Acute optic neuritis

Optical coherence tomography.

Assessment of structural changes in the course of ON has been revolutionized over the past 2 decades by advances in optical coherence tomography (OCT), a technique that uses interferometry of reflected light to obtain images of the retinal layers¹³ (figure 2). Most OCT studies of patients with ON have used time-domain OCT (TD-OCT), which provides cross-sectional images from different tissue levels. Since the peripapillary retinal nerve fiber layer (RNFL) is composed of unmyelinated optic nerve axons, RNFL thinning detected by OCT is directly interpretable as neuroaxonal degeneration. More modern systems using spectral-domain OCT (SD-OCT) provide considerably improved resolution and speed and can be used to generate 3-dimensional images for measurements of thickness of neuronal layers.

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Figure 2 Optical coherence tomography of the human retina

A) Detailed retinal segmentation sample on spectral-domain optical coherence tomography (OCT) image. Six intraretinal layer borders can be automatically segmented. (B) Correlation of anatomy with OCT for the human retina. On the left is a hematoxylin & eosin stain of the human retina, in the center is a schematic representation of the cell composition of the human retina, and on the right is a magnification of the image obtained with spectral-domain OCT (bottom), with indications of the retina layers identified. Figure 2B reprinted with permission from Santiago Ortiz-Perez. BM = Bruch membrane; CC = choriocapillaris layer; GCL = ganglion cell layer; ILM = inner limiting membrane; INL = inner nuclear layer; IPL = inner plexiform layer; OLM = outer limiting membrane; ONL = outer nuclear layer; OPL = outer plexiform layer; PL = photoreceptor layer; RNFL = retinal nerve fiber layer; RPE = retinal pigment epithelium.

Acute ON often results in inflammatory swelling of the RNFL of the affected eye. The inflammatory swelling generally resolves within 3 months¹⁴ and is accompanied by a period of RNFL thinning that continues for up to 7–12 months but is most prominent in the first 6 months after acute ON onset.^5,15 The initial period of swelling prevents examination of the timing of axonal loss in the RNFL with TD-OCT. In contrast, the thickness of the retinal ganglion cell layer (RGCL) appears to be less affected by edema,^16,17 so the more detailed resolution with SD-OCT may allow for a better assessment of the timing of thinning in reference to acute ON. Recent studies suggest that thinning of the RGCL starts within several weeks after an episode of ON and may precede RNFL thinning.^16,17 Ultimately, RNFL thinning in affected eyes correlates with visual acuity, low-contrast letter acuity, visual field, color vision, and VEPs (see also below),^18,19 thereby supporting its functional relevance, and RNFL thickness <75 μm has been shown to predict reduced visual field function.^5,20 Although it is not yet clear whether preventing RNFL thickness from crossing that threshold can reduce the extent of associated visual deficits, it is worth noting that it is also near the lower limit of RNFL thickness, when virtually all retinal ganglion cell (RGC) axons have been lost (20–40 μm).²¹

Thinning of the RNFL following an episode of ON is thought to result from axonal loss subsequent to axonal injury during the inflammatory demyelinating lesion of the affected optic nerve. However, it is noteworthy that detectable RNFL thinning and associated visual deficits are also observed in unaffected eyes of patients with MS in the absence of history of ON.¹⁵ One possibility is that some “mild” attacks are not reported or do not result in deficits that are immediately evident to patients. Thus, in nonacute ON eyes there is a component of RNFL thinning that may be attributable to other causes, such as subclinical optic nerve inflammation, neurodegeneration within normal-appearing white matter, or transsynaptic degeneration associated with lesions elsewhere in the visual pathway.^22,–,24

The increased resolution of SD-OCT and the use of segmentation algorithms have allowed a more detailed analysis of the effects of ON and MS on retinal structure²⁵ (figure 2). These studies found that RNFL thinning associated with MS with or without ON is not confined to the peripapillary region but also affects the macula. In addition, a similar pattern of thinning is observed for the ganglion cell layer/inner plexiform layers (GCL + IPL) in the peripapillary region and macula. A recent study in patients with ON found that decreases of ≥4.5 μm in GCL + IPL thickness after 1 month predicted low-contrast visual acuity dysfunction at 6 months, whereas decreases of ≥7 μm predicted visual field and color vision deficits.¹⁶ In another study in patients with MS with or without a history of ON, thinning of GCL + IPL was most closely associated with visual function and vision-specific QOL.²⁶ Results of these studies suggest that degeneration associated with ON and MS is widespread in the RGCL.

Together, these studies provide compelling evidence for structural damage from acute ON, and they also provide a powerful demonstration of the potential for SD-OCT as a tool to assess neurodegenerative changes in acute ON. However, both TD-OCT and SD-OCT appear to be less sensitive than VEPs for assessing the clinical and subclinical effects of ON,^27,28 so interpretation of OCT may require complementary assessments using functional techniques. Furthermore, improvements are needed to standardize and reduce test-retest variability in SD-OCT systems.²⁹ Given the rapid evolution of the technology, the technical expertise required, and differences between commercially available instruments,³⁰ it is also important that criteria be established to ensure quality control for OCT as a validated outcome measure, a process that is under way.³¹

VEPs.

Standard VEPs elicited by visual stimuli and measured in the occipital cortex can be used to detect functional changes in the visual pathway, including the optic nerve.³² In multifocal VEPs (mfVEPs), visual stimuli are provided independently to localized regions of a wider visual field (48°) and responses to the stimuli are measured individually,³³ allowing for a more detailed analysis of visual function covering a much larger area of the visual pathway than standard VEPs (figure 3).

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Figure 3 Multifocal visual-evoked potentials in optic neuritis

Figure shows the visual-evoked potentials (VEPs) in 52 sectors of the retina. (A, B) A case of acute optic neuritis with diffuse impairment of the VEPs in the affected eye (A) compared with the unaffected eye (B), with significant impairment of the latencies and amplitudes. (B, C) After recovery from the acute optic neuritis, the VEPs show a significant decrease of amplitude and latencies in most of the sectors of the affected eye (C) compared with the unaffected eye (D). Reprinted with permission from Ana Tercero.

The severity of an attack of ON and the extent of inflammation are correlated with an acute reduction in the amplitude of VEPs.³⁴ Reduction in VEP amplitude is thought to reflect functional impairment of axonal conduction either transiently (e.g., due to acute inflammation or demyelination) or persistently (due to axonal loss). Within 3–4 months after the acute episode, the amplitude generally shows some recovery, reflecting resolution of edema, and the waveform of the VEP is well-preserved, but the latency is significantly increased. This residual latency delay is thought to result from demyelination of surviving axons, which interferes with saltatory conduction of the action potential along the optic nerve lesion. Some investigators have reported subsequent improvement in latency for up to 2 years,⁶ whereas others have reported no further recovery after 4 months.⁸ Prolongation of latency is most evident in the central visual field, perhaps indicating that the central (macular) region of the optic nerve is more susceptible to demyelination or resistant to remyelination.³² The central region of the optic nerve contains the greatest density of parvocellular fibers that convey static information (e.g., form and color), but VEP latency in patients with ON correlates more strongly with dynamic functions (e.g., motion detection) than with static functions. This may suggest more specific effects on magnocellular fibers or greater vulnerability of fibers required for accurate signal timing.⁸

Effects of ON on VEPs have also been shown to reflect structural changes in the RNFL. In a study of 21 patients following a first episode of unilateral ON, VEP latency prolongations and amplitude reductions of affected eyes at baseline and 3 months after onset were associated with RNFL thinning,¹⁹ suggesting a relationship between the initial structural loss and residual functional impairment. In a separate study of 25 patients with ON with incomplete recovery after 1 year, similar relationships between VEP latency/amplitude and RNFL thinning were still evident,¹⁸ further supporting the clinical relevance of this technique.

mfVEPs have been used in a growing number of small studies to examine the pathology of ON in greater detail.^35,–,38 mfVEPs detect functional changes associated with onset and evolution of acute ON³⁸ and may be particularly useful to assess treatment outcomes in clinical trials as it appears to be more reproducible than standard VEPs.³⁹ One study of 25 patients with ON between 6 and 12 months after onset found an apparent discrepancy between structural and functional measures in these patients.³⁵ As RNFL thinning progressed in the affected eyes over this time period, the mfVEP amplitude partially recovered, suggesting that functional recovery may be due in part to remyelination and/or neuronal plasticity.

Functional data provided by VEPs and mfVEPs make an ideal counterpart to structural retinal assessments using OCT. However, as with OCT, criteria need to be established to ensure reproducibility and validity of VEP results. Furthermore, larger-scale studies are needed to confirm the results of current smaller studies.

MRI.

Nonconventional MRI techniques offer novel tools to examine the structure of CNS tissues in detail. For example, magnetization transfer (MT) imaging exploits the difference in resonance in free protons and protons associated with macromolecules (e.g., myelin), the ratio of which may provide a measure of myelin content.⁴⁰ Diffusion tensor imaging (DTI) can be used to measure asymmetric radial diffusivity (RD), axial diffusivity (AD), or fractional anisotropy (FA) of water as a gauge of tissue in major nerve tracts (e.g., optic nerve and optic radiations).⁴¹

A small number of studies have provided support for use of these techniques to assess pathologic changes in ON. For example, in an MT study in 11 patients with ON, MT ratios of affected optic nerves closely followed the course of the disease: they were significantly higher at baseline (within 8 days of onset) but were reduced at months 3 and 6.⁴² In a separate study in 37 patients with ON, MT ratios of affected optic nerves were not found to be different from those of unaffected nerves until 3 months after onset.⁴³ In that study, ON-associated alterations in MT ratios at 3 months correlated with high- and low-contrast visual deficits and with VEP latency at 6 months as well as with RNFL thinning at 12 months.

In a study of DTI performed within 30 days of onset and after 1 year in 12 patients with ON, FA of affected optic nerves (which is also considered a potential measure of myelination) was the only parameter correlated with vision at onset but did not correlate with the extent of recovery of visual acuity or contrast sensitivity at 1 or 3 months.⁴⁴ The AD (considered a measure of axonal integrity) was the only parameter that was correlated with worse contrast sensitivity at 1 and 3 months. This was confirmed in a follow-up study in 25 patients, in which a lower baseline AD was also found to be correlated with the extent of RNFL thinning and with VEP amplitude and latency.⁴⁵ These were small studies and should be interpreted with caution as eye motion makes imaging of the optic nerve by MT ratio and DTI challenging, but they do not seem to support a model in which the extent of neurodegeneration is determined solely by chronic demyelination. Rather, they suggest that the initial neuroaxonal effects of the acute inflammatory injury may be more important.

Although these “nonconventional” MRI techniques hold promise as a tool to investigate underlying processes and assess recovery in ON, there are substantial challenges to widespread use. For example, the acquisition times are frequently longer than is practical for routine human studies, and imaging is complicated by motion artifacts caused by moving the eye or head.⁴⁶ In addition, there is no consensus on sequences and protocols for their application in ON. These factors have limited widespread adoption of these approaches and have likely contributed to the inconsistencies in findings. Thus, further technological improvements and standardization of techniques for imaging of ON lesions will be required before they can be considered as reliable measures of outcomes in clinical trials.