The afferent visual pathway is commonly affected in MS. Assessment of the afferent visual pathway using clinical, imaging and electrophysiological methods not only provides insights into the pathophysiology of MS, but also provides a method of investigating potential therapeutic measures in MS. This review summarises the various assessment methods, in particular imaging techniques of the visual pathway. Retinal nerve fibre layer (RNFL) thickness is usually reduced following an episode of optic neuritis. Techniques such as optical coherence tomography, scanning laser polarimetry, and confocal scanning laser ophthalmoscopy are used to quantify RNFL thickness. MRI of the optic nerve is not routinely used in the diagnosis of MS or optic neuritis, but is valuable in atypical cases and in research. T2- weighted images of the optic nerve usually show the hyperintense lesion in optic neuritis and gadolinium enhancement is seen in the acute attack. Quantifying atrophy of the optic nerve using MRI gives an indication of the degree of axonal loss. Magnetization transfer ratio (MTR) of the optic nerve provides an indication of myelination. Diffusion tensor imaging (DTI) of the optic nerve and optic radiation provide information about the integrity of the visual white matter tracts. Functional MRI following visual stimulation is used to assess the contribution of cortical reorganisation to functional recovery following optic neuritis. Investigations including logMAR visual acuity, Sloan contrast acuity, Farnsworth- Munsell 100-hue colour vision tests and Humphrey perimetry provide detailed quantitative information on different aspects of visual function. Visual evoked potentials identify conduction block or delay reflecting demyelination. These collective investigative methods have advanced knowledge of pathophysiological mechanisms in MS and optic neuritis. Relevant ongoing studies and future directions are discussed.

Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data.

In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: (i) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; (ii) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and (iii) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and eight healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: (i) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); (ii) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); (iii) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and (iv) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings ...

Early neuroplasticity in higher visual areas appears to be an important determinant of recovery from ON, independent of tissue damage in the anterior or posterior visual pathway, including neuroaxonal loss (as measured by MRI, VEP, and OCT) and demyelination (as measured by VEP).