Phenytoin May Offer Neuroprotection to Patients With Optic Neuritis

Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.

In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.

Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.

The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm³. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.

The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.

“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the pheny­toin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.

—Bianca Nogrady

Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.

In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.

Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.

The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm³. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.

The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.

“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the pheny­toin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.

—Bianca Nogrady

Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.

In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.

Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.

The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm³. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.

The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.

“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the pheny­toin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.

—Bianca Nogrady