The often incomplete recovery of function from relapses in multiple sclerosis (MS) is thought to be related to axonal loss (1). Optic neuritis is a convenient model for studying relapses in MS as it is a typical first presentation of MS. Moreover, optic neuritis can occur as a relapse of MS, and the pathology found in the lesion of optic neuritis is similar to other types of central nervous system lesions found with MS relapses (2). MRI, electrophysiological and clinical measures of anterior visual pathway function have provided insights into the pathophysiological mechanisms associated with relapse and recovery in optic neuritis (3-6).
Several studies using optical coherence tomography (OCT) in patients with optic neuritis and MS have demonstrated retinal nerve fiber layer (RNFL) thinning (7-10). Some have demonstrated a relationship with visual function (8-10) and electrophysiologic measurements (7,8), indicating that the RNFL thinning is of functional relevance and represents axonal loss.
Scanning laser polarimetry (SLP) utilizes a scanning laser ophthalmoscope to determine the peripapillary RNFL thickness, pixel by pixel, by measuring the total retardation of polarized light reflected from the retina. It therefore differs in terms of its physical basis from the interferometry method of OCT. Retardation of light reflected through the birefringent RNFL, which is measured by SLP, has been correlated with RNFL thickness determined by histology of primate retina (11,12). Therefore, SLP has the potential to be a specific measure of axonal loss. Axonal microtubules are believed to be the source of birefringence from the RNFL (13,14). The SLP measure of RNFL thinning distinguishes well between normal and glaucomatous eyes (15), and RNFL thickness measurements correlate with visual field measures in glaucoma (16,17). Previous studies have used SLP to study patients with optic neuritis and MS. One study (18) used an early model of SLP without variable corneal compensation (VCC); the second study (19) used SLP as a tool for detecting the presence of optic nerve disease in MS without presenting any quantitative RNFL data. Two recent studies employing SLP with VCC have detected RNFL thinning in patients with MS, which correlates with some aspects of visual function (20,21) and also the visual evoked potential (VEP) (21). RNFL measurements with OCT and SLP have correlated well (20,21).
In this study, we hypothesized that axonal loss of the RNFL is a major substrate of persistent visual dysfunction following optic neuritis and can be quantified by reduction of RNFL retardation using SLP. The aims of this study were to use SLP to 1) determine the extent of axonal loss following a single episode of optic neuritis with incomplete recovery compared to unaffected fellow eyes and healthy control eyes, 2) look for a relationship between the degree of axonal loss in patients and the degree of residual visual dysfunction measured clinically and electrophysiologically, and 3) compare these findings with those obtained in a previous study of the same cohort using OCT (8) and with 2 recent SLP studies in MS (20,21).
The patients and controls in this study were the same as those in a previous OCT study (SLP and OCT were performed on the same day) where full details of the subjects' demographics and visual function have previously been reported (8) (Table 1). Twenty-five patients who had a single clinical attack of acute unilateral optic neuritis at least 1 year previously without recurrence were recruited from the case records of the Neuro-ophthalmology Clinic, Moorfields Eye Hospital, London, England. Fourteen had clinically isolated optic neuritis and 11 had MS (22). Appropriate tests had been performed to exclude alternative diagnoses where indicated. A selection bias was introduced toward those with incomplete visual recovery in order to study a range of visual deficits. This bias was introduced by preferentially selecting patients who had a last documented visual acuity worse than 20/20, a persisting visual field abnormality or impaired color vision on testing with Ishihara plates. Fifteen control subjects were recruited, none of whom had any ophthalmological or neurological disorder.
Approval for the study was obtained from the joint Ethics Committee of the Institute of Neurology and the National Hospital for Neurology and Neurosurgery, which was accepted by the Moorfields Eye Hospital Research Governance Committee. Informed consent in writing was obtained from all subjects, in accordance with the Declaration of Helsinki.
Scanning Laser Polarimetry
SLP images were acquired with a GDxVCC device and software (Carl Zeiss Meditec, Dublin, CA; software version 5.5.0). All subjects had an ametropia <10 diopters. Scans were performed at the Glaucoma Research Unit, Moorfields Eye Hospital by an examiner who was masked to the clinical status of each subject. The GDxVCC incorporates a variable corneal compensator to achieve individualized anterior segment retardation compensation. One scan was acquired for each eye through an undilated pupil. Measurements were calculated from a measurement annulus centered on the optic disc with an internal diameter of 2.4 mm and an external diameter of 3.2 mm. The mean total RNFL thickness around the optic disc was obtained, and the RNFL thickness in quadrants (temporal, superior, nasal, and inferior) was derived for comparison with corresponding regions of the visual field. A previous study of reproducibility of GDxVCC mean RNFL measurements produced coefficient of variation values as low as 3.67% (23).
Optical Coherence Tomography
OCT images were acquired as described previously (8) with a Stratus OCT Model 3000 (Carl Zeiss Meditec, Inc). Pupils were dilated if imaging was impaired by a small pupil size. The Stratus OCT device and software were used to acquire three 3.4-mm-diameter circular scans centered on the optic disc for each eye. The mean was used to express RNFL thickness as a single average value for the whole 360° scan and also as RNFL quadrants (temporal, superior, nasal, and inferior). Macular thickness was measured once for each eye by means of 6 radial lines to compose a macular thickness/volume map.
Visual Function Testing
The visual function testing methods (8) were as follows. A retroilluminated Early Treatment Diabetic Retinopathy Study chart was used to measure visual acuity, with appropriate refractive correction, and was recorded as the 4m logMAR (minimum angle of resolution) acuity. The 30-2 program of the Humphrey field analyzer (Carl Zeiss Meditec) was used to assess the visual field and the visual field mean deviation (MD). The visual field data were divided into 4 sectors based on the relationship between the optic disc and the central field, derived from a previously published optic disc-visual field map (24). The RNFL quadrants from SLP correspond to these 4 visual field sectors. One patient was unable to reliably complete automated perimetry and had high levels of fixation losses and false-negative responses, despite having near-normal acuity and normal visual fields by clinical examination. The Farnsworth-Munsell 100-hue test (25) was used to assess color vision and was scored as a square root of the error score (√FM 100-hue score) because this follows a normal distribution in controls. Two patients with a congenital anomaly of color vision did not complete this test.
VEPs were recorded to monocular stimuli using skin-surface electroencephalographic electrodes attached over the occiput 5 cm above the inion and referred to a frontal electrode at Fz (10-20 System). The ground electrode was at Cz. The interelectrode impedance was less than 5 kilohms, and the gain was 10,000. The mean luminance of the screen was 32 cd/m2 and the contrast 93%. The analysis time was 250 milliseconds. Two repetitions of each VEP were recorded to ensure reproducibility and subsequently averaged together. The stimuli comprised reversal of a checkerboard pattern in the whole field and in the central field (26). Central field responses were unobtainable in 1 patient and 1 control. The pattern electroretinogram (PERG) was recorded to binocular stimulation of the whole field, subtending 28° horizontally by 20° vertically, using corneal surface electrodes (DTL Plus; Retina Technologies, Scranton, PA) referred to skin-surface electrodes over the ipsilateral outer canthus. Forty-minute check sizes were used, reversing 4.3 times per second. The luminance of the bright squares was 60 cd/m2 and of the dark squares was 4 cd/m2. The amplifier corner frequencies were 1 and 1,000 Hz. The sampling rate was 3 samples per millisecond, and the sweep duration was 170 milliseconds. We made 3 averages of 200 responses and subsequently averaged them together. Sweeps containing artifacts of more than 165 μV were automatically rejected.
These studies were performed in accordance with standards of the International Society for Clinical Electrophysiology of Vision (ISCEV). Analysis was performed by investigators who were masked as to the status of each subject.
SLP data were expressed as absolute values for the patient's affected and unaffected fellow eyes and for one randomly selected eye from each control. Differences between patients and controls are reported from 2 sample t tests. Linear regression was used to confirm that there was no confounding by age or gender and to investigate possible differences between patient subgroups. Paired t tests were used to investigate differences between affected and unaffected fellow eyes in patients.
The relationship within patients between pathologically induced changes in RNFL thickness and functional measures was studied. Because there is considerable interindividual variability in RNFL thickness within the normal population, it is better to investigate the relationships between affected eye values while adjusting for unaffected eye values as regression covariates (since the unaffected patient eye can also sometimes have subclinical abnormality (27), this approach can underestimate pathology and lead to conservative results). Accordingly, relationships between visual function (or electrophysiological variables) and SLP measures were investigated using linear regression of the affected eye visual function (or electrophysiological measure) on affected eye SLP measure, with unaffected eye visual function (or electrophysiological measure) and SLP measures as covariates. Similar regressions were used to investigate quadrant-specific relationships and with patient subgroup interaction terms to investigate whether the associations varied by clinical subgroup (clinically isolated optic neuritis or MS). Possible confounding by age and gender was investigated in the regressions, and these covariate terms were retained in models where they contributed at P < 0.05. For some relationships, 2 potentially influential outliers emerged, and results both with and without these are reported where their exclusion materially altered model conclusions. Analyses were implemented in Stata 9.2 (Stata Corporation, College Station, Tx).
SLP data from this study were compared with OCT data from the same cohort (8), using Bland-Altman plots (28), and mixed effects linear regression analysis (to allow inclusion of both patient eyes), in order to determine whether there was agreement between the 2 devices.
Differences in Retinal Nerve Fiber Layer Thickness Between Patients and Controls
The average RNFL thickness in affected eyes from patients was significantly reduced compared to that in clinically unaffected fellow eyes and control eyes (Table 2). There were no significant differences in visual function or RNFL thickness between the patients with MS and those with clinically isolated optic neuritis.
Relationship Between Retinal Nerve Fiber Layer Thickness and Visual Function in Affected Patient Eyes
Reduced RNFL thickness was associated with significantly worse visual function in terms of logMAR visual acuity, visual field (MD), and color vision (√FM 100-Hue score) (Table 3). These relationships, which remained significant whether or not 2 outliers were included, are graphically represented in Figure 1 (in order to simplify graphical presentation of these fellow eye-adjusted associations, the corresponding affected minus unaffected fellow eye values are illustrated).
Relationship Between the Retinal Nerve Fiber Layer Quadrant Thicknesses and Their Corresponding Visual Field Sectors in Affected Patient Eyes
A 1-μm reduction in superior and inferior RNFL quadrant thickness was related to a −0.17 dB (95% confidence interval [CI], −0.22 to −0.11; P < 0.001) and a −0.10 dB (95% CI, −0.19 to −0.02; P = 0.02) decrease in the superior and inferior visual field sectors' MDs, respectively. There was no association between the nasal and temporal RNFL quadrants and their corresponding visual field sectors.
Relationship Between the Retinal Nerve Fiber Layer Thickness and Electrophysiology in Affected Patient Eyes
Reduced RNFL thickness correlated with reduced whole field and central field VEP amplitudes. The latter relationship became substantially more significant when 2 outliers were excluded (Table 3). There was no relationship between RNFL thickness and VEP latency or PERG amplitudes or latencies.
Agreement and Relationship Between Scanning Laser Polarimetry and Optical Coherence Tomographic Retinal Nerve Fiber Layer Findings
Mixed effects linear regression analysis was performed on all of the patient and control nerves (n = 65). The regression coefficient was 1.93 (P < 0.001) with a constant of −12.8 μm producing the equation: oct = 1.93 × slp − 12.8 where oct is the OCT-quantified RNFL thickness (μm) and slp is the SLP-quantified RNFL thickness (μm). The relationship was not affected by either subject status or disease status of the eye. The regression plot is shown in Figure 2.
The agreement between oct and slp in affected eyes was assessed by Bland-Altman plots. The difference between oct and slp measurements increased as the RNFL thickness measurement by each device increased. Therefore, it was advisable to use a log transformation of oct and slp. The Bland-Altman plot produced a mean difference of log(oct) − log(slp) = 0.42, which transforms to a ratio on the raw scales for oct:slp of 1.52; 95% of observed ratios between the measures are predicted to lie within the 95% limits of agreement: 1.08, 2.15.
The Bland-Altman plots were repeated for unaffected fellow eyes and control eyes combined, and again the difference between oct and slp increased with increasing oct and slp. Therefore, it was necessary again to use a log transformation of oct and slp. The Bland-Altman plot produced a mean difference of log(oct) − log(slp) = 0.54, which transforms to a ratio on the raw scales for oct:slp of 1.72; 95% of observed ratios are predicted to lie within the 95% limits of agreement: 1.30, 2.28.
SLP using the GDxVCC device was able to detect mean reductions in RNFL thickness in affected patient eyes of 23% and 20% compared to that in control eyes and unaffected patient eyes, respectively, values that were highly statistically significant (Table 2). The mean decrease of 4% in RNFL thickness in unaffected patient eyes relative to control eyes was not statistically significant.
The first study to employ SLP in patients with optic neuritis (18) used an early commercially available model, which had fixed corneal compensation (FCC) rather than the VCC used in the present study. The disadvantage of FCC compared to VCC is that it does not permit individualized correction of anterior segment birefringence, resulting in inaccurate RNFL measurements. Accordingly, we cannot use that study for comparison (29).
Two recent studies have used SLP with VCC to study patients with MS (20,21). Zaveri et al (20) studied 155 eyes from 80 patients with MS and 85 eyes from 43 controls. RNFL thickness in the 68 eyes affected by optic neuritis was reduced by 14% compared to that in control eyes. Pueyo et al (21) studied 100 eyes from 50 patients with MS and 25 eyes from 25 controls. RNFL thickness in the 25 eyes affected by optic neuritis was also reduced by 14% compared to that in control eyes. Given that the same GDxVCC technology was used in these studies, the greater reduction in RNFL thickness in our study can be explained by the deliberate bias toward incomplete visual recovery.
In our study, RNFL thinning was significantly related to measures of visual acuity, visual fields, and color vision, replicating the findings of the previous OCT study of this cohort (8). As for OCT, the SLP-measured superior and inferior RNFL quadrants (but not the temporal or nasal quadrants) were related to their corresponding visual field sector measures, supporting a structure-function relationship with both devices. The lack of correlation in the temporal and nasal quadrants in this study and the previous OCT study could be explained by the fact that the nasal and temporal RNFL are thinner than the superior and inferior RNFL (30) and the OCT and SLP devices may be less sensitive in detecting change in these thinner sectors. Also, these RNFL quadrants are responsible for a relatively smaller area of the central visual field (24), and the number of perimetry test points in the nasal and temporal sectors is significantly less than in the superior and inferior sectors-reduced sampling could contribute to the lack of correlation in these sectors. In addition, the lack of correlation in the temporal sector may be due in part to differences in spatial summation in the central field served by the temporal RNFL (31).
Zaveri et al (20) found relationships between SLP-quantified RNFL thinning and low-contrast letter acuity and, to a lesser extent, high-contrast letter acuity. No other visual function tests were performed. Pueyo et al (21) demonstrated correlations between SLP-quantified RNFL thinning and high-contrast acuity and visual field MD. These findings were replicated in our study.
The pattern of the relationships between SLP-measured RNFL thickness and the electrophysiological parameters mirrors that seen in the OCT study. Reductions in whole field-VEP and, to a lesser extent, central field-VEP amplitude were related to RNFL thinning. No relationships were evident with VEP latencies or with the PERG. These findings indicate that SLP-detected RNFL thinning is related to an electrophysiological measure of optic nerve axonal functional integrity. Two of the previous SLP studies did not include electrophysiological testing (18,20), but Pueyo et al (21) did show that RNFL thinning was correlated with VEP amplitude and latency. They proposed that their additional finding of an association with VEP latency might be due to the presence of MS in their study cohort, predisposed this group to greater degrees of demyelination.
The absolute values for RNFL thickness quantified by OCT and SLP cannot be directly compared because of the fundamental difference in the physical basis of the 2 imaging techniques. OCT is based on the principle of interferometry. The RNFL thickness is derived from the distance between the first imaging reflection from the retinal surface and the bottom of the RNFL. The latter has been defined by a threshold change in the refractivity of the retinal tissue, indicating a change in the nature of the retinal tissue as it moves from the RNFL to deeper retinal layers. However, the definition of the bottom of the RNFL measurement has not been rigorously proven (32). SLP utilizes the ability of a birefringent structure, in this case, the RNFL, to retard 1 vector of polarized light that passes through it. The amount of retardation is used to calculate the thickness of the RNFL. Retardation correlates with histological RNFL thickness in primate retina (11,12). The absolute RNFL thickness values produced by either device have not been definitively validated in postmortem human studies. A problem of such an investigation is the propensity for the RNFL to swell or shrink after fixation (33). It is therefore unclear at this time what the true in vivo values are for RNFL thickness.
The ability of Stratus OCT and GDxVCC to discriminate between normal and glaucomatous eyes has been studied (34,35), but there are few data directly comparing the relationship between RNFL values produced by the 2 devices. Leung et al (36) studied healthy controls and patients with glaucoma using Stratus OCT and GDxVCC. They found that RNFL thickness measured by the 2 devices correlated well together with r = 0.852 using linear regression analysis. The analysis looked at the strength of the relationship between the 2 measures but not assess the agreement between them. The latter requires the construction of Bland-Altman plots (28). Shewry et al (37) also attempted to address the issue of agreement between Stratus OCT and GDxVCC by studying normal, ocular hypertensive, and glaucoma subjects. They used linear regression analysis and Bland-Altman plots to investigate the relationship and agreement between the devices. The data have only been published in abstract form, and only the regression data were presented. When the regression was forced through the origin, the equation oct = 1.8 × slp was produced (P < 0.001 for the regression coefficient), which suggested that there was a scaling factor of 1.8 between the 2 devices.
As the present SLP study and previously published OCT study (8) both used the same patient and control eyes studied at the same time, there was an opportunity to study the relationship between RNFL values measured by the 2 devices in optic neuritis, although the study was not specifically designed and powered to evaluate this relationship. Using the linear regression method employed by Shewry et al (37), a similar equation was produced: oct = 1.93 × slp − 12.8 (P < 0.001 for the regression coefficient). Furthermore, the relationship was not affected by subject status or disease status of the eye, suggesting that there is a true scaling factor between the measurements produced by the 2 devices. However, the observed regression coefficient can only be a rough guide to the true relationship because of measurement error in both variables. Agreement was assessed with Bland-Altman plots, which produced oct:slp ratios in the same order of magnitude to the scaling factor produced by linear regression but with wide 95% limits of agreement. This suggests that the 2 devices have only a modest level of agreement when applied to the subjects in this study despite producing RNFL values showing a good relationship with regression analysis. This may be partly explained by the low subject numbers in this study.
Zaveri et al (20) have previously compared OCT and SLP RNFL measurements in the same patients using linear correlation and stated that there was a significant yet moderate relationship (r = 0.67; P < 0.001). Pueyo et al (21) also found a similar degree of correlation (r = 0.60; P < 0.0005). Neither study specifically looked at agreement between the measurements from the 2 devices. New generation OCT uses techniques with higher sensitivity, for example, spectral domain OCT (38). These contemporary OCT techniques may provide different results to Stratus OCT, and further comparison of SLP with spectral domain OCT will be informative.
This study has shown that SLP using GDxVCC is able to detect functionally relevant axonal loss in the RNFL of eyes affected by optic neuritis and thus replicates the findings of a previous OCT study of the same cohort and replicates the findings of 2 recent SLP studies in patients with MS (8). In addition, there appears to be a scaling factor between the RNFL values produced by the 2 devices, but there is only modest agreement between OCT and SLP in this study. SLP may have similar potential to OCT in the study of axonal loss in optic neuritis and MS and could be used to monitor the efficacy of future neuroprotective therapies in clinical trials.
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