Our findings corroborate the results of prior studies that have found RNFL thickness reduction is more pronounced in MS eyes with a history of acute optic neuritis.12,14,22,23
In addition, we have shown an association between abnormal mean RNFL thicknesses and classification of eyes by neurologists as having optic atrophy and between abnormal mean RNFL ratios and detection of APDs. This finding provides evidence that clinical signs of optic atrophy and RNFL thicknesses determined by OCT evaluation are evaluating similar clinical phenomena.
As expected, in this cohort the probability of classifying eyes as having optic atrophy or as having an APD during clinical examination increased as the severity of RNFL defects increased. Using the OCT software 5th percentile cutoff for abnormal, our data suggest that OCT can detect more retinal abnormalities than are observed by clinical examination of optic atrophy or APD, at least among a cohort of academic neurologists. Furthermore, these results indicate that a substantial degree of axonal loss in the RNFL and optic nerve occurs before eyes are classified as having optic atrophy or an APD.
While the sensitivity of detecting clinical abnormalities increased as the severity of RNFL abnormalities increased in both the overall study cohort and within the subcohorts examined by each physician, neurologists' likelihood to classify eyes as having optic atrophy and APDs at a given severity of RNFL defects varied substantially. Whether this difference was due to a physician's clinical experience and training, the assortment of patients encountered by each physician, or both is unclear. If clinical experience was a factor, additional training in the examination of the optic nerve and retina may be beneficial during neurology residency and subspecialty training. In addition, OCT could be useful as a training tool to correlate with clinical findings. However, these data must also be interpreted with caution, as the measures of sensitivity and positive predictive value are estimated with poor precision within each physician due to the small number of patients examined by each physician.
Few studies have assessed the association between clinical examination and OCT findings. One recent study compared RNFL defects in patients with retinitis pigmentosa to detailed funduscopic examinations.24
All patients with moderate to severe optic atrophy and retinal abnormalities on funduscopic examination had at least 1 quadrant or 2 clock-hour segments with abnormal RNFL thicknesses. Only 7% of individuals with normal optic discs or mild disc pallor had an abnormal quadrant thickness, and only 13% had an abnormal clock-hour thickness measure. The investigators concluded that RNFL thinning could be present in patients with normal-appearing optic discs during the clinical examination and in patients without significant loss of visual acuity. However, the probability of RNFL thinning increased with the severity of optic atrophy. The results of our study are remarkably similar. For example, eyes classified as having optic atrophy in our cohort averaged more than 1 quadrant and more than 2 clock-hour segments with abnormal RNFL thickness measures ().
Two human studies and 1 animal study investigating the correlation between APDs and mean RNFL ratios have been reported.19–21
In both human studies, APDs were quantified using log-scaled neutral density filters over the unaffected eye during the swinging flashlight test. In a study of 20 patients with unilateral optic atrophy of various etiologies, the mean RNFL thickness of the affected eye was significantly less than the unaffected eye, and the correlation coefficient between a clinically detectable APD and the mean RNFL ratio was 0.48.20
In addition, the investigators found that an APD was clinically undetectable until the mean RNFL ratio was ≤0.75. In a similar study in 29 patients with glaucoma, the correlation coefficient between an APD and mean RNFL ratio was 0.49, and an APD was clinically undetectable until the mean RNFL ratio was ≤0.73.21
In this study, too, the mean RNFL thickness in the affected eye was significantly less than in the unaffected eye. A study in monkeys investigating the correlation between an APD and RNFL thickness also found that a 25% to 50% decrease in RNFL thickness was necessary to produce a clinically detectable APD.19
Despite the more quantitative methods used to detect APDs in the previously reported studies, our results were similar. In our cohort, mean RNFL thickness was also significantly less in eyes in which an APD was detected than in eyes without an APD (). While a significant increase in sensitivity was seen when the threshold for an abnormal RNFL ratio was decreased from 0.80 to 0.70 ()—a level consistent with the findings of the previously reported studies—most APDs identified in this study were detected at RNFL ratios >0.7. This may be the result of noise from the poor resolution and high coefficient of variance of OCT, which is one limitation to its clinical utility.
Despite the consistency of these results with previously published studies, our study has several limitations. While each neurologist included in the analyses examined at least 15 patients, none of the patients was examined by more than 1 physician. Therefore, we cannot directly compare agreement between neurologists' classifications of optic atrophy and APDs among the same cohort of patients. In addition, only 1 OCT evaluation was performed on each eye in study participants. Using average RNFL measurements obtained from repeated scans would help reduce random noise and variability associated with OCT RNFL measurements. Another important limitation is the multiple etiologies of optic nerve disease among our study cohort. It is possible that each disease etiology could have a different relationship between detection of optic atrophy or an APD and RNFL thickness reduction. However, the majority of patients in our cohort had demyelinating disorders and most had a diagnosis of MS, making significant pathophysiologic heterogeneity unlikely.
Clinical and OCT examinations were also performed during routine neurologic clinic visits. While physicians were blinded to the results of the OCT examination, they did have knowledge of a patient's clinical history, including whether a history of optic neuritis was present and results of previous investigations that had been performed. This is appropriate in the clinical setting, as it cannot be overemphasized that the identification of true optic atrophy does depend upon the presence of suggestive clinical findings, including visual dysfunction, color desaturation, and the APD.
However, due to concern that knowledge of ON history would bias the clinical assessment, we also analyzed the data after excluding eyes with a known history of ON. While the differences in OCT characteristics between eyes with and without optic atrophy remained significant, the differences between eyes with and without APD were no longer significant. Whether the loss of significance was due to eliminating bias obtained from clinical history or to the small number of eyes with APD remaining in this analysis (n = 44 eyes with APD when ON eyes are included; n = 16 eyes with APD when ON eyes are excluded) is difficult to determine.
In addition, OCT and clinical examinations were performed by non-ophthalmologists on undilated eyes and did not incorporate equipment such as red-free filters for ophthalmoscopy, neutral density filters, infrared pupillography, or stereo fundus photographs. Optic atrophy was identified in only 34% of patients with a history of optic neuritis, which is a lower proportion than expected. However, we purposed to examine whether OCT may provide useful information to supplement clinical examination in everyday outpatient practices. Therefore, we did not provide specialized training in the identification of atrophy or APD. It is therefore not surprising that clinical assessments were heterogenous among participating neurologists, since they relied upon the physicians' prior knowledge and skills. However, despite the nonstandardized examination conditions, our results are remarkably similar to previously published results in study cohorts with different diagnoses and are potentially applicable to routine clinical practice.
Finally, the lack of a detailed ophthalmologic assessment of study participants limited our ability to adjust for factors that may have influenced RNFL thickness or funduscopic findings suggestive of optic atrophy. Previous studies have found that increased ophthalmic axial length, decreased optic disc area, and myopia are associated with thinner RNFL measurements in normal and abnormal eyes independent of disease processes.25–27
However, these variables were not measured for study participants, so RNFL measurements could not be adjusted for these factors in our statistical analyses. In addition, a recent report demonstrated that visual evoked potentials were more sensitive than OCT in detecting optic neuritis. However, because demyelination alone does not cause optic atrophy, we believe OCT was the best method with which to associate atrophy as they represent axonal loss.28
Despite these limitations, our results add to the growing literature suggesting that OCT may allow for earlier detection of MS axonal loss in the visual pathway as measured by RNFL defects. Our study also supports the utility of OCT as a structural marker of axonal loss in clinical trials of neuroprotective drugs, and suggests a future clinical role. Our results demonstrate that OCT evaluation may be a useful adjunct to routine clinical management of patients with demyelinating and axonal degenerative disorders and may well provide complementary and confirmatory information to that which can be obtained from clinical examination. Earlier and more accurate detection of RNFL defects using OCT may be indicative of subclinical disease activity and could allow for earlier and more aggressive disease management.