Quantifying Retrograde Trans-Synaptic Degeneration of the Visual Pathway in Multiple Sclerosis.
Sargis Manukyan1, Gabriela Zabala2, Laura Locke2, Brooke Guerrero2, Marwa Kaisey2, Afshin Khodabakhsh3, Nancy Sicotte2, Pascal Sati4, Omar Al-Louzi1
1Visual Outcomes Laboratory, 2Department of Neurology, 3Department of Ophthalmology, 4Neuroimaging Program, Cedars-Sinai Medical Center
Objective:
To develop a method for quantifying retrograde trans-synaptic degeneration (rTSD) in multiple sclerosis (MS) and investigate its association with demographic characteristics and visual function.
Background:
Neurodegeneration occurs early in MS, contributes to irreversible clinical disability, and is poorly mitigated by currently available treatments. rTSD is a phenomenon in which injury to one neuroaxonal unit propagates retrogradely, amplifying neuronal loss from MS lesions. There are no effective ways of quantifying rTSD in the visual pathway and its impact on visual function has not been elucidated.
Design/Methods:

In this cross-sectional single-center study, patients with MS (pwMS) and non-MS controls underwent clinical, standard automated perimetry and optical coherence tomography assessments. Using customized retinal layer segmentation in nasal and temporal hemimacular sectors, we developed an rTSD-index, which compares ganglion cell hemimacular projections corresponding to each cerebral hemisphere, with positive values reflecting right-hemisphere driven rTSD and vice versa, and absolute rTSD-index (ArTSD) values indicating severity.

Results:

A total of 79 pwMS and 23 non-MS controls were included (average age 45±13 and 37±14, 67% and 61% female, respectively). On average, pwMS had higher ArTSD values (mean difference 1.5, p=0.02). Evidence of rTSD was detected in 13/79 (16%) pwMS and 0/23 non-MS controls at an ArTSD threshold of 3.5. In pwMS, longer disease duration was associated with increased ArTSD severity (β=0.9 for each decade of increased disease duration, p=0.03). For each 1 point increase in ArTSD value, there was on average a 0.1 dB worsening in corresponding visual hemifield function after excluding subjects with optic neuritis history (p=0.02).

Conclusions:

rTSD-index is a novel method to quantify rTSD of the visual pathway in MS, which occurs in 1 out of 6 pwMS, is associated with longer disease duration and subclinical visual field defects. Future studies investigating its association with clinical disability, MRI findings, and methods to mitigate it are needed.

10.1212/WNL.0000000000202253