Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations

Klistorner, Alexander; Graham, Elizabeth C.; Yiannikas, Con; Barnett, Michael; Parratt, John; Garrick, R.; Wang, Chen; You, Yuyi; Graham, Stuart L.

doi:10.1111/ene.13404

Cited by 45 publications

(33 citation statements)

References 37 publications

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“…MS. 9,13,[28][29][30][31] RGC and its axon are thought to be analogous to brain gray and white matter. Therefore, studying mechanisms of its damage in MS may provide crucial insights into pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 99%

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

You¹,

Barnett²,

Yiannikas

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons.MethodsProgressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve.ResultsAlthough both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination.ConclusionsAlthough the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS.

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Section: Discussionmentioning

confidence: 99%

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

You¹,

Barnett²,

Yiannikas

et al. 2020

Neurol Neuroimmunol Neuroinflamm

View full text Add to dashboard Cite

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“…MOVING had no specific rules in place to limit the delay between ON onset and initiation of corticosteroid therapy, which may affect visual recovery [84,85]. Moreover, we did not evaluate focal lesions in the posterior visual pathways, which were recently described to be associated with RNFLT loss and delayed VEP [86,87].…”

Section: Discussionmentioning

confidence: 99%

Fingolimod after a first unilateral episode of acute optic neuritis (MOVING) – preliminary results from a randomized, rater-blind, active-controlled, phase 2 trial

et al. 2020

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Background: Neuroprotection and promotion of remyelination represent important therapeutic gaps in multiple sclerosis (MS). Acute optic neuritis (ON) is a frequent MS manifestation. Based on the presence and properties of sphingosine-1-phosphate receptors (S1PR) on astrocytes and oligodendrocytes, we hypothesized that remyelination can be enhanced by treatment with fingolimod, a S1PR modulator currently licensed for relapsing-remitting MS. Methods: MOVING was an investigator-driven, rater-blind, randomized clinical trial. Patients with acute unilateral ON, occurring as a clinically isolated syndrome or MS relapse, were randomized to 6 months of treatment with 0.5 mg oral fingolimod or subcutaneous IFN-β 1b 250 μg every other day. The change in multifocal visual evoked potential (mfVEP) latency of the qualifying eye was examined as the primary (month 6 vs. baseline) and secondary (months 3, 6 and 12 vs. baseline) outcome. In addition, full field visual evoked potentials, visual acuity, optical coherence tomography as well as clinical relapses and measures of disability, cerebral MRI, and self-reported visual quality of life were obtained for follow-up. The study was halted due to insufficient recruitment (n = 15), and available results are reported.Results: Per protocol analysis of the primary endpoint revealed a significantly larger reduction of mfVEP latency at 6 months compared to baseline with fingolimod treatment (n = 5; median decrease, 15.7 ms) than with IFN-β 1b treatment (n = 4; median increase, 8.15 ms) (p < 0.001 for interaction). Statistical significance was maintained in the secondary endpoint analysis. Descriptive results are reported for other endpoints. Conclusion: Preliminary results of the MOVING trial argue in support of a beneficial effect of fingolimod on optic nerve remyelination when compared to IFN-β treatment. Interpretation is limited by the small number of complete observations, an unexpected deterioration of the control group and a difference in baseline mfVEP latencies. The findings need to be confirmed in larger studies.Trial registration: The trial was registered as EUDRA-

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“…A limitation of this study is the fact that we did not investigate whether this problem also occurs with OCT machines and segmentation software by other manufacturers. For example, a number of studies in MS have been performed with the Cirrus OCT by Carl Zeiss Meditec (16,(21)(22)(23)(24)(25) and five with the Cirrus OCT (15,(26)(27)(28)(29). It is plausible that this problem might occur with these OCT devices as well, but this still remains to be investigated and these groups are well placed to investigate this point.…”

Section: Discussionmentioning

confidence: 99%

Software updates of OCT segmentation algorithms influence longitudinal assessment of retinal atrophy

Coric

Petzold²,

Uitdehaag

et al. 2018

Journal of the Neurological Sciences

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Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations

Cited by 45 publications

References 37 publications

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

Fingolimod after a first unilateral episode of acute optic neuritis (MOVING) – preliminary results from a randomized, rater-blind, active-controlled, phase 2 trial

Software updates of OCT segmentation algorithms influence longitudinal assessment of retinal atrophy

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