Raftopoulos, RE; (2016) A phase II, double blind, randomised, placebo-controlled trial of neuroprotection with phenytoin in acute optic neuritis. Doctoral thesis , UCL (University College London).

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Abstract

Acute optic neuritis is a common and often presenting feature of multiple sclerosis, and attacks can lead to persistent visual impairment through neurodegeneration in the retina and optic nerve. The acute inflammatory lesion in the optic nerve resembles the demyelinating plaques elsewhere in the CNS. As with other MS relapses, corticosteroids have no or little impact on the extent to which vision recovers nor do they prevent optic nerve atrophy on MRI or improve VEP latency after an attack of optic neuritis. There is currently no treatment for the acute phase of the disease to improve long-term visual outcome, and in this context neuroprotection remains a major unmet need. Progress in the development of potential neuroprotective therapies in optic neuritis and MS relies upon the identification of key mechanisms and treatment targets. Among possible mechanisms of neurodegeneration, there is growing evidence of a cascade of accumulation of sodium ions in demyelinated axons that arises from neuronal energy failure leading to the reverse operation of the Na+ /Ca2+ exchanger and subsequent toxic accumulation of injurious calcium ions. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models of inflammatory demyelination. The anterior visual system has many advantages for testing neuroprotective treatments in MS. In particular, the retinal nerve fibre layer is a relatively pure compartment of unmyelinated axons whose thickness can be measured sensitively and non-invasively using optical coherence tomography making it an attractive biomarker of axonal loss. In this thesis I investigated whether early and sustained sodium channel inhibition with phenytoin is neuroprotective in acute optic neuritis. 86 people were randomized within 2 weeks of optic neuritis symptom onset to receive phenytoin or placebo for 3 months. Retinal nerve fibre layer (RNFL) thickness and macular volume (MV) were measured at baseline, then 6 months later, using optical coherence tomography. Visual function, optic nerve MRI, and visual evoked potentials were also measured. The primary outcome was mean RNFL thickness in the affected eye at 6 months, adjusted for fellow eye RNFL thickness at baseline. In the intention to treat comparison, average affected eye RNFL thickness at 6 months was 7.15 µm greater in the active group (n=39) vs. placebo (n=42), a 30% protective treatment effect (p=0.021). Adjusted MV was 0.20 mm3 greater in the active group, a 34% treatment effect (p=0.005). There was also a near significant treatment effect on optic nerve crosssectional area (p=0.06). Per protocol comparisons showed similar treatment effects. Treatment did not affect visual outcome. These findings support the concept of neuroprotection with phenytoin in acute optic neuritis. Inhibition of voltage-gated sodium channels could also be neuroprotective in other relapses of multiple sclerosis, and further investigation of its effect is warranted in this major area of unmet therapeutic need.

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