Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis

Abstract

Background and ObjectivesTo investigate the long-term effect of permanent demyelination on axonal attrition by examining an association between intereye asymmetry of the multifocal visual evoked potential (mfVEP) latency delay and subsequent thinning of retinal ganglion cell axons in patients with a long-standing history of unilateral optic neuritis (ON).MethodsOnly patients with a significant degree of chronic demyelination (intereye latency asymmetry >5 ms) were included in this study. The level of optic nerve demyelination was estimated at baseline by the latency delay of mfVEP, while the degree of axonal loss was assessed by thinning of the retinal nerve fiber layer (RNFL) thickness between baseline and follow-up visits. Low-contrast visual acuity (LCVA) was also evaluated at baseline and follow-up. Patients were examined twice with an average interval of 6.1 ± 1.4 years.ResultsFrom 85 examined patients with multiple sclerosis, 28 satisfied inclusion criteria. Latency of the mfVEP was delayed, and RNFL thickness was reduced in ON eyes compared with fellow eyes at both visits. There was significant correlation between latency asymmetry and baseline or follow-up intereye RNFL thickness asymmetry. Intereye asymmetry of LCVA at baseline correlated with baseline latency asymmetry of mfVEP and baseline asymmetry of RNFL thickness. Latency of the mfVEP in ON eyes improved slightly during the follow-up period, whereas latency of the fellow eye remained stable. By contrast, RNFL thickness significantly declined in both ON and fellow eyes during the follow-up period. The rate of RNFL thinning in ON eyes, however, was more than 2 times faster compared with the fellow eyes (p < 0.001). Furthermore, baseline latency asymmetry significantly correlated with the rate of RNFL thinning in ON eyes during the follow-up (p < 0.001), explaining almost half of the variability of temporal RNFL progression. For each millisecond of latency delay (i.e., ∼0.5 mm of demyelination along the optic nerve), temporal RNFL thickness was annually reduced by 0.05%.DiscussionOur study provides clear in vivo evidence that chronic demyelination significantly accelerates axonal loss. However, because this process is slow and its effect is mild, long-term monitoring is required to establish and confidently measure the neurodegenerative consequences of demyelination.

Evolution of retinal degeneration and prediction of disease activity in relapsing and progressive multiple sclerosis

“…The correlation of pRNFL, mRNFL, and GCIPL with VA and VEP latency in both relapsing and progressive subtypes and phases of the disease in our study indicates the functional relevance of these structural measurements and corroborates and expands upon previous reports 39 – 41 .…”

Utility of the visual system to monitor neurodegeneration in multiple sclerosis

“…A decrease in LGN volume has also been associated with lesions in the optic radiations ( Papadopoulou et al, 2019 ), which are axons from dLGN neurons that project to the occipital cortex ( Figure 1 ). This is consistent with a study by Klistorner et al (2022) showing that chronic demyelination drives axonal loss in the visual pathway, with mfVEP latency (measure of demyelination) associating with the rate of RNFL loss (measure of axonal loss). These studies indicate that retrograde and anterograde neurodegeneration occurs in the visual system following demyelinating activity in various white matter tracts and can be used to assess progressive axonal loss.…”

Axonal and myelin changes and their inter-relationship in the optic radiations in people with multiple sclerosis

“… 9 Chronic demyelination of the optic nerve after an episode of ON is found to accelerate retinal damage in both affected and non-affected eyes. 39 As the relation found between retinal damage and OR metrics was more pronounced in the setting of remote ON, this provides further evidence linking prior disease in the optic nerve and clinical functioning in ON to accumulating axonal damage and demyelination of the OR in MS—two structures that are synaptically connected at the LGN. As this process might evolve slowly and its effects might be mild, 39 long-term monitoring is required to establish and reliably measure the neurodegenerative consequences of optic nerve demyelination.…”