Trans-synaptic degeneration in the optic pathway. A study in clinically isolated syndrome and early relapsing-remitting multiple sclerosis with or without optic neuritis

Abstract

ObjectiveIncreasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset.Methods50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0±3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich’s Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi’s sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+).ResultsNo difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01).ConclusionsOur findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL.

MS optic neuritis-induced long-term structural changes within the visual pathway

“…18 In conclusion, the diffusion alterations identified within the OR of HON patients' lesions within the postchiasmatic visual pathway further strengthen the concept of anterograde transsynaptic degeneration in inflammatory autoimmunity involving the visual pathway. 45 In addition to previous results documenting trans-synaptic degeneration within 1 year after an ON, 8,11 we have shown that a single clinical ON episode can also induce long-term (mean [SD] duration after ON was 8.3 [3.7]) WM alterations, which have also been related to neuronal damage in longstanding disease course. 39 Retinal damage has also been shown in large cohorts comparing NON eyes with healthy controls but was less severe compared with HON eyes.…”

“…5 Combining structural and quantitative MRI with optical coherence tomography (OCT), which allows rapid in vivo quantification of both neuronal (ganglion cell layer [GCL]) and axonal (retinal nerve fiber layer [RNFL]) retinal tissues, nearly the entire visual pathway can be probed both in the presence and in the absence of an acute inflammatory event that manifests clinically as optic neuritis (ON). As a consequence, the visual pathway could represent an ideal model to assess trans-synaptic degeneration in MS [6][7][8] as a model system for different functional CNS loops.…”

“…To date, combined OCT and MRI studies in MS have not considered the timespan after the clinical episode of ON 9,10 or have focused on short-term structural changes within the WM, such as the optic radiation (OR) 8,11 or global GM, 12 as well as cortical abnormalities. 13 In addition, the sensitivity and reliability of volumetric measures of deep GM were lower when MRIs had been acquired on 1.5 T scanners 14 and OR results depended critically on the fiber tracking techniques applied.…”

Optical coherence tomography in multiple sclerosis

“…Others have proposed that it could be caused by primary degeneration of the GCIPL neurons due to MS. Lastly, many have suggested that lesions in the optic radiation via trans-synaptic degeneration could lead to loss of retinal ganglion cells and their axons. Indeed, Puthenparampil et al [5] found an inverse correlation between the thickness of the temporal RNFL and the ipsilateral optic radiation white matter lesion load (r = −0.7, p < 0.05) in patients with MSON. Furthermore, they observed an inverse correlation between the nasal RNFL and the contralateral optic radiation white matter lesion load (r = −0.8, p < 0.01 for both the superior and inferior nasal quadrant).…”

Optic Chiasm Morphometric Changes in Multiple Sclerosis: Feasibility of a Simplified Brain Magnetic Resonance Imaging Measure of White Matter Atrophy

“…They speculated that this might have arisen from retrograde degeneration owing to optic neuritis, but the concurrent presence of specific atrophy in numerous other WM structures throughout the brain seemed to suggest that OC atrophy may have been part of a generalized atrophic process. On the other hand, there is evidence that in patients with optic neuritis, the ON inflammation cooperates with optic radiation WM lesion load to determine a more diffuse damage specifically in the optic pathway, owing to trans‐synaptic degeneration that links inflammation and neurodegeneration in these patients (Puthenparampil et al, ). Another potential confounding issue that we did not consider in selecting our MS patients was the possibility that atrophy of the OC could have occurred owing to direct OC inflammation, similar to optic neuritis.…”