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

Gabilondo, Iñigo; Martínez-Lapiscina, Elena H.; Martínez‐Heras, Eloy; Fraga-Pumar, Elena; Llufriú, Sara; Ortiz, Santiago; Bullich, Santiago; Sepúlveda, María; Falcon, Carles; Berenguer, Joan; Sáiz, Albert; Sánchez-Dalmau, Bernardo; Villoslada, Pablo

doi:10.1002/ana.24030

Cited by 220 publications

(225 citation statements)

References 38 publications

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“…(2016) and due to the cross‐sectional design, our study does not allow to provide an explanation of the pathophysiology leading to the observed correlation patterns. From a pathophysiologic point of view, the association between OCT outcomes and focal cortical volume might be explained by anterograde and retrograde neurodegeneration within the visual system and its connections to major integrating network hubs (Gabilondo et al., 2014). Steenwijk and colleagues called this a “second‐order effect” where focal neurodegeneration leads to accentuate gray matter loss in important network hubs along defined anatomical structures.…”

Section: Discussionmentioning

confidence: 99%

“…In comparison with the macular RNFL (mRNFL) thickness, combined ganglion cell layer and inner plexiform layers (GCIPL) thickness appear to have a better but still only moderate correlation with gray matter volume which is linked to disability in MS (Balcer et al., 2015). Moreover, OCT and MRI are promising tools to detect anterograde neurodegeneration after acute optic neuritis as well as retrograde neurodegeneration due to MS lesions in the posterior visual pathway (Gabilondo et al., 2014; Klistorner et al., 2014). How other functional networks aside from the primary visual system might be associated with neuronal loss within the anterior visual system has not been analyzed in depth (Saidha et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

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Pattern of gray matter volumes related to retinal thickness and its association with cognitive function in relapsing–remitting MS

et al. 2016

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BackgroundNeurodegeneration in multiple sclerosis (MS) may be investigated in the visual system as optical coherence tomography (OCT) and magnetic resonance imaging (MRI) allows examining structural integrity in detail. The association between thickness of retinal layers and focal cortical volumes beyond the primary visual system has not been thoroughly investigated.ObjectiveTo investigate the association between focal cortical volume and thickness of retinal layers.MethodsFifty‐four patients (relapsing–remitting MS, mean age 40.5 years, mean disease duration 7.6 years, median EDSS 2) underwent OCT and MRI. The association between focal cortical volume and OCT measurements was investigated with voxel‐based morphometry (VBM). Patterns of association were determined with Yeo's functional network atlas and the Harvard‐Oxford cortical atlas. We used GEE models with cortical volumes from the FreeSurfer parcellation to confirm VBM results. Post hoc, we analyzed the association between OCT, focal cortical volumes, and an extended neuropsychological assessment in a subgroup of 14 patients.ResultsMacular retinal nerve fiber layer (mRNFL) and ganglion cell /inner plexiform layer (GCIPL) showed a robust association with mainly the insular cortex and the cingulate cortex. VBM findings were confirmed with FreeSurfer volumes. The post hoc analysis detected significant correlations between both OCT outcomes and cognition.ConclusionBesides the primary visual system, OCT outcomes show a correlation pattern with cortical regions that are known to be important for cognitive performance, predominantly the insula in both hemispheres. Thus, OCT should be further investigated as a marker for neurodegeneration in MS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pattern of gray matter volumes related to retinal thickness and its association with cognitive function in relapsing–remitting MS

et al. 2016

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“…9,31,32 In reality, axonotemesis in the hard-wired visual pathways will always lead to bidirectional transsynaptic axonal degeneration. 33 One should allow a 3-month interval after an acute attack of optic neuritis before attempting to quantify peripapillary atrophy of the RNFL.…”

Section: Thinningmentioning

confidence: 99%

“…7,8 In this Review, we emphasize that optic neuritis represents a pragmatic model for testing structural-functional relationships. 9,10 The visual system is the best-understood and most accessible part of the human CNS. In each eye, 100 million rod photoreceptors capture light, which is then converted by 12 types of bipolar cell into a digitally coded electrical signal, 11 which passes through the 1,158,000 axons of the optic nerve.…”

Section: Introductionmentioning

confidence: 99%

The investigation of acute optic neuritis: a review and proposed protocol

et al. 2014

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| Optic neuritis is an inflammatory optic neuropathy that affects many patients with multiple sclerosis (MS) at some point during their disease course. Differentiation of acute episodes of MS-associated optic neuritis from other autoimmune and inflammatory optic neuropathies is vital for treatment choice and further patient management, but is not always straightforward. Over the past decade, a number of new imaging, laboratory and electrophysiological techniques have entered the clinical arena. To date, however, no consensus guidelines have been devised to specify how and when these techniques can be most rationally applied for the diagnostic work-up of patients with acute optic neuritis. In this article, we review the literature and attempt to formulate a consensus for the investigation of patients with acute optic neuritis, both in standard care and in research with relevance to clinical treatment trials.

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“…Beyond focal axonal damage and its direct mid-term consequences, the question has emerged as to whether trans-synaptic degeneration may play an additional significant role in chronic disease development and neurodegeneration [23]. Subclinically silent tissue destruction following inflammatory damage due to ON or white matter lesions may serve as an example for white matter destruction in MS in general.…”

Section: Ms Visual Pathway White Matter Damage Patternsmentioning

confidence: 99%

Diffusion tensor imaging for multilevel assessment of the visual pathway: possibilities for personalized outcome prediction in autoimmune disorders of the central nervous system

et al. 2017

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The afferent visual pathway represents the most frequently affected white matter pathway in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Diffusion tensor imaging (DTI) can reveal microstructural or non-overt brain tissue damage and quantify pathological processes. DTI facilitates the reconstruction of major white matter fiber tracts allowing for the assessment of structure-function and damage-dysfunction relationships. In this review, we outline DTI studies investigating the afferent visual pathway in idiopathic optic neuritis (ON), NMOSD, and MS. Since MS damage patterns are believed to depend on multiple factors, i.e., ON (anterior visual pathway damage), inflammatory lesions (posterior visual pathway damage), and global diffuse inflammatory and neurodegenerative processes, comprehensive knowledge on different contributing factors using DTI in vivo may advance our understanding of MS disease pathology. Combination of DTI measures and visual outcome parameters yields the potential to improve routine clinical diagnostic procedures and may further the accuracy of individual prognosis with regard to visual function and personalized disease outcome. However, due to the inherent limitations of DTI acquisition and post-processing techniques and the so far heterogeneous and equivocal data of previous studies, evaluation of the true potential of DTI as a possible biomarker for afferent visual pathway dysfunction is still substantially limited. Further research efforts with larger longitudinal studies and standardized DTI acquisition and post-processing validation criteria are needed to overcome current DTI limitations. DTI evaluation at different levels of the visual pathway has the potential to provide markers for individual damage evaluation in the future. As an imaging biomarker, DTI may support individual outcome prediction during personalized treatment algorithms in MS and other neuroinflammatory diseases, hereby leveraging the concept of predictive, preventive, and personalized medicine in the field of clinical neuroimmunology.

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

Abstract: Our results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in MS.

Cited by 220 publications

References 38 publications

Pattern of gray matter volumes related to retinal thickness and its association with cognitive function in relapsing–remitting MS

Pattern of gray matter volumes related to retinal thickness and its association with cognitive function in relapsing–remitting MS

The investigation of acute optic neuritis: a review and proposed protocol

Diffusion tensor imaging for multilevel assessment of the visual pathway: possibilities for personalized outcome prediction in autoimmune disorders of the central nervous system

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