Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis

Authors

  • Iñigo Gabilondo MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Elena H. Martínez-Lapiscina MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Eloy Martínez-Heras MSc,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Elena Fraga-Pumar BO,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Sara Llufriu MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Santiago Ortiz MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
    2. Department of Ophthalmology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Santiago Bullich PhD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Maria Sepulveda MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Carles Falcon PhD,

    1. Medical Imaging Platform and Biomedical Research Networking Center for Bioengineering, Biomaterials, and Nanomedicine, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Joan Berenguer MD,

    1. Department of Radiology and Imaging Diagnostic Center, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Albert Saiz MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Bernardo Sanchez-Dalmau MD,

    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
    2. Department of Ophthalmology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Pablo Villoslada MD

    Corresponding author
    1. Center of Neuroimmunology and Department of Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Barcelona, Spain
    • Address correspondence to Dr Villoslada, Center of Neuroimmunology, IDIBAPS, Casanova 143, 08036 Barcelona, Spain. E-mail: pvilloslada@clinic.ub.es

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Abstract

Objective

To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans-synaptic degeneration in multiple sclerosis (MS).

Methods

We performed a longitudinal evaluation on a cohort of 100 patients with MS, acquiring retinal optical coherence tomography to measure anterior visual pathway damage (peripapillary retinal nerve fiber layer [RNFL] thickness and macular volume) and 3T brain magnetic resonance imaging (MRI) for posterior visual pathway damage (volumetry and spectroscopy of visual cortex, lesion volume within optic radiations) at inclusion and after 1 year. Freesurfer and SPM8 software was used for MRI analysis. We evaluated the relationships between the damage in the anterior and posterior visual pathway by voxel-based morphometry (VBM), multiple linear regressions, and general linear models.

Results

VBM analysis showed that RNFL thinning was specifically associated with atrophy of the visual cortex and with lesions in optic radiations at study inclusion (p < 0.05). Visual cortex volume (β = +0.601, 95% confidence interval [CI] = +0.04 to +1.16), N-acetyl aspartate in visual cortex (β = +1.075, 95% CI = +0.190 to +1.961), and lesion volume within optic radiations (β = −2.551, 95% CI = −3.910 to −1.192) significantly influenced average RNFL thinning at study inclusion independently of other confounders, especially optic neuritis (ON). The model indicates that a decrease of 1cm3 in visual cortex volume predicts a reduction of 0.6μm in RNFL thickness. This association was also observed after 1 year of follow-up. Patients with severe prior ON (adjusted difference = −3.01, 95% CI = −5.08 to −0.95) and mild prior ON (adjusted difference = −1.03, 95% CI = −3.02 to +0.95) had a lower adjusted mean visual cortex volume than patients without ON.

Interpretation

Our results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in MS. ANN NEUROL 2014;75:98–107

Ancillary