The antiepileptic drug phenytoin protected retinal nerve cells from degeneration in a new study in patients with optic neuritis, a validated model of multiple sclerosis.
The authors say this is proof of concept that phenytoin and other drugs acting as sodium channel blockers are neuroprotective in MS.
"While there have been other studies of neuroprotectant agents in MS, our results are the most convincing demonstration of neuroprotection for MS to date," lead author Raju Kapoor, MD, from the National Hospital for Neurology and Neurosurgery, London, United Kingdom, told Medscape Medical News. "We've been looking for something like this for a long time. This is a big step forward."
Full results will be presented this week at the American Academy of Neurology (AAN) 67th Annual Meeting.
"Very Important Study"
Commenting for Medscape Medical News, Timothy L. Vollmer MD, from the University of Colorado Health Sciences Center, Denver, who was not involved in the research, agreed this was "a very important" study.
"This study provides the first evidence that neuroprotection with phenytoin may be possible in MS patients," he added. "It lays the foundation for combination studies, where phenytoin can be added to currently available disease-modifying therapies to see if we can further improve the effect of anti-inflammatory therapies on preservation of brain volume and, consequently, long-term outcomes for our MS patients."
Dr Kapoor explained that there are many therapies now available for MS that delay relapses, "but we haven't been so good at preventing disability caused by the underlying neurodegeneration."
His team has been researching ways of protecting the neurons from damage, with particular focus on the sodium channel.
"In inflamed areas, the axons of nerve cells get flooded with sodium, which causes an influx of calcium, which in turns causes cell death," he elaborated. "If we can block sodium entry into the cell, we may be able to prevent this. Optic neuritis, which is an inflammatory event and is often the first symptom of MS, gives us a window of opportunity to study active inflammation early on in the disease process."
In the current study, the researchers examined the effect of phenytoin, an established drug for epilepsy, which is known to be a partial blocker of sodium channels, on the thickness of the nerve fiber layer in the retina after an optic neuritis attack.
They found that patients taking phenytoin had less damage to these nerves and also had a larger macula volume.
For the study, 86 patients with acute optical neuritis were randomly assigned within 2 weeks of symptom onset to receive either phenytoin (4 mg/kg/day) or placebo for 3 months.
Retinal nerve fiber layer thickness and macular volume were measured at baseline and then 6 months later, using optical coherence tomography.
Prevented One Third of the Damage
Results showed that the average retinal nerve fiber layer thickness at 6 months was 7.15 μm higher in the active group than in the placebo group (P = .02), which was a 30% protective treatment effect. Adjusted macular volume was 0.20 mm3 higher in the active group (P = .005), for a 34% protective treatment effect.
"The drug appeared to prevent about one third of the damage caused by an optic neuritis attack," Dr Kapoor said.
The researchers also used magnetic resonance imaging to measure the width of the optic nerve and found near-significant (P = .06) protection with phenytoin. "There was less shrinkage in the treated group," Dr Kapoor reported.
He pointed out that previous work has been done with the glutamate receptor antagonist memantine, which showed a marginal effect. "But our study shows a robust effect on both the retina and the optic nerve, which are clear, validated treatment targets."
He believes neuroprotectant drugs such as phenytoin would be a complement to existing immunomodulating therapies and potential remyelination approaches. "If you don't have any nerve fibers, you can't remyelinate them. The ideal would be protect the nerve cells with therapies like phenytoin and repair them with a remyelination approach, using several strategies to preserve function."
Other outside commentators were also impressed with the results. Peter Calabresi, MD, from Johns Hopkins, Baltimore, Maryland, who was part of the team that first proposed use of optic neuritis and optical coherence tomography to study neuroprotection, told Medscape Medical News: "This appears to be an important finding with major significance for treating exacerbations of MS."
"What happens in the eye seems to mirror the rest of the brain, so potentially this approach could be used to treat more than just eye attacks, but any flare up of the disease," he added. "We have nothing that rescues axons after the attack in MS has started, so this could be very important if reproduced."
Paul O'Connor, MD, from St. Michael's Hospital, University of Toronto, Ontario, Canada, said the study was "extremely promising" and that he believes a phase 3 study should now go ahead.
Use at Disease Onset
Dr Vollmer suggested this study gives more evidence that neuroprotective agents are going to be most effective if used during the most inflammatory phase of MS.
"This is well documented to be at onset with a steady decrease in the rate of inflammatory disease over time," Dr Vollmer said. "Thus, if we want to maximize the effect of neuroprotective therapies, they must be used at the onset of MS."
He believes such agents will have little to no effect if used in older patients or those who have entered the progressive phase of the disease and have exhausted their neurologic reserve, which he says masks the majority of the inflammatory disease in relapsing-remitting MS.
"Patients and physicians dealing with MS must become aware of the phenomenon of neurological reserve and the implications for the treatment," he stressed.
This study was funded by the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Great Britain and Northern Ireland and was supported by a nonpromotional grant from Novartis and by the National Institute for Health Research Clinical Research Network and University College London Hospitals Biomedical Research Center.
American Academy of Neurology (AAN) 67th Annual Meeting: Abstract 9094. To be presented April 24, 2015.
Medscape Medical News © 2015 WebMD, LLC
Send comments and news tips to firstname.lastname@example.org.
Cite this: Phenytoin Neuroprotective in MS - Medscape - Apr 19, 2015.