Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

Optical Coherence Tomography and Magnetic Resonance Imaging in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder.

Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool that has been used in MS, NMOSD, and other diseases to quantify damage to the retina, including the ganglion cells and their axons. The fact that these are the only unmyelinated axons within the central nervous system (CNS) renders the afferent visual pathway an ideal model for studying axonal and neuronal degeneration in neurodegenerative diseases. Structural magnetic resonance imaging (MRI) can be used to obtain anatomical information about the CNS and to quantify evolving pathology in MS and NMOSD, both globally and in specific regions of the visual pathway including the optic nerve, optic radiations and visual cortex. Therefore, correlations between brain or optic nerve abnormalities on MRI, and retinal pathology using OCT, may shed light on how damage to one part of the CNS can affect others. In addition, these imaging techniques can help identify important differences between MS and NMOSD such as disease-specific damage to the visual pathway, trans-synaptic degeneration, or pathological changes independent of the underlying disease process. This review focuses on the current knowledge of the role of the visual pathway using OCT and MRI in patients with MS and NMOSD. Emphasis is placed on studies that employ both MRI and OCT to investigate damage to the visual system in these diseases.