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Effects of Phenytoin on the Retinal Ganglion Cell-Inner Plexiform Layer in Acute Optic Neuritis: Analysis of a Phase
Srikirti Kodali1, Alessia Bianchi1,2, Rhian Raftopoulos3
1Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Science, University College London, United Kingdom.
Background And Objectives:
Acute demyelinating optic neuritis (AON) can lead to irreversible neuroaxonal loss. We investigated the neuroprotective effects of phenytoin on macular ganglion cell-inner plexiform layer (mGCIPL) thickness.
Methods:
We reanalyzed Spectralis optical coherence tomography scans from the phenytoin AON trial (NCT01451593), a randomized, placebo-controlled, double-blind phase 2 trial. Participants attended 2 trial centers in London or Sheffield, United Kingdom. Patients with unilateral AON, age 18-60 years, within 2 weeks of onset, with visual acuities 6/9 or worse, were randomly assigned (1:1) to oral phenytoin (4-6 mg/kg/d) or placebo for 3 months, stratified by onset time, center, previous multiple sclerosis diagnosis, disease-modifying treatment, and corticosteroid use. Macular ganglion cell-inner plexiform layer thicknesses were extracted at baseline and 6 months. Linear regression models evaluated treatment effects on 6-month affected eye mGCIPL, adjusting for 6-month full-field visual evoked potential (VEP) latency and amplitude and baseline variables including mGCIPL thicknesses, steroid use, baseline acuity, and time interval to treatment. We also compared neuroprotective effects between peripapillary retinal nerve fiber layer (pRNFL) and mGCIPL outcomes.
Results:
Eighty patients (39 phenytoin: 41 placebo) with a mean age of 33.59 years, 70% female, participated in this study. At 6 months, significant treatment effects were estimated for phenytoin vs placebo (affected eye mGCIPL thicker by 6.79 μm, p = 0.006, [SE = 2.35 µm]); estimated means for mGCIPL thickness for phenytoin vs placebo were 73.8 μm (SE = 2.40 μm) and 67.0 μm (SE = 2.2 μm), respectively. Treatment effects appeared to be greater for worse baseline acuities. At 6 months, higher mGCIPL thicknesses were associated with lower VEP latencies (p < 0.0001) and higher VEP amplitudes (p = 0.013). Neuroprotective effects on mGCIPL outcomes were more robust than for pRNFL outcomes.
Discussion:
This study supports superiority of the mGCIPL over the pRNFL as a neuroprotective marker after AON and demonstrates strong associations with myelination, providing additional mechanistic insights.
Trial Registration Information:
This trial is registered with ClinicalTrials.gov, number NCT01451593; submitted for registration on October 11, 2011; first patient enrollment was on February 2, 2012.
Classification Of Evidence:
This study provides Class II evidence that compared with placebo, phenytoin is associated with greater preservation of the mGCIPL thickness in patients with acute demyelinating optic neuropathy.
