopia, and ataxia).

The treatment of acute optic neuritis with oral, IV, and retrobulbar CS was common before the first publication of the ONTT in 1992,¹ based largely on anecdotal and small trial evidence.¹

The ONTT was the first large RCT to study the effect of IV MP and low-dose oral prednisone (OP) on acute optic neuritis. In the ONTT, 457 patients with acute optic neuritis were randomized to three groups: (1) IV MP 250 mg four times a day for 3 days, followed by OP 1 mg/kg for 11 days; (2) OP 1 mg/kg for 14 days; or (3) placebo. Acute optic neuritis was defined as a monocular visual deficit of no more than 8 days’ duration with an ipsilateral afferent pupillary defect in a patient aged between 18 and 46 years. Patients were entered into the trial only if they had had no previous episodes of optic neuritis in that eye, no previous CS treatment for MS, and no other systemic condition associated with optic neuritis apart from MS.

The ONTT end points were visual acuity, visual fields (Humphrey and Goldmann),
color vision (Farnsworth-Munsell 100-hue), contrast sensitivity (Pelli-Robson chart), and other neurologic deficits as assessed by a neurologist. All patients underwent brain MRI and blood tests for antinuclear antibody and treponemal antigen, and a chest x-ray directed at sarcoidosis. Lumbar puncture was optional and less than half the cohort underwent it. The examining neurologists were masked to treatment but the patients who received IV MP knew that they had received it.

Neither CS regimen produced any benefit on visual outcome. Visual function improved more rapidly in the IV MP group, but the difference was relatively trivial. These findings held up in the follow-up evaluations up to 15 years after study entry. Patients who had been treated with OP without a preceding regimen of IV MP had a doubling of the recurrence rate of optic neuritis in the affected and the contralateral eye. The IV MP group had a reduction in the development of CDMS after 2 years, but that effect had evaporated by 3 years after study entry.

The implications for clinical practice derived from the ONTT are that the IV MP regimen, chosen because it was common in the treatment of organ transplant rejection, had no impact on visual recovery and only a temporary effect on conversion to MS. OP had no impact on visual recovery and doubled the recurrence rate of optic neuritis in the same or contralateral eye.

Similarly defined cohorts of 66 optic neuritis patients in an English RCT¹¹ and a Japanese RCT¹² also found no benefit on visual recovery of an IV MP regimen similar to that of the ONTT. A Danish RCT¹³ of 60 patients found that oral MP 500 mg/day for 3 days with a 10-day taper had exactly the same impact on visual recovery as did the ONTT IV MP regimen.

Like IV MP, IVIG appears to have no meaningful impact on visual recovery in optic neuritis. In a Danish RCT¹⁴ of 68 patients with acute optic neuritis, five infusions of IVIG 0.4 g/kg body weight administered on days 0, 1, 2, 30, and 60 after symptom onset produced no benefit in standard measures of visual function at 6 months. An IVIG RCT from the Mayo Clinic,¹⁵ using a similar regimen, showed that there was no meaningful impact on visual function in 55 patients with persistent visual dysfunction from optic neuritis in MS. In an IVIG nonrandomized open label prospective study conducted at a Detroit medical center,¹⁶ 23 patients with optic neuritis refractory to CS treatment (defined as visual acuity ≤ 20/400 at 60-90 days after onset of neuritis) received IVIG 0.4 g/kg body weight on days 0 to 5 followed by once-monthly infusion for 5 months. There was significant improvement in the VA of the IVIG group, with 78% reaching visual acuity of 20/30 or better with only 12.5% of the control group responding similarly.

Multiple trials of patients with relapsing-remitting multiple sclerosis (RRMS) have established that chronic beta interferon 1a (Avonex, Biogen Idec; Rebif, EMD Serono) and 1b (Extavia, Novartis Pharmaceutical Corp; Betaferon, Schering) or glatiramer acetate (Copaxone, Teva Pharmaceutical) treatment reduces the clinical relapse rate and reduces the accumulation of MRI signal abnormalities over a 2- to 3-year period.²¹ Because these agents also experimentally attenuate the immune process involved in MS, they have been called “immune-modulating agents” (IMAs).

It was logical, then, to explore whether chronic treatment with any of the IMAs, begun shortly after onset of acute optic neuritis, brain stem, or spinal cord manifestations (called “clinically isolated syndromes”) and brain MRI abnormalities typical of MS, would reduce the conversion to CDMS and the accumulation of MRI abnormalities.

Two beta interferon 1a trials, one conducted in the United States with Avonex (Controlled High Risk Avonex Multiple Sclerosis Study = CHAMPS group),¹⁷ the other in Europe with Rebif (Early Treatment of Multiple Sclerosis = ETOMS trial),¹⁸ a beta interferon 1b trial conducted in Europe with Betaferon
(Betaferon/Betaseron in Newly Emerging MS for Initial Treatment = BENEFIT),¹⁹ and a multinational study with glatiramer acetate (PreCISe)²⁰ included patients who had at least two MRI signal abnormalities typical of MS (the ONTT had shown that such abnormalities would predict a high likelihood of later development of CDMS) (Fig. 16.1).