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In the Clinic-Optic Neuritis
Study Stirs Debate: IV or Oral Corticosteroids for Optic Neuritis?

ARTICLE IN BRIEF

Figure

MRI of the optic nerve in acute demyelinating optic neuritis. (A) Axial image shows enhancement of the right optic nerve (arrow) with “spillover” to the optic nerve sheath leading to enhancement of this structure as well (arrowheads). (B) Coronal image shows enlargement and enhancement of the right optic nerve.

A new study found that IV corticosteroids and oral corticosteroids had equivalent treatment outcomes for people with optic neuritis. But some experts questioned the findings.

Researchers comparing high-dose oral corticosteroids versus intravenous steroids for acute optic neuritis found that both treatments resulted in improved eyesight at a similar rate after six months.

The study, published in the March 5 online edition of JAMA Neurology, acknowledged that based on the seminal 1992 Optic Neuritis Treatment Trial (ONTT), IV administration of corticosteroids became the standard of care for the treatment of acute optic neuritis.

However, in that 1992 study, the oral prednisone dose was relatively low at 1 mg per kilogram of body weight for 14 days and the IV methylprednisolone dose was 1 gram per day for three days.

STUDY DESIGN

In the new study, 45 participants were randomized to IV methylprednisolone sodium succinate (1000 mg) or an equivalent dose of oral prednisone (1250 mg) for three days.

“The aim of the study was not to prove that the oral steroids change the long-term outcome,” said the lead author Sarah A. Morrow, MD, MS, FRCPC, associate professor of neurology at Western University in London, Ontario. “It was to examine the one-month and six-month outcomes to see if visual recovery is similar when oral treatment was given at the higher dose bioequivalent to the IV dose.”

The primary endpoint in the study was recovery of the visual evoked potential (VEP) P100 component latency in the affected eye six months after corticosteroid treatment.

The study found that eyesight improved using both treatments and that there was no significant difference between the IV and the oral steroids.

By the six-month period, the IV group's median eyesight had improved to 20/20 and the oral steroid group improved to 20/32. Dr. Morrow explained that the oral steroid's baseline had been worse at the start — 20/100 versus 20/160, with 10 participants in the oral group with counting fingers only versus five in the IV group — and the primary outcome was change from baseline.

Optic neuritis involves an inflammation of the optic nerve, often appearing suddenly, with a painful eye and blurred vision, she explained. In some patients, the lesion can be seen on a magnetic resonance imaging (MRI) scan.

Optic neuritis can be the first sign of symptoms of multiple sclerosis (MS), the study authors noted, adding that half of all people with first-time optic neuritis will eventually develop MS.

The landmark 1992 ONTT study involved 457 patients, none of whom had been diagnosed with MS or had optic neuritis before.

The Canadian study included 45 patients, 13 of whom had a previous diagnosis of MS, and several already had optic neuritis in one eye; although if the subject had optic neuritis in the same eye previously, he or she was excluded. This limited the ability to study both recurrence and MS diagnosis, said Dr. Morrow, who noted that this was not the aim of the study.

EXPERT COMMENTARY

But several neurologists who were not involved in the research said the study did not address the reason why most doctors choose IV steroids: that there is less optic neuritis reoccurrence and that IV treatment can delay the onset of multiple sclerosis by years.

They noted the small number of patients in the Canadian study, as well as the fact that some already had MS and previous episodes of optic neuritis.

Although vision improved in both groups by the six-month mark, they pointed out that in patients given no steroid treatment, visual acuity typically improves to the same levels in six months on its own.

Steven L. Galetta, MD, FAAN, professor and chair of neurology at NYU Langone Medical Center, said the ONTT found that patients who received oral steroids had higher recurrences of optic neuritis when compared to IV steroids in a multiyear study. Furthermore, the final visual outcome at one year was no different in patients receiving the IV steroids, oral prednisone, or placebo in the ONTT.

He also pointed out that studies show that treating first-time optic neuritis patients with a combination of intravenous steroids followed by an oral corticosteroid taper lowered their risk of developing MS within the next two years.

Because this study looked at neither of these major reasons for giving IV steroids, he found the results to be of questionable significance.

“This is a very complicated topic and it's even confusing for neurologists,” said Dr. Galetta. “I'm afraid this study may add to the confusion. There are many limitations to this study. It's small in size, short in duration, and it has a variable population of patients with optic neuritis, so it is not a pure cohort.”

“The results are limited — even with comparable oral and IV doses of steroids — because the short-term delay of developing MS and recurrence of optic neuritis are not studied here,” he continued.

Finally, he said, VEP latencies were the primary endpoint in this study and unfortunately these values may not correlate well with visual outcomes or quality of life measures.

Roy W. Beck, MD, PhD, was the lead researcher of the original Optic Neuritis Treatment Trial. Now executive director of the Jaeb Center for Health Research in Florida, Dr. Beck said the authors are to be commended for addressing a clinically relevant issue. Moreover, he said, the authors' premise that oral corticosteroids of equivalent dose are as effective as IV steroids for acute optic neuritis may be correct.

Dr. Beck agreed, however, that the study was too small to draw any meaningful conclusion. “I think the idea of comparing high-dose oral steroids or IV is worth considering, but I don't think this paper helps one way or another,” he said.

Dr. Beck had concerns about drawing conclusions with respect to visual acuity and contrast sensitivity. He also noted that the p value was not strong enough to draw conclusions, and he said it would have been useful to present at least the interquartile range and the data on change from baseline to better understand the visual acuity distributions.

Asked to respond to the criticism, Dr. Morrow, the lead author, noted that 50 percent of Canadian doctors give oral steroids for MS relapses, and that patients usually prefer oral steroid treatment to IV. The goal of the study was not to look at first-time patients, she said, or to do a long-term observation, or to examine if steroids change the long-term outcome of optic neuritis. Rather, it was to examine if bioequivalent doses of high-dose oral steroids are a viable alternative to IV steroids. Oral steroids are less costly and more convenient for patients, she added.

Dr. Morrow said VEP and contrast sensitivity at one and six months is a more objective measure of eyesight improvement. Further, previous studies have demonstrated that VEP is a good surrogate for optic nerve function, and contrast sensitivity, combined with visual acuity, is considered the gold standard in these types of studies.

“I was worried about the side effects, because in the group taking the oral steroid, they have to take 25 tablets a day,” she said. “But we did not see any difference in the rate of side effects or the type.”

Not all doctors were critical of the study, however. Benjamin J. Osborne, MD, associate professor of neurology and ophthalmology at MedStar Georgetown University

Hospital in Washington DC, said he sees cases of optic neuritis frequently, and if it is a patient's first attack, they will get an MRI of the optic nerve and typically treat with IV steroids if there is moderate to severe vision loss. But with mild vision loss, the vision usually comes back on its own within a week or two.

Dr. Osborne said that he agreed with Dr. Galetta that the trial did not address the recurrence rates of optic neuritis or the risk of MS. But he said he was impressed that one clinic had enrolled 45 patients.

He said the study was “intriguing,” and giving oral steroids would be cheaper and easier for patients, as well as more time efficient.

“This confirmed what I was suspecting in terms of vision improvement,” he said. “I would offer it to patients as an option, because usually when giving steroids, speed is optimal, and they could probably get the oral steroids at the pharmacy on the way home and start taking them immediately. Depending on where you are, getting into an infusion center isn't always easy.”

The neurologists interviewed said they wish the study had answered this question: Would oral steroids, given at the same dose as the IV treatment, have the same impact on optic neuritis recurrences and also delay MS onset for patients just presenting with the disease? But they agreed that would need a longer-term, multicenter study, which would be difficult to arrange.

TREATMENT RECOMMENDATIONS

Kenneth S. Shindler, MD, PhD, associate professor of ophthalmology and neurology at the University of Pennsylvania Perelman School of Medicine and the Scheie Eye Institute, said: “There's no known treatment to improve the visual outcome — steroids can speed it up and get there a little faster, but ultimately, and importantly, after six months, no one treatment makes a big difference.

“The more important thing is — if they don't have a history of MS, then they need to get an MRI scan because if they have a lesion in their brain showing they've had inflammation before, they are at high risk for developing MS, and that's when IV treatment is important because studies show it can delay developing MS symptoms.”

Dr. Galetta, of NYU, said the discovery of new antibodies such as neuromyelitis optica antibodies allows for further refinement of the diagnosis of demyelinating optic neuritis. New markers have allowed doctors to determine that some patients have a far worse prognosis regarding recovery than the routine form of optic neuritis. Using these markers might lead to a stronger clinical trial, focusing on a particular kind of optic neuritis and, like the ONTT, follow their prognosis long-term.

But for now, he said, the standard of care should be IV steroids, particularly for those presenting for the first time with optic neuritis symptoms.

“No one uses IV steroids thinking they are going to improve the final visual outcome,” he said. “That's not the reason we use IV steroids, and I worry that this will be very confusing because patients will prefer oral steroids because it's cheaper and easier and not understand the potential risks.”

LINK UP FOR MORE INFORMATION:

• Morrow SA, Fraser JA, Day C, et al. Effect of treating acute optic neuritis with bioequivalent oral vs intravenous corticosteroids: A randomized clinical trial https://jamanetwork.com/journals/jamaneurology/article-abstract/2673723?redirect=true. JAMA Neurol 2018; Epub 2018 Mar 5.