“The adjusted mean difference in 6-month RNFL in the affected eye was 7.15 μm (95% CI 1.08 to 13.22; P=0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo,” the authors wrote. Additionally, the extent of macular volume loss was reduced by 34% in the treatment group vs placebo. Phenytoin was generally well-tolerated: 12% of patients in that group had a serious adverse event, though only one (severe rash) was attributable to the medication.
“Our study provides proof of concept for neuroprotection in a typical relapse of MS,” Dr Kapoor said. “Phenytoin is thought to be neuroprotective through inhibition of voltage-gated sodium channels, which are crucial for both injurious axonal sodium/calcium overloading and for microglial activation in the acute inflammatory demyelinating lesion of optic neuritis.” Though no statistically significant improvement in vision was observed, the researchers were not surprised, as the trial was intended to test whether phenytoin could prevent retinal damage. “We were trying to prove the concept of neuroprotection with a surrogate marker,” so the trial was not powered to demonstrate a significant improvement in vision, he said.
Larger studies will be needed to confirm the findings in optic neuritis and relapsing MS, Dr Kapoor said. Such studies should include “more sophisticated, reliable, and reproducible OCT–as well as MRI–outcome measures including estimates of ganglion cell layer thickness, such as from the composite thickness of the ganglion cell and inner plexiform layers,” Shiv Saidha, MD, assistant professor of neurology at Johns Hopkins University School of Medicine, and co-author of an editorial on the topic, told Neurology Advisor.7
These “have been shown to not swell during the acute phase of optic neuritis thereby allowing net, accurate, determination of true neurodegeneration subsequent to the optic neuritis event,” he said. Dr Saidha and his co-author, Peter A. Calabresi, MD, Professor of Neurology at the Johns Hopkins School of Medicine and Director of the Johns Hopkins Multiple Sclerosis (MS) Center, also noted that the lack of regular outcome assessments earlier in treatment makes interpretation of the findings difficult. Dr Kapoor added that future trials should also consider whether treatment should be administered earlier in relapse, since significant nerve damage could already have occurred by the time the patients began treatment in the present study.
Though the results are encouraging overall, given the limitations of such preliminary findings, they should not be over-interpreted “as being definitive proof or substantive evidence to provide a basis for pursuing the employment of this therapy in widespread practice at this point,” Dr Saidha advised.
- Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016; 15(3): 259-69.
- Al-Izki S, Pryce G, Hankey DJ, et al. Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 2014; 137(Pt 1):92-108.
- Lo AC, Saab CY, Black JA, Waxman SG. Phenytoin protects spinal cord axons and preserves axonal conduction neurological function in a model of neuroinfl ammation in vivo. J Neurophysiol. 2003; 90: 3566–71.
- Garthwaite G, Goodwin DA, Batchelor AM, Leeming K,Garthwaite J. Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience. 2002; 109(1):145-55.
- Hickman SJ, Toosy AT, Miszkiel KA, et al. Visual recovery following acute optic neuritis: a clinical, electrophysiological and magnetic resonance imaging study. J Neurol. 2004; 251(8):996-1005.
- Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010; 9(7):681-8.
- Saidha S, Calabresi PA. Phenytoin in acute optic neuritis: neuroprotective or not? Lancet Neurol. 2016; 15(3): 233-35