Remyelination of optic nerve lesions: spatial and temporal factors

Abstract

Optic neuritis provides an in vivo model to study demyelination. The effects of myelin loss and recovery can be measured by the latency of the multifocal visual evoked potentials. We investigated whether the extent of initial inflammatory demyelination in optic neuritis correlates with the remyelinating capacity of the optic nerve. Forty subjects with acute unilateral optic neuritis and good visual recovery underwent multifocal visual evoked potentials testing at 1, 3, 6 and 12 months. Average latency changes were analyzed. Extensive latency delay at baseline significantly improved over time with rate of recovery slowed down after 6 months. Magnitude of latency recovery was independent of initial latency delay. Latency recovery ranged from 7 to 17 ms across the whole patient cohort (average = 11.3 (3.1) ms) despite the fact that in a number of cases the baseline latency delay was more than 35-40 ms. Optic nerve lesions tend to remyelinate at a particular rate irrespective of the size of the initial demyelinated zone with smaller lesions accomplishing recovery more completely. The extent of the initial inflammatory demyelination is probably the single most important factor determining completeness of remyelination. The time period favorable to remyelination is likely to be within the first 6 months after the attack.

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

“…20,21 VEP was also used in single or small multicentre clinical studies assessing high-dose intravenous immunoglobulin, erythropoietin, simvastatin, and phenytoin in patients with acute optic neuritis, [22][23][24][25] and in natural recovery observational studies after an acute optic neuritis episode. 12,16,17,[26][27][28] When baseline characteristics of participants enrolled in RENEW were compared with those in trials of other candidate remyelinating or neuroprotective drugs, age and percentage of women were similar, mean number of days from fi rst acute optic neuritis symptom to fi rst dose was 24 days in RENEW versus 5-20 days in previous acute optic neuritis studies. 7,[22][23][24][25] A study testing erythropoietin reported shorter VEP latencies at week 16 for erythropoietin than for placebo, but the reported VEP latency was already shorter at baseline, resulting in an absence of treatment eff ect.…”

“…To overcome this limitation in the design of the RENEW study, we calculated the diff erence in aff ected eye VEP latency over time using the unaff ected fellow eye baseline value as the pretreatment normal reference value. 12,16 Although variable between individuals, 11 VEP usually has a very small inter-eye latency variation in the absence of disease pathology and is highly reproducible for sequential testing under standardised testing conditions. 12,16,17 To ensure that the baseline of the fellow eye was normal, participants with a diagnosis of multiple sclerosis or ophthalmological disorders were excluded and the fellow eye had to have a normal VEP at screening.…”

“…12,18,19 VEP has been used in animal models to assess neurological or potential eff ects on remyelination of the adenosine A1 receptor agonist N6-cyclohexyladenosine and siRNAs against the Nogo receptor. 20,21 VEP was also used in single or small multicentre clinical studies assessing high-dose intravenous immunoglobulin, erythropoietin, simvastatin, and phenytoin in patients with acute optic neuritis, [22][23][24][25] and in natural recovery observational studies after an acute optic neuritis episode.…”

Multifocal VEP assessment of optic neuritis evolution

“…To determine sufficient amplitude, software automatically calculate signal to noise ratio (SNR) at each segment of the stimulated visual field. The signal was considered non-recordable in segments where amplitude of the response was less than 1.96 times of the noise level (determined as Standard Deviation of the trace within the interval 400-1000 ms) (Klistorner et al, 2010).…”

Predictors of response to opicinumab in acute optic neuritis

“…While some spontaneous remyelination occurs, most patients have residual structural and clinical deficits 1, 2, 3, 4. A physiological hallmark of AON is prolonged visual evoked potential (VEP) latency, resulting from persistent demyelination of the affected optic nerve 2, 5…”