EDITORIAL Robert A. Bermel, MD Pablo Villoslada, MD Correspondence to Dr. Bermel: bermelr@ccf.org Neurology ® 2014;82:2152–2153 See page 2165 Retrograde trans-synaptic degeneration in MS A missing link? There has been substantial activity in recent years studying the visual pathways in patients with multiple sclerosis (MS). One of the driving forces has been the evolution of optical coherence tomography (OCT) as a highly accessible test that allows precise quantification of retinal structures. Pertinent to neurology, OCT gives us the ability to measure the thickness of retinal layers containing neuronal cell bodies (the ganglion cell layer) and unmyelinated axons (the peripapillary retinal nerve fiber layer [RNFL]) of the first-order (anterior) sensory neurons of the visual pathway. Other features of the visual system that make it a particularly appeal- ing model are the availability of sensitive and reliable clinical outcome measures, such as low-contrast visual acuity and visual evoked potentials for detection of functional changes related to axonal loss or demyelina- tion; related to this, optic neuritis can serve as a “nat- ural experiment” that helps us understand the working of the visual system. The ultimate goal of studying a single functional system is to determine structure– function correlations, facilitating broader understand- ing of how the CNS is affected by and adapts in MS. With OCT as a tool to measure the first-order neurons (within the retina) and MRI as a tool to mea- sure the second-order neurons (within the brain), the visual pathways are proposed as an ideal model to study trans-synaptic degeneration—the degeneration of neurons that connect to the initially affected neu- rons. One could conceptualize trans-synaptic degen- eration as occurring in an anterograde (optic neuritis causing subsequent degeneration of posterior visual pathways) or retrograde (lesion in optic radiation causing ganglion cell and axon degeneration) direc- tion. Trans-synaptic degeneration carries broader interest because, although it is less easily quantified outside the visual system, it may be a key mechanism underlying progressive disability and brain atrophy in MS. A model that accurately quantifies trans-synaptic degeneration could be used to test drug efficacy in clinical trials of neuroprotection. In this issue of Neurology ® , Klistorner et al. 1 report their study examining the effect of posterior visual path- way pathology on the retina, finding an association between MRI measures of optic radiation integrity and retinal integrity measured by temporal quadrant RNFL thickness using OCT. This finding supports the occurrence of trans-synaptic degeneration in MS, in this case in a retrograde direction. The authors eval- uated the posterior pathways with 2 methods—lesion analysis and diffusion tensor imaging—with each yield- ing similar results, increasing confidence in the results and exposing both lesional and nonlesional pathology. In this cohort, with optic neuritis–affected eyes specifi- cally excluded, posterior visual pathway pathology ac- counted for as much as 35%–40% of the atrophy of the RNFL. There was also an association between posterior visual pathway integrity and low-contrast letter acuity. Although retrochiasmal lesions may not lead to per- sistent visual field defects in MS, 2 awareness of their importance has been greatly facilitated by OCT (figure). The contribution of retrochiasmal lesions to retinal degeneration and impairment of low-contrast letter acu- ity has received more attention since an elegant study by Reich et al. 3 The time course of retinal trans-synaptic neurodegeneration has recently been described follow- ing stroke 4 and for patients with MS. 5 The study re- ported here builds on this prior work, with some unique features. Specific exclusion of eyes with a history of optic neuritis aids the ability to study the effect of pos- terior visual pathway lesions selectively. Use of spectral- domain OCT allows more reliable quantitation of indi- vidual quadrants of the peripapillary RNFL than older time-domain OCT. The authors also vigilantly evalu- ated for retrochiasmatic presynaptic lesions (in the optic tract), which were very uncommon in this cohort. Whether trans-synaptic degeneration is a “missing link” between focal tissue damage early in MS and progressive disability occurring in progressive forms of the disease remains to be proven, although some avail- able evidence supports this theory. Atrophy of the thal- amus (the lateral geniculate nucleus, relay station of the visual pathway, is part of this structure) occurs early in MS and is disproportionate to atrophy of other gray matter structures. 6 Trans-synaptic degeneration is one possible mechanism for accelerated thalamic degenera- tion in MS, given that structure’s highly interconnected From the Mellen Center for Multiple Sclerosis Treatment and Research (R.A.B.), Cleveland Clinic, OH; and the Center of Neuroimmunology, Institute Biomedical Research August Pi Sunyer (IDIBAPS) (P.V.), Hospital Clinic of Barcelona, Spain. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 2152 © 2014 American Academy of Neurology