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Anatomical Wiring and Functional Networking Changes in the Visual System Following Optic Neuritis

Educational Objective
To investigate how anatomic and functional connectivity is associated with recovery after optic neuritis.
1 Credit CME
Key Points

Question  How are anatomical connectivity and functional connectivity associated with recovery after optic neuritis?

Findings  In this study of 18 patients with optic neuritis as a clinically isolated syndrome and 21 patients with clinically isolated syndrome and damage elsewhere in the central nervous system, intact postgeniculate visual pathways were found but functional modification occurred as well, suggesting that functional network changes may be part of the recovery process.

Meaning  Potentially adaptive modifications in functional connectivity may be important in explaining recovery following demyelinating injury, with specific evidence provided from the visual pathway.


Importance  Clinical outcome in multiple sclerosis was suggested to be driven by not only remyelination but also adaptive reorganization. This mechanism needs to be further understood.

Objective  To explore anatomical and functional visual networks in patients with optic neuritis (ON) to assess the relative weight of each connectivity modality to expedite visual recovery.

Design, Setting, and Participants  Between March 11, 2011, and May 26, 2014, 39 patients with either clinically isolated syndrome (CIS) ON (n = 18) or other CIS (non-ON) (n = 21) were recruited 1 to 28 months following an initial clinical event. These patients enrolled in an ongoing prospective cohort study (107 participants at the time of this present study) about the disease course of CIS and multiple sclerosis. Inclusion criteria were an age of 18 to 65 years, the suggestive clinical and paraclinical diagnosis of CIS or multiple sclerosis after relevant differential diagnoses have been ruled out, the existence of complete imaging data, and no ocular comorbidities. Anatomical connectivity was evaluated by diffusion tensor imaging, and functional connectivity was evaluated by resting-state functional magnetic resonance imaging. The visual pathways, including optic tracts, optic radiations, and splenial fibers, were delineated, and the resting-state visual networks were detected. Data analysis took place from September 1, 2015, to December 1, 2015.

Main Outcomes and Measures  Connectivity changes were quantified and compared to determine the association of ON with the visual network.

Results  This study included 18 patients with CIS ON, 11 (61%) of whom were women with a mean (SD) age of 32.83 (8.53) years, and 21 patients with CIS non-ON (11 [52%] of whom were women with a mean [SD] age of 30.86 [7.54] years). With the use of diffusion tensor imaging, reduced diffusivity (mean [SD] fractional anisotropy, 0.35 [0.03] vs 0.38 [0.03]; P < .01) was evident along the optic tracts of patients with ON, suggesting the extension of axonal injury from the damaged optic nerve. Neither the optic radiations nor the splenial fibers showed evidence of loss of integrity. Yet, in the presence of an intact postgeniculate anatomical network, the functional connectivity within the visual network was higher in the ON cohort. Functional connectivity observed in cortical motion–related areas was inversely correlated with the visual evoked potential–measured conduction velocity (r = −0.59; P < .05).

Conclusions and Relevance  In this cohort, local optic nerve demyelinating damage does not affect distant wiring, but even in the presence of an intact anatomical network, functional modification may occur. These functional network changes may be part of the recovery process, but further research is needed to elucidate this process.

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Article Information

Corresponding Author: Netta Levin, MD, PhD, Functional Imaging Unit, Department of Neurology, Hadassah-Hebrew University Medical Center, POB 12,000, Jerusalem 91120, Israel (netta@hadassah.org.il).

Accepted for Publication: October 8, 2017.

Published Online: January 2, 2018. doi:10.1001/jamaneurol.2017.3880

Author Contributions: Drs Paul and Levin contributed equally to the manuscript. Ms Backner and Dr Levin had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analyses.

Study concept and design: Backner, Raz, Paul, Levin.

Acquisition, analysis, or interpretation of data: Backner, Kuchling, Massarwa, Oberwahrenbrock, Finke, Bellmann-Strobl, Ruprecht, Brandt, Zimmermann, Paul.

Drafting of the manuscript: Backner, Massarwa, Raz, Levin.

Critical revision of the manuscript for important intellectual content: Backner, Kuchling, Oberwahrenbrock, Finke, Bellmann-Strobl, Ruprecht, Brandt, Zimmermann, Paul, Levin.

Statistical analysis: Backner, Massarwa, Oberwahrenbrock, Brandt.

Obtained funding: Backner, Ruprecht, Raz, Paul, Levin.

Administrative, technical, or material support: Kuchling, Finke, Bellmann-Strobl, Ruprecht, Brandt, Zimmermann, Paul.

Study supervision: Brandt, Paul, Levin.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded in part by research grant 5128-A-1 from the National Multiple Sclerosis Society and by the Teva Pharmaceutical Industries Ltd as part of the Israeli National Network of Excellence in Neuroscience. Dr Paul is supported by grant DFG Exc 257 from the Deutsche Forschungsgemeinschaft. Drs Brandt and Paul are supported by Bundesministerium für Bildung und Forschung (BMBF/Neu2, 16GW0079: N2-ADVISIMS Retinal imaging in neuroimmunological disorders).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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