The Effect of Erythropoietin on Visual Outcomes in Optic Neuritis

Optic Neuritis
Optic Neuritis
In a phase 3 trial, researchers assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome.

After optic neuritis, erythropoietin, a human cytokine, as an adjunct to corticosteroids did not have a neuroprotective effect on the visual pathways. These findings, from a randomized, placebo-controlled, double-blind, phase 3 trial, were published in Lancet Neurology.

Erythropoietin has been observed to have a neuroprotective effect in animal models. However, there have been ambiguous results of whether these findings translate to humans in phase 2 trials of patients with optic neuritis. The phase 3 TONE trial ( Identifier: NCT01962571) is the first sufficiently powered trial to assess the effects of erythropoietin in optic neuritis and the largest in regard to optic neuritis neuroprotection, according to the researchers.

To assess erythropoietin in the optic neuritis setting, patients (N=103) with unilateral optic neuritis were recruited within 10 days of symptom onset at 12 university-affiliated medical centers in Germany between 2014 and 2017. All patients received 1000 mg intravenous methylprednisolone and in addition were randomized to receive 33,000 IU intravenous human recombinant erythropoietin (n=52) or placebo (n=51) for three days. Up to 24 months, patients were evaluated by the Expanded Disability Status Scale (EDSS), a physical exam, magnetic resonance imaging (MRI), and spectral domain optic coherence tomography (OCT).

The treatment and control cohorts were aged median 30 (interquartile range [IQR], 25-36) and 30 (IQR, 26-37) years, 73% and 65% were women, EDSS scores were 3.0 (IQR, 2.0-3.0) and 3.0 (IQR, 2.5-3.0), 19% and 25% had disc swelling, 77% and 86% painful eye movement, and 13% and 22% had newly diagnosed multiple sclerosis, respectively.

At baseline, the peripapillary retinal nerve fiber layer (pRNFL) was 4.3 mm thicker among individuals in the placebo group and high contrast visual acuity in the affected eye was median 43.5 (IQR, 15.5-64.5) among the erythropoietin recipients and 45.0 (IQR, 11.0-64.0) among control individuals.

After treatment, there was no effect on pRNFL atrophy (adjusted mean difference [aMD], 1.02; 95% CI, -5.51 to 7.55) or low contrast letter acuity (aMD, -4.03; 95% CI, -13.06 to 5.01).

No significant effect on secondary outcomes of pRNFL thickness at any sector, total macular volume, ganglion cell layer volume, ganglion cell/inner plexiform layer volume, high contrast visual acuity, contrast sensitivity, perimetric mean defect, visually evoked potential peak time or amplitude, National Eye Institute Visual Function Questionnaire, multiple sclerosis-free rate, or EDSS were observed.

Adverse events occurred among 81% of both groups. An adverse event possibly related to the study drug occurred among 17% of erythropoietin and 15% of patients who received a placebo. The most common system organ class for a serious event was injury, poisoning, and procedural complication (n=5).

This study may have been limited by the unknown rate of asymptomatic disease prior to recruitment.

These data did not support the use of erythropoietin for the treatment of optic neuritis.

“We obtained clear results indicating that erythropoietin confers neither structural nor functional benefits in the visual system,” stated the researchers. They added, “However, our findings might imply efficacy on other subclinical lesions, because erythropoietin recipients converted less frequently from clinically isolated syndrome to multiple sclerosis.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Lagrèze WA, Küchlin S, Ihorst G, et al. Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study. Lancet Neurol. Published online December 1, 2021. doi:10.1016/S1474-4422(21)00322-7