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. 2017 Aug 29;12(8):e0183957.
doi: 10.1371/journal.pone.0183957. eCollection 2017.

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

Marco Puthenparampil  1 , Lisa Federle  1 , Davide Poggiali  1 , Silvia Miante  1 , Alessio Signori  2 , Elisabetta Pilotto  3 , Francesca Rinaldi  1 , Paola Perini  1 , Maria Pia Sormani  2 , Edoardo Midena  3 , Paolo Gallo  1
Affiliations

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

Marco Puthenparampil et al. PLoS One. .

Abstract

Objective: Increasing 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.

Methods: 50 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+).

Results: No 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).

Conclusions: Our 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.

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Conflict of interest statement

Competing Interests: Puthenparampil Marco received travel grant from Novartis, Genzyme, Biogen Idec, Teva and Sanofi Aventis; he has been consultant for Genzyme. Federle Lisa has received funding for travel from Novartis, Merck Serono, Biogen Idec, Sanofi-Aventis, Bayer Schering Pharma, Almirall, Genzyme, Teva and honoraria from Genzyme, Merk Serono, Teva and Almirall. Poggiali Davide received travel grant from Biogen Idec, Novartis, Sanofi Aventis and Teva. Miante Silvia received travel grant form Biogen Idec, Novartis, Sanofi Aventis and Teva. Signori Alessio has nothing to disclose. Pilotto Elisabetta has nothing to disclose. Rinaldi Francesca serves as an advisory board member of Biogen-Idec and has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, Teva and Bayer Schering Pharma. Perini Paola has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, and Bayer Schering Pharma and has been consultant for Merck Serono, Biogen Idec and Teva. Sormani Maria Pia received personal fees from Merck Serono, Biogen, Novartis, Genzyme, Teva, Synthon, Roche. Midena Edoardo has nothing to disclose. Gallo Paolo has been a consultant for Bayer Schering, Biogen Idec, Genzyme, Merck Serono and Novartis; has received funding for travel and speaker honoraria from Merck-Serono, Biogen Idec, Sanofi-Aventis, Novartis Pharma and Bayer-Schering Pharma, Teva; has received research support from Bayer, Biogen Idec/Elan, Merk Serono, Genzyme and Teva; and has received research grant from the University of Padova, Veneto Region of Italy, the Italian Association for Multiple Sclerosis, the Italian Ministry of Public Health. These competing of interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1
Double inversion recovery images (A Axial and B coronal) showing an inflammatory lesion (hyperintense signal) in the left optic nerve (arrows).
Fig 2
Fig 2. Comparison of the RNFL’s sector values.
Healthy Controls: HC-OCT; Not Optic Neuritis MS patients: MSON-; Optic Neuritis MS patients: MSON+; affected eye MSON+: aON+; not affected eye MS ON+: naON+.
See this image and copyright information in PMC

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