Illustrations of the Afferent Visual Pathway and Concepts Surrounding Trans-Synaptic Neuroaxonal Degeneration in the Visual Pathway in Multiple Sclerosis

Image 1 title: Functionally-eloquent organization of the afferent visual pathway; Image 1 description: The afferent visual pathway is a sensory pathway comprised of 3 neurons. The 1st order neurons are the shortest neurons in the pathway and are entirely unmyelinated. The cell bodies of the 1st order neurons lie in the retinal inner nuclear layer (INL), with the axons travelling to the retinal ganglion cell layer (GCL) where they synapse with the cell bodies of the 2nd order neurons. The INL and GCL are highlighted here on a spectral domain optical coherence tomography image of a healthy retina (Spectralis HD-OCT, Heidelberg, Germany). The axons of the 2nd order neuron pass through the peripapillary retinal nerve fiber layer and coalesce to make up the optic nerve, becoming myelinated after they pass through lamina cribrosa. Axons from the nasal half of the retina are organized within the optic nerve and cross over to the contralateral cerebral hemisphere at the optic chiasm, while axons from the temporal half of the retina remain uncrossed and continue their path within the ipsilateral cerebral hemisphere. After traversing the optic tracts, the axons of the 2nd order neurons synapse with the cell bodies of the 3rd order neurons in the lateral geniculate nucleus of the thalamus, with each thalamus receiving signals from the right and left eye, due to the crossed and uncrossed nature of the pathway. The axons of the 3rd order neurons then travel within the optic radiations to reach the primary visual cortex of the occipital lobe.; ; Image 2 title: Neuroaxonal degeneration in the afferent visual pathway following axonal injury; Image 2 description: This figure illustrates the potential patterns of neuroaxonal degeneration that may occur after injury to an axon in the afferent visual pathway (e.g. with optic neuritis), or in other synaptically-connected pathways. Following axonal injury, the affected neuron may degenerate in both an anterograde (‘dying forward') or retrograde (‘dying back') direction. Following degeneration of the injured neuron, neurodegeneration may proceed trans-synaptically to the other neurons in the chain, again in an anterograde or retrograde direction, resulting in loss of distant uninjured but synaptically-connected neurons.; ; Image 3 title: Patterns of trans-synaptic degeneration in the afferent visual pathway in multiple sclerosis; Image 3 description: The afferent visual pathway is a functionally eloquent sensory pathway made up of 3 neurons, travelling from the retina to the primary visual cortex of the occipital lobe. The axons of the 2nd order neurons (travelling from the retinal ganglion cell layer through the optic nerve and optic tracts to the thalami) are highly-organized, with the axons from the nasal half of the retina crossing over to the contralateral cerebral hemisphere within the optic chiasm, while the axons from the temporal half of the retina remain uncrossed and continue their path within the ipsilateral cerebral hemisphere. The crossed and uncrossed nature of the pathway means that each thalamus and visual cortex receives inputs from the right and left eye in a homonymous pattern. In optic neuritis, injury to the axons of the 2nd order neurons (prior to the optic chiasm) can result in anterograde degeneration of affected axons, a process which may then proceed trans-synaptically, resulting in degeneration of the 3rd order neurons travelling from both thalami to both primary visual cortices. Neuroaxonal degeneration after optic neuritis may also proceed in the retrograde direction, resulting in loss of cell bodies in the ipsilateral retinal ganglion cell layer (GCL), and potentially trans-synaptically to the 1st order neurons contained in the ipsilateral retinal inner nuclear layer (INL). On the other hand, if a demyelinating lesion causes axonal injury to the 3rd order neurons (e.g. within the optic radiations), anterograde neuroaxonal degeneration may result in atrophy of the ipsilateral visual cortex, while retrograde degeneration may proceed to the ipsilateral thalamus, and potentially trans-synaptically to the highly-organized crossed and uncrossed 2nd order neurons, resulting in a homonymous pattern of atrophy of the retinal ganglion cell layer (and possibly even trans-synaptically again to the 1st order neurons within the retinal inner nuclear layer).