Optical coherence tomography (OCT) uses light interference patterns to produce a cross-sectional image of the retina. It is capable of measuring the unmyelinated axons of the retinal ganglionar cells as they converge on the optic disc. In a disease like multiple sclerosis (MS), in which axonal loss has been identified as an important cause of sustained disability, it may prove an invaluable tool. OCT has demonstrated that axonal loss occurs after each episode of optic neuritis and that the degree of axonal loss is correlated to visual outcomes. Furthermore, axonal loss occurs in MS even in the absence of inflammatory episodes, and the degree of this loss is correlated with the duration of the disease process, with more thinning as the disease advances and in progressive forms. Thus, OCT retinal nerve fiber layer measurements may represent an objective outcome measure with which to evaluate the effect of treatment.
The optic nerve as it leaves the eye is the only tissue composed of unmyelinated axons which can be imaged directly. The retinal nerve fiber layer (RNFL) is made up of the axons of the retinal ganglionar cells that convey the visual information from the retina to the lateral geniculate nucleus; until they exit the eye, they do not acquire the protective myelin sheath. This extraordinary circumstance allows us to study the influence on isolated axons of several diseases. Ganglionar cells and their axons, besides being the main retinal component around the optic nerve (90% of retinal thickness) are also representative at the macula (30–35%).
Both time-domain and spectral-domain optical coherence tomographies (OCT) use light interference patterns to produce a tomogram, or cross-section, through the layers of the retina. From this information, the OCT software constructs a two-dimensional (time-domain, TD-OCT) or three-dimensional (spectral-domain, SD-OCT) image of the retina and the optic nerve and is capable of measuring the different layers of the retina with a margin of error of 4–6
Axonal loss, in contrast to demyelination, is not reversible and is therefore an important cause of sustained disability. In patients diagnosed with multiple sclerosis, it has been demonstrated that axonal loss occurs in the early stages of the disease. This is one of the reasons that support the early use of neuroprotective drugs. Monitoring axonal loss has become a priority in multiple sclerosis and OCT as a sensitive, precise, and reproducible technique is acquiring increasing importance for both neurologists and ophthalmologists [
Optic neuritis is one of the manifestations of multiple sclerosis; it has been described as the second most frequent mode of presentation. The Optic Neuritis Treatment Trial (ONTT) has shown us that a patient diagnosed with a first episode of optic neuritis has a risk of 50% of developing multiple sclerosis in the following 15 years. The risk increases to 72% in those patients with at least one demyelinated lesion on magnetic resonance imaging (MRI) and decreases to 25% in those without lesions [
Optical coherence tomography has a high sensitivity for detecting acute optic nerve oedema in anterior optic neuritis (Figure
Fundus photograph, visual fields, and optical coherence tomography of a 30-year-old man who consulted due to ocular pain and visual loss in his left eye for two weeks. Optical coherence tomography shows an increased retinal nerve fiber layer thickness in his left eye due to optic nerve edema.
Following an initial episode of optic neuritis, OCT can detect axonal loss as a thinning of the RNFL, occurring mainly in the first three to six months (Figure
Patient who developed retrobulbar neuritis in his right eye as an initial clinically isolated syndrome. In only three months, axonal loss can be detected in the eye that suffered the neuritis.
Prospective studies estimate that there is a 20 to 25% loss in the RNFL thickness when compared to the fellow unaffected eye (Table
Comparison of RNFL thickness (
Patients | ON eye | Fellow eye | Control | |
---|---|---|---|---|
Outteryck et al.[ | Non-MS | 92.27 (12.82) | — | 98.71 (9.08) |
Grazioli et al. [ | MS | 81.7 (19.2) | 93.6 (15.3) | — |
Klistorner et al. [ | MS and non-MS | 84.5 (15. 1) | 103.8 (10.8) | 104.0 (9.2) |
Siger et al. [ | MS | 83.92 (17.63) | 91.08 (19.3) | — |
Costello et al. [ | Non-MS | 86.1 | 101.6 | — |
Noval et al. (data not published) | MS and non-MS | 84.95 (23.45) | 103.40 (15.27) | 105.5 (10.51) |
Fisher et al. [ | MS | 85 (17) | 96 (14) | 105 (12) |
Costello et al. [ | Non-MS | 77.5 (29.87) | 99.8 (32.5) | — |
Trip et al. [ | MS and non-MS | 68.7 (18.8) | 94.6 (14.9) | 102.9 (14.6) |
Parisi et al. [ | MS | 59.79 (10.80) | 82.73 (10.73) | 111.11 (11.42) |
MS: multiple sclerosis.
NON: MS healthy subjects.
ON: optic neuritis.
Axonal loss affects diffusely the whole peripapillary RNFL, although the temporal quadrant is often the most affected. This loss may be detected as soon as two months after the event, when compared to the fellow eye and healthy controls [
The optic nerve can become pale after an episode of optic neuritis. This pallor can be diffuse or located in the temporal quadrant and reflects the RNFL loss detectable with OCT. Because the temporal quadrant of the optic disc is relatively thinner than other quadrants, even diffuse atrophy may be perceived only as temporal pallor on exam. Our study group also found a mild increase in the cup to disc ratio of approximately 0.1 to 0.2 when compared to the fellow eye, in accordance with previous clinical observations [
Since RNFL loss after an episode of optic neuritis stabilizes after six months, most studies that analyze the relationship between axonal loss and visual outcome are performed at or after this time point. Costello et al. found that patients with incomplete visual recovery after optic neuritis suffer a greater RNFL loss and through regression analysis obtained a threshold of RNFL thickness (75
Visual fields represent a subjective method of measuring visual function, which requires active collaboration and attentiveness from the patient. Visual fields usually improve after a first episode of optic neuritis to normal or near normal levels. However, OCT often reveals subclinical permanent axonal damage, which may not be reflected by subjective explorations. Thus, 60% of patients with normal visual fields in our study had abnormal RNFL thickness measurements by OCT at the six-month visit [
Low contrast letter acuity (LCLA) is being increasingly used now as a visual outcome measure in MS and ON studies. Talman et al. demonstrated that progressive RNFL thinning occurs as a function of time in MS and is associated with clinically significant visual loss by low-contrast letter acuity. They found that visual loss by the 2.5% contrast chart was significantly associated with RNFL thinning. Scores from the 1.25% contrast chart, however, correlated less well with RNFL loss [
Thus, both LCLA and RNFL thinnings are being introduced as surrogate markers for disability in MS trials. However, it should be taken into account that some patients may present with visual loss even in the presence of a preserved RNFL thickness, while on the other hand patients with decreased RNFL thickness may not present severe dysfunction if nerve fiber loss does not affect the papillo-macular bundle. Furthermore, patients with visual loss adapt with time to their scotomas, so that visual function may improve as they learn to manage with their limitations.
The development of a clinically isolated syndrome (CIS) represents the earliest clinical stage of multiple sclerosis. Outteryck et al. studied 56 patients with CIS, 18 with optic neuritis, and 38 without it. Two-thirds of the patients had dissemination in space according to the Barkhof criteria. All of the patients had a normal overall RNFL thickness. However, 14 patients (25%) and 7 controls (22%) had RNFL atrophy in at least 1 quadrant, according to the OCT database (Figure
Patient who suffered a motor clinical isolated syndrome and fulfilled Barkhof’s magnetic resonance imaging criteria. Optical coherence tomography shows a decreased retinal nerve fiber layer in both eyes (more intense in the right eye) even without a history of optic neuritis.
In the absence of optic neuritis, retrograde trans-synaptic retinal ganglion cell degeneration due to multiple sclerosis lesions within the posterior optic pathways could cause RNFL loss. Progressive axonal loss could also explain the RNFL thinning found in eyes of patients with multiple sclerosis without a history of optic neuritis (Table
Comparison of RNFL thickness (
MS with ON | MS without ON | Control | |
---|---|---|---|
Siepman et al. [ | 72.2 (14.4) | 89.5 (14.2) | — |
Khanifar et al.* [ | 83.0 (14.0) | 90.5 (13.2) | 97 |
Costello et al. [ | 79.5 (18.8) | 97.0 (14.3) | — |
Bock et al. [ | 86.2 (16.2) | 97.0 (13.1) | 105.2 (9.4) |
Quelly et al. [ | 78.01 (17.43) | 95.24 (11.64) | — |
Merle et al. [ | 80.81 (18.4) | 96.7 (15.8) | 106 (12.2) |
Oreja-Guevara et al. [ | 76.42 (16.87) | 89.45 (17.68) | — |
Frohman et al. [ | 70.3 (13.4) | 101.8 (6) | 101.9 (8.9) |
Burkholder et al. [ | 85.7 (19.0) | 95.6 (14.5) | 104.5 (10.7) |
Spain et al. [ | 75.81 | 90.93 | — |
Siger et al. [ | 83.92 (17.63) | 94.38 (15.0) | 100.3 (12.1) |
Pueyo et al. [ | 84.46 | 94.20 | 104.97 |
Zaveri et al. [ | 81.8 (19.3) | 95.6 (15.0) | 104.6 (10.3) |
Pulicken et al. [ | 84.2 (14.7) | 95.9 (14) | 102.7 (11.5) |
Gundogan et al. [ | — | 107.6 (16.3) | 110.9 (10.3) |
Cheng et al. [ | 76.12 (14.92) | 96.45 (11.73) | — |
Fisher et al. [ | 85 (17) | 96 (14) | 105 (12) |
*Heidelberg Spectralis. Value for normals taken from normative database.
MS: multiple sclerosis.
ON: optic neuritis.
On average, 10
A moderate correlation has been found between RNFL thickness and the time from diagnosis of multiple sclerosis [
RNFL thinning is greater when multiple sclerosis patients suffer an optic neuritis [
Optical coherence tomography has become the most useful tool for the diagnosis of macular edema. This is not a common isolated manifestation; however, it could appear in multiple sclerosis patients with intermediate uveitis or as a side effect of therapies.
Costello et al. compared eyes with isolated optic neuritis to eyes with recurrent episodes of patients with different forms of MS and found an additional thinning when the inflammation recurs [
Magnetic resonance image findings are currently considered the most sensitive and reliable markers for assessing inflammatory and axonal pathology in patients with multiple sclerosis. Conventional techniques are designed to be largely sensitive to inflammation (T2-weighted lesions) and not specifically reflect axonal damage with only modest correlation with clinical disability [ brain parenchymal fraction (which computes the volumes of various intracranial compartments and total brain parenchyma) [ diffusion tensor imaging values [ gray matter [ increase in cerebrospinal fluid volume [ magnetization transfer ratio [ T1-lesion volumen [
Frohman et al. studied twelve patients with multiple sclerosis and found that low contrast visual acuity, RNFL thickness, and optic nerve radius were the variables with the highest predictive value in discerning differences between healthy controls and patients. Both the radius of the affected eyes and its fractional anisotropy predicted the RNFL of the affected eye; however, the RNFL thickness was the only independent predictor of lower contrast sensitivity. T1 and T2 lesion volumes, measures of optic nerve atrophy, and measures of grey matter atrophy were related to RNFL thickness, however, they explained only about 20% of variance [
In multiple sclerosis patients without optic neuritis, axonal loss seems to correlate better with MRI parameters than in those that have suffered optic neuritis [
There seem to be different patterns of axonal loss among the different types of multiple sclerosis according to their clinical course (Table
Comparison of RNFL thickness (
RRMS | SPMS | PPMS | Control | ||
---|---|---|---|---|---|
Albrecht et al. [ | 86.91 (21.51) | 70.57 (16.76) | 80.45 (17.76) | 103.4 (10.96) | |
Henderson et al. [ | Non-ON | Not supplied | 88.4 (10.9) | Not supplied | Not supplied |
Pulicken et al. [ | 94.4 (14.6) | 81.8 (15.6) | 88.9 (13.3) | — |
RRMS: recurrent remittent multiple sclerosis.
SPMS: secondary progressive multiple sclerosis.
PPMS: primary progressive multiple sclerosis.
Pulicken et al. also found RNFL thinning in the progressive forms, which was more pronounced than in patients with RRMS [
Costello et al. studied patients who had had isolated optic neuritis (without a diagnosis of MS) and patients who had had an episode of neuritis and were already diagnosed with RRMS, SPMS, or PPMS. Optic atrophy was more severe in the secondary progressive group with more pronounced differences in the temporal quadrant. The differences among multiple sclerosis types are more difficult to appreciate in eyes without optic neuritis [
Total macular volumes also differed between multiple sclerosis disease subtypes, with lower values seen in SPMS [mean (SD], 6.25(0.52] mm3) than in PPMS (mean (SD), 6.57(0.50] mm3) [
Multiple sclerosis patients have worse contrast sensitivity and visual fields if they have suffered an episode of optic neuritis, in accordance with their decreased RNFL thickness, than if they just have subclinical axonal loss [
Visual prognosis after an episode of optic neuritis is good, since approximately three out of four patients retain a visual acuity of 20/20 after 15 years [
Visual acuity in patients with multiple sclerosis without optic neuritis does not differ from healthy controls. However, when tests that explore spatial (Sloan and Pelli-Robson charts) and temporal (frequency doubling technology perimetry) contrast sensitivity are employed, visual function is found to be worse in multiple sclerosis patients when compared to control subjects [
Visual fields may be normal even if RNFL loss is detected: Cheng et al. found no perimetric defects in 4% patients with mean RNFL atrophy and in 18% with at least sectorial atrophy according to normative data [
Patient with multiple sclerosis and severe bilateral RNFL thinning with history of optic neuritis. SD-optical coherence tomography analysis found no further loss during a year.
Lower RNFL values have been correlated with reduced visual acuity and mean deviation. Every 10
Longitudinal studies have been performed to assess changes in RNFL thickness. Talman et al. followed 299 patients with multiple sclerosis for at least six months, with a median followup of 18 months, ranging between 6 months and four and a half years. They found that each year of followup was associated on average with a 2.0
Visual prognosis is much worse if optic neuritis occurs in patients with neuromyelitis optica. Only one episode is capable of producing legal blindness in almost one third of patients and only about 45% of them completely recover visual function [
Comparison of RNFL thickness (
NMO ON eye | NMO fellow eye | MS ON eye | MS fellow eye | Control | |
---|---|---|---|---|---|
Nakamura et al. [ | 63.84 (23.47) | 106.36 (14.55) | 84.28 (14.18) | 109.45 (12.78) | — |
Naismith et al. [ | 54.8 (3.7) | — | 76.5 (2.4) | — | — |
Merle et al. [ | 65.44 (24.19) | 83.85 (24.12) | 106.24 (12.46) |
MS: multiple sclerosis.
NMO: neuromyelitis optica.
The mean RNFL thickness of the unaffected fellow eye in NMO has been found to be greater than the unaffected multiple sclerosis eyes. This sparing of the unaffected felloe eye in NMO compared to MS may be explained by a more common occurrence of subclinical optic neuritis in multiple sclerosis: axonal attrition in multiple sclerosis independent of optic neuritis or an increased predilection of multiple sclerosis lesions in the optic chiasm or tracts [
As in multiple sclerosis, mean RNFL is correlated with best-corrected visual acuity. Studies agree on the fact that there is a critical value of RNFL thickness below which further decreases of the RNFL lead to incomplete visual recovery. This critical value has been set at 71.41
In a retrospective study, Nakamura et al. evaluated the effects of high dose intravenous methyl-prednisolone on the outcomes after optic neuritis in patients with neuromyelitis optica. Early treatment, especially within 3 days after onset, led to a greater probability of preserving an RNFL > 71.41
Even if RNFL loss is greater in NMO as compared to MS, at each level of visual function there was a considerable overlap in OCT measures, limiting the role of OCT to differentiate the two conditions on an individual basis (Figure
Teenager diagnosed of neuromyelitis optica who has suffered bilateral optic neuritis as well as myelitis. Although normative data are not available, the retinal nerve fiber layer thickness measured with optical coherence tomography is extremely low.
Optical coherence tomography confirms the presence of optic disc edema in anterior neuritis, reflected as a thickening of the RNFL.
Axonal atrophy develops after optic neuritis so that six months after the event, the RNFL thickness is predictive of visual and neurological disability. However, it may be more optimally used in little or moderately disable patients.
Optical coherence tomography can detect subclinical axonal loss in patients with normal visual acuity and visual fields. Contrast sensitivity seems to be the most useful test to detect subtle visual impairment.
The temporal quadrant is the most vulnerable to the disease process.
Temporal RNFL thickness may be decreased as soon as two months after the event. Reduced temporal thickness is often the only sign that may differentiate multiple sclerosis patients from healthy subjects and between primary and secondary progressive forms. It may provide important insights regarding relapse related activity in multiple sclerosis patients.
During the progressive phases of multiple sclerosis, axonal loss also occurs at the optic nerve; this axonal loss is detected by OCT as RNFL loss and is greater in the SPMS type.
When multiple sclerosis patients are followedup, an approximate decrease of 2
Brain atrophy is at least moderately correlated to RNFL thickness and multiple sclerosis patients have decreased RNFL thickness even without a history of optic neuritis. These results suggest that the RNFL thinning reflects pathology that extends beyond local injury to the optic nerve by optic neuritis.
A stronger correlation with MRI results is unlikely since axons are not the only component of the brain and because brain atrophy also reflects synaptic changes, loss of myelin, gliosis, and changes in water content.
Visual prognosis is much worse if optic neuritis occurs in patients with neuromyelitis optica, which leads to a more sever thinning of the RNFL when compared to optic neuritis in multiple sclerosis patients.
OCT thus seems to be a promising outcome measure for neuroprotective trials. However, overall RNFL thickness is not always directly correlated with visual function and measuring both mean RNFL thickness and temporal RNFL thickness (usually more related to visual acuity) would require more patients to be included into the studies. Furthermore, it may be difficult to distinguish axonal loss related to age with axonal loss due to the disease process in MS. The relationship between axonal loss and OCT is not clear: future studies need to evaluate it.