Neuroprotection powers for phenytoin in acute optic neuritis

By Lucy Piper, Senior medwireNews Reporter

Selective sodium channel blockade with the anti-epileptic drug phenytoin protects against acute demyelinating optic neuritis, researchers report.

Their phase II study findings showed that treatment with phenytoin at 4 or 6 mg/kg per day for 3 months reduced the extent of retinal nerve fibre layer (RNFL) loss by a significant 30% compared with placebo, with a 7.15 µm difference at 6 months after accounting for RNFL thickness in the unaffected eye at baseline.

Macular volume loss was also significantly reduced by 34%, with a 6-month adjusted difference between phenytoin and placebo of 0.20 mm3. Phenytoin was associated with less optic nerve area loss, but not significantly so.

“These results are consistent with the suggestion that phenytoin protects the ganglion cells (which make up about 34% of macular volume) and their axons in the RNFL and the optic nerve via partial inhibition of the voltage-gated sodium channels in an episode of inflammatory demyelination”, say researcher Raju Kapoor (National Hospital for Neurology and Neurosurgery, London, UK) and team.

They randomly assigned 86 patients within 14 days of onset of visual loss to receive phenytoin or placebo; five were lost to follow-up leaving 39 in the phenytoin group and 42 in the placebo group.

Due to expected swelling of the RNFL in the affected eye at baseline, the team compared RNFL thickness loss in the affected eye at 6 months with that of the unaffected eye at baseline.

This showed an average decrease of 16.69 µm among patients taking phenytoin, compared with 23.79 µm among those taking placebo. Significant reductions in RNFL thickness at 6 months were also seen in 10 patients who were withdrawn early from phenytoin due to a skin rash.

The corresponding decreases in macular volume were 0.39 mm3 for the phenytoin group versus 0.59 mm3 for the placebo group.

There was no effect on low-contrast visual acuity or visual evoked potentials, however.

Phenytoin treatment was generally well tolerated among the patients who continued treatment for 3 months, with no acute deterioration of vision or evidence of blood count or liver dysfunction. There was also no rebound deterioration when the drug was stopped.

Reporting in TheLancet Neurology, the researchers point out that using the RNFL in the unaffected fellow eye at baseline for comparison, “is prone to error”, and they would recommend using optical coherence tomography (OCT) segmentation methods to avoid this issue in future trials.

This recommendation was upheld by Shiv Saidha and Peter Calabresi, from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, who say in a related comment that regular OCT measures between baseline and 6 months would have excluded a possible anti-inflammatory effect by monitoring for resolution of initial RFNL swelling and optic nerve inflammation.

The commentators also suggest that measuring ganglion cell plus inner plexiform layer thickness as an estimate of ganglion neuronal integrity may be a better alternative to RNFL thickness because it does not swell during acute optic neuritis.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent OCT sampling, as well as more detailed OCT-segmentation derived retinal measures”, they conclude.

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