Erythropoietin for Optic Neuritis: Improvements in Structure, but Will Function Follow?
Erythropoietin for Optic Neuritis: Improvements in Structure, but Will Function Follow?
Abstract & Commentary
By Marc Dinkin, MD, Assistant Professor of Ophthalmology, Weill Cornell Medical College. Dr. Dinkin reports no financial relationships relevant to this field of study.
Synopsis: Intravenous erythropoietin therapy appears to reduce retina nerve fiber layer thinning 16 weeks after onset of optic neuritis, but larger studies needed to detect differences in visual outcome.
Source: Sühs KW, et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol 2012;72:199-210.
The prognosis for visual recovery in patients with a first episode of optic neuritis is good, with > 95% of patients recovering to better than 20/40 visual acuity at 1 year, with or without treatment with IV methylprednisolone. Yet, the remaining 5% of patients may be left with severe visual loss, and many of those with excellent recovery to 20/20 still complain of disturbing changes in their vision such as trouble with low contrast or peripheral field defects. Furthermore, with repeated attacks of optic neuritis, incremental small, but permanent, changes in vision ultimately can result in significant impairment. It is therefore imperative that new therapies are identified that will protect the optic nerves and improve visual outcome in these patients. Unfortunately, although the optic neuritis treatment trial (ONTT) demonstrated a faster speed of recovery in optic neuritis patients who receive IV methylprednisolone, visual acuity, color vision, and visual fields were not significantly altered by the medication. Perhaps with this in mind, Sühs et al report on a prospective, double-blind, placebo-controlled trial evaluating the effects of a putative neuro-protective agent, erythropoietin, on patients with optic neuritis, not yet diagnosed with multiple sclerosis (MS). In addition to stimulating red blood cell formation, erythropoietin has been shown to have some neuroprotective properties in animal models of MS and optic neuritis and, importantly, can cross the blood-brain barrier when given systemically.
In this study, the authors gave standard methylprednisolone plus 33,000 units of IV recombinant human erythropoietin to 21 patients in the experimental arm, while the 19 control patients received methylprednisolone plus placebo. The primary outcome measure was the degree of thinning of the retinal nerve fiber layer (RNFL) at 16 weeks, as measured by optical coherence tomography (OCT), reflecting the growing recognition that the axonal loss reflected in thinning of this unmyelinated layer is associated with permanent changes in visual function in all manners of optic nerve injury. Changes in optic nerve diameter measured by MRI, delay of P100 on visual evoked potential (VEP), and visual acuity and fields were secondary outcome measures.
The authors found that RNFL thicknesses, which normally average around 100 µm, decreased by a median of 7 µm (to 3.5 µm less than the unaffected eye) in the erythropoietin group vs 17 µm (7 µm less than the unaffected eye) in the placebo group. MRI showed a drop of 0.1 mm in optic nerve diameter in the placebo group, and none in the treated group. VEP latencies were shorter in the treated group (median of 113.15 ms) than the placebo group (132.73 ms). There was no difference in visual acuity or automated fields.
Commentary
In the nearly 20 years since the ONTT, this study represents the first prospective, double-blinded, placebo-controlled trial of a neuroprotective agent as a treatment for optic neuritis. The results are exciting, as they appear to indicate a significant reduction in the degree of RNFL thinning in those who received erythropoietin. The limitation of the treatment is of course that there was no significant effect on either visual acuity or fields, and some therefore might question the drug's value for this condition at all. However, as it has been shown that acuity drops begin to be irreversible when a certain threshold of RNFL thinning (< 75 µm) occurs, it stands to reason that the patients who received erythropoietin, were, on average, left with that much more cushion against significant vision loss, should another episode of optic neuritis ensue in the future. Furthermore, it is conceivable that these patients' color vision and low contrast visual acuity (LCVA), which have been shown to correlate well with RNFL thickness, may have been better preserved in the erythropoietin patients. For this reason, it is disappointing that the authors did not test these parameters as part of this study.
The positive results of this study must be tempered by the recognition that the mean baseline VEP latency was longer in the placebo group (153.54 ms vs 139.88 ms), suggesting that optic neuritis was, on average, more severe among those who did not receive erythropoietin. Prior studies have shown that more severe cases of optic neuritis have a worse prognosis for full recovery, so this may have confounded the results. Furthermore, their observation that MRI-determined reduction in optic nerve diameter was less in the erythropoietin group may have simply reflected the fact that the degree of initial optic nerve thickening was higher (by approximately 150%) in the placebo group. Finally, as the authors point out, one of the patients in the placebo group demonstrated a very high degree of initial RNFL thickening (> 100 µm more than the fellow eye). The subsequent reduction in that initial edema, while counted as RNFL "thinning," in fact mostly reflects a resolution of thickening. When the authors removed that patient, the remaining P-value was barely significant.
Despite these limitations, this study presents a strong argument for further testing of erythropoietin as a therapy for optic neuritis and offers hope that it may pan out as the first treatment to significantly affect the outcome in this disease. With larger sample sizes, they may more convincingly demonstrate sparing of the RNFL, and most importantly, a reduction of ensuing vision loss in these patients.
Intravenous erythropoietin therapy appears to reduce retina nerve fiber layer thinning 16 weeks after onset of optic neuritis, but larger studies needed to detect differences in visual outcome.
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