A serial study of retinal changes following optic neuritis with sample size estimates for acute neuroprotection trials

Abstract

Following an episode of optic neuritis, thinning of the retinal nerve fibre layer, which indicates axonal loss, is observed using optical coherence tomography. The longitudinal course of the retinal changes has not been well characterized. We performed a serial optical coherence tomography study in patients presenting with optic neuritis in order to define the temporal evolution of retinal nerve fibre layer changes and to estimate sample sizes for proof-of-concept trials of neuroprotection using retinal nerve fibre layer loss as the outcome measure. Twenty-three patients (7 male, 16 female, mean age 31 years) with acute clinically isolated unilateral optic neuritis were recruited to undergo optical coherence tomography, visual assessments and visual evoked potentials at presentation (median 16 days from onset of visual loss) and after 3, 6, 12 and 18 months. Compared with the clinically unaffected fellow eye, the retinal nerve fibre layer thickness of the affected eye was significantly increased at presentation and significantly reduced at all later time points. The evolution of retinal nerve fibre layer changes in the affected eye fitted well with an exponential model, with thinning appearing a mean of 1.6 months from symptom onset and the rate of ongoing retinal nerve fibre layer loss decreasing thereafter. At presentation, increased retinal nerve fibre layer thickness was associated with impaired visual acuity and prolonged visual evoked potential latency. Visual function after 12 months was not related to the extent of acute retinal nerve fibre layer swelling but was significantly associated with the extent of concurrent retinal nerve fibre layer loss. Sample size calculations for placebo-controlled trials of acute neuroprotection indicated that the numbers needed after 6 months of follow up are smaller than those after 3 months and similar to those after 12 months of follow-up. Study power was greater when investigating differences between clinically unaffected and affected eyes rather than retinal nerve fibre layer thickness of the affected eye alone. Inflammation in the optic nerve and impaired axonal transport (implied by retinal nerve fibre layer swelling) are associated with visual dysfunction and demyelination (long visual evoked potential latency) during acute optic neuritis. Retinal nerve fibre layer thinning is usually evident within 3 months. Optical coherence tomography-measured retinal nerve fibre layer loss after 6 months is a suitable outcome measure for proof-of-concept trials of acute neuroprotection in optic neuritis.

How strong is the relationship between glaucoma, the retinal nerve fibre layer, and neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis?

“…Macular volume is also lost in eyes affected with ON when compared with disease-free control eyes. 14 Significant RNFL thinning was found after ON in a study by Henderson et al, 106 evident within 3 months with 99% of the total loss occurring within 5 months of the episode of ON. Eyes with greater RNFL loss had a worse visual prognosis at 3 months.…”

Time to steroid treatment in severe acute optic neuritis

“…The fact that the thickness of the peripapillar and macular retinal nerve fiber layer (pRNFL and mRNFL) and ganglion cell layer combined with the inner plexiform layer (GCIP) were reduced in the affected eye after 6 months, confirms that these cells are the primary cellular site of the disease (Al‐Louzi et al., 2015; Gabilondo et al., 2015; Henderson et al., 2010). The GCIP layer was the preferred outcome measure over the pRNFL and mRFNL, since the GCIP layer is unaffected by optic disc edema and therefore provides more precise information on the structural retinal changes caused by ON (Syc et al., 2012).…”

“…Among patients with severe ON, an inverse relationship between pRNFL thickness (i.e., optic disc edema) and visual acuity was observed for nontreated patients, which is in agreement with previous findings (Beck et al., 1992; Henderson et al., 2010; Malik et al., 2014). The possible mechanism for the steroid treatment effect may involve a suppression of the inflammation associated with acute ON, which in turn may limit the neuronal damage and accelerate visual function recovery (Beck et al., 1992; Kapoor et al., 1998; Sellebjerg, Nielsen, Frederiksen, & Olesen, 1999).…”

“…3) Carry‐over of values between 6 and 12 months. This was done for BCVA, contrast sensitivity and Rayleigh match (all tests in three patients, Rayleigh match in one patient), and for macular scans (11 scans in six patients: unsuccessful bilateral scan in two patients and in one patient's affected eye at 6 months; not performed bilateral scan in three other patients at 12 months) (Beck, Cleary, & Backlund, 1994; Costello et al., 2015; Henderson et al., 2010). Results presented in this article are from primary modified ITT analysis.…”

Retinal ganglion cell and axonal loss in optic neuritis: risk factors and visual functions

“…14 Previous studies have reported the timing of pRNFL and GCIPL thinning after the onset of ON. 14,19 Henderson et al 19 showed that RNFL thinning can be observed during the first 6 months following ON and that 490% of this fiber loss occurred by the end of the third month. Another study reported that RNFL thinning occurred gradually, up to 6-9 months after ON, and that GCL thinning occurred earlier than RNFL thinning, within a few weeks after acute ON.…”