A phase II randomised controlled trial of amiloride as a neuroprotective treatment in optic neuritis : studying in vivo neurodegeneration, neuroprotection and cortical plasticity after an inflammatory insult to the visual system

• Main Author: McKee, Justin
• Format: Dissertation
• Language: English
• Published: University of Oxford 2017
• Subjects: Amiloride; Diffusion Tensor imaging; Multiple sclerosis; Neurodegeneration; Neuroplasticity; Optic Neuritis; Optical coherence tomography; Resting state

Basic science and early clinical trial evidence suggest the safe diuretic drug amiloride, may exert a neuroprotective effect in multiple sclerosis (MS) through blockade of the acid sensing ion channel. Neuroprotective treatments are a key unmet need in multiple sclerosis. Optic neuritis (ON) is a discrete CNS inflammatory event leading to neuro-axonal injury in the optic nerve and retina. The optic nerve is part of the visual system, one of the most functionally and structurally eloquent systems in the central nervous system, which affords a number of unique modalities to assess neurodegeneration and neuroprotection. The visual system can be classified into two parts, the anterior and posterior visual systems, which are defined by the lateral geniculate nucleus, where the two components synapse. The extent of neurodegeneration following ON in the anterior visual system can be imaged in vivo through scanning laser polarimetry (GDx) and optical coherence tomography (OCT). The posterior visual system can be imaged by quantitative and functional magnetic resonance imaging (MRI) of the brain, giving insights into white matter structural integrity and cortical plasticity over time. Combining these modalities in a longitudinal study, allows assessment of the impact of neurodegeneration in the anterior visual system on neurodegeneration downstream in the posterior visual system and on changes in functional connectivity over time in the visual cortex. Furthermore, in the clinical trial setting the neuroprotective effect of any intervention both on direct anterior neurodegeneration and downstream processes can be assessed. The functional relevance of changes in all of these biomarkers can be tested through a number of visual measures, including low contrast visual acuity. In MS, the contribution of transsynaptic neurodegeneration to the global neuronal loss experienced by patients is an area of incomplete understanding. In addition, the role of the visual cortex, through neuroplasticity, in aiding visual recovery from optic neuritis, is unclear. To address these issues, this thesis reports the results of the first clinical trial of amiloride in ON, and shows that despite the pre- and early clinical evidence of neuroprotection of amiloride, no neuroprotective benefit was found. It goes on to explore reasons for this lack of effect including the finding of early retinal neurodegeneration in ON, and the need for early recruitment windows in the future. From there, it makes a detailed assessment of the longitudinal changes in retinal OCT for 12 months following ON, including a novel finding of the temporal evolution of inner nuclear layer swelling, previously reported only cross-sectionally. Next, for the first time macular retinal neurodegeneration is shown to influence diffusion tensor MRI derived measures of white matter integrity in the optic radiations, indicating transsynaptic neurodegeneration. Finally, longitudinal changes in resting state functional connectivity following ON are found in the visual system for the first time. The interaction between this cortical functional, retinal neurodegeneration and visual recovery is probed.