Journal of Neuro-Ophthalmology:
Should Optical Coherence Tomography Be Used to Manage Patients With Multiple Sclerosis?
Costello, Fiona MD, FRCP; Van Stavern, Gregory P. MD
Section Editor(s): Lee, Andrew G. MD; Biousse, Valérie MD
MS Clinic, Department of Clinical Neurosciences; Department of Surgery; Hotchkiss Brain Institute; and Foothills Medical Centre, University of Calgary (FC), Calgary, Alberta, Canada
Departments of Ophthalmology and Visual Sciences, and Neurology, Washington University School of Medicine (GPVS), St Louis, Missouri.
Address correspondence to Gregory P. Van Stavern, MD, Departments of Ophthalmology and Visual Sciences, and Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110; E-mail: firstname.lastname@example.org
Dr Costello has received grant support from the Canadian National Institute for the Blind (E.A. Baker Foundation); the Multiple Sclerosis Society of Canada; Neurosciences Canada; Networks of Centres of Excellence; and Stem Cell Network.
The authors report no conflict of interest.
Over the past decade, optical coherence tomography (OCT) has become widely used in neuro-ophthalmology, mostly to assess the thickness of the peripapillary retinal nerve fiber layer (RNFL) and macular volume (1,2). OCT allows for objective and quantitative assessment of structural damage in the visual pathways, with a multitude of clinical and research applications. Thinning of RNFL and loss of macular volume have been found in multiple sclerosis (MS) patients, both with and without distinct episodes of optic neuritis (ON) suggesting ongoing loss of axons and neurons within the anterior visual system (1–3). There is strong evidence that accrual of neurologic dysfunction in MS correlates best with axonal and neuronal loss (rather than demyelination), but the magnetic resonance imaging (MRI) techniques available to measure such loss are cumbersome, expensive, and time consuming. OCT has emerged as a noninvasive and relatively inexpensive technique for capturing what we infer to be loss of central nervous system (CNS) axons and neurons.
Whether OCT should be used mostly as an outcome measure in clinical trials or routinely to evaluate and follow patients with optic neuropathies, particularly those with ON and demyelinating disease, remains debated, as illustrated by the case below.
A 31-year-old Caucasian woman was evaluated in the neuro-ophthalmology clinic for subacute painful visual loss in the right eye. Her examination was consistent with an isolated right retrobulbar optic neuropathy. She was diagnosed with right optic neuritis, likely secondary to demyelinating disease. She reported episodes of tingling over her left arm, and her brain MRI demonstrated multiple white matter lesions, some of which enhance. The diagnosis of clinically definite MS was made. She received intravenous methylprednisolone and was started on immunomodulating treatment for MS. Her visual function recovered over a few weeks, and she developed mild right optic nerve pallor. The treating neurologist requests a baseline OCT of the peripapillary RNFL.
PRO—OCT Should Be Obtained in This Patient: Fiona Costello, MD, FRCP
In my opinion, a baseline OCT should be obtained to better understand what the diagnoses of ON and MS may mean for this patient.
In the case provided, the patient has experienced a clinical episode of ON in the right eye, whereas the left eye is presumed to be normal. Previous OCT studies have demonstrated that RNFL measurements and macular volumes are lower in both the ON eyes and presumed unaffected eyes of MS patients relative to healthy controls (Fig. 1) (3–6). A recent systematic review and meta-analysis of time-domain OCT (TD-OCT) studies showed an estimated RNFL loss of −20.38 μm (95% confidence interval, −22.86 to −17.91) in the ON eyes of MS patients as compared to control eyes (6). In eyes with no evidence of ON, TD-OCT measured RNFL values were reduced by −7.08 μm relative to the eyes of healthy controls, and the estimated RNFL loss in ON eyes vs unaffected eyes of MS patients was –14.57μm (95% confidence interval, −16.50 to −12.63) (6). One advantage to obtaining a baseline OCT scan would be to better define the extent of anterior visual pathway damage and CNS involvement in this patient.
While the diagnoses of ON and MS seem quite straightforward in the case provided, distinguishing ON in MS patients from ON associated with neuromyelitis optica (NMO) can at times be challenging. This has important clinical implications because early initiation of immunosuppressive therapy can prevent vision loss and reduce neurological disability in NMO patients. In patients with prior unilateral ON, an intereye difference in RNFL thickness exceeding 15 μm is more commonly seen in NMO patients (75%) compared to patients with relapsing-remitting MS (24%) (Fig. 2) (7). It has been suggested that NMO-IgG antibody testing not only be considered for patients with a history of bilateral ON, poor visual recovery, but also when there is an intereye asymmetry in RNFL thickness exceeding 15 μm 3 or more months after an ON event (7).
In the case provided by Drs Lee and Biousse, quantifying the intereye asymmetry in RNFL thickness with a baseline OCT will likely lend further support for the diagnosis of relapsing‐remitting MS. Furthermore, for patients who experience incomplete recovery from ON and/or lack classical MRI evidence of MS, a baseline OCT could aid in the early diagnosis of NMO.
From the Optic Neuritis Treatment Trial (ONTT), we have learned that most ON patients recover normal high-contrast visual function (mean visual acuity at 1 year after entry into the ONTT was better than 6/5 [Snellen equivalent], with less than 10% of patients having a visual acuity worse than 6/12) (8,9). High-contrast visual acuity testing is known to be a relatively insensitive means of capturing visual dysfunction in MS patients (1,5). Vision after ON can be highly variable, with patients frequently reporting symptoms of heat-associated vision loss (Uhthoff symptom), problems with motion perception, and fatigue-related visual dysfunction. Previous OCT studies have shown robust correlations between lower RNFL values and reduced visual function scores after ON (1,3–6,10), providing a structural basis for the functional deficits frequently reported by MS patients. Below a threshold RNFL thickness of approximately 75 μm, there is a corresponding decrease in visual recovery after ON (1,10). Therefore, obtaining an OCT in this case could be helpful in establishing the relation between structural integrity and functional recovery in the anterior visual pathway for this patient, using ON as a single-lesion relapse model of MS.
There is some debate about whether RNFL loss in the absence of ON occurs in an insidious progressive manner or arises as a consequence of episodic inflammatory insults to the anterior visual pathways in MS patients (10–12). In a prior prospective case series, serial OCT measurements were used to detect subclinical ON in previously unaffected eyes of ON patients (10). In these cases, the patients did not report a history of pain or vision loss, but ophthalmic testing showed a new visual field deficit, an abnormal visual evoked potential, and newly detected thinning of the RNFL to support the diagnosis of subclinical ON (10). More recently (12), OCT testing performed in 299 patients (593 eyes) with at least 6 months of follow-up showed that RNFL thinning increased over time, with average losses of 2.9 μm at 2–3 years and 6.1 μm at 3–4.5 years. The pooled analysis (MS and ON affected and unaffected eyes) in this study showed that each year of follow-up was associated with an average 2-μm increase in RNFL thinning (P < 0.001, generalized estimating equation models) (12). From their findings, the authors concluded that progressive RNFL thinning occurs over time in MS, even in the absence of ON (12). Obtaining a baseline OCT in concert with ophthalmic testing could potentially provide the means to monitor RNFL thinning over time; and in turn, provide insights into mechanisms of brain injury and neurological disability in this patient, by distinguishing episodic inflammatory events from insidious disease progression.
MS traditionally has been viewed as an inflammatory demyelinating disorder of the CNS. Recently, the contributions of early axonal damage and neuronal loss toward neurological disability in MS patients have gained greater recognition. A recent study suggested that OCT testing may have identified a unique subset of MS patients, referred to as the macular thinning predominant phenotype. These patients manifested disproportionate thinning of the inner and outer nuclear layers, secondary to a presumed primary retinal pathology. Patients with the macular thinning predominant phenotype had worse overall neurological disability, with primary neuronal loss as a possible underlying disease mechanism. The findings from this study may indicate a potential role for OCT as a method of distinguishing different disease mechanisms in MS patients. As our knowledge regarding the interpretation of OCT findings in MS continues to evolve, we may gain insights that challenge conventional wisdom and advance our current understanding disease mechanisms and potential treatments for MS. For this reason, I would obtain a baseline OCT in this patient so that I may learn more about the potential factors that contribute to neurological disability in MS, which could enhance my ability to care for these patients in the future.
CON—OCT Is Not Necessary in This Patient: Gregory P. Van Stavern, MD
Although there is considerable evidence that OCT-measured RNFL values correlate (to some degree) with impaired visual and neurologic function, the degree to which this information can impact the day-to-day clinical management of ON and MS remains uncertain. I do not believe that we currently have enough evidence to justify the routine use of OCT and OCT-measured RNFL thickness in the management of ON and MS.
The utility of any clinical diagnostic test ultimately rests upon the degree to which it influences clinical decision making. In this context, we can envision several potential uses for OCT in daily practice, including to 1) establish a diagnosis in symptomatic patients, 2) screen for disease in asymptomatic patients, 3) provide prognostic information in patients with established disease, and 4) monitor efficacy of therapy, or progression of disease with or without therapy.
As the acute and chronic changes in RNFL and macular volume are nonspecific and can occur in a wide variety of ophthalmic diseases (14), OCT plays no major role in the clinical diagnosis of either typical ON or MS aside from screening for other conditions that can mimic ON (Fig. 3).
Early loss of RNFL after acute ON has been shown to predict incomplete recovery. A 2010 study (11), building on previous work by Dr Costello et al (10) described 23 patients with acute, clinically isolated ON, who had an OCT performed at baseline followed at 6, 12, and 18 months. Measurements included RNFL and macular volume. The mean time to loss of 90% of initial RNFL was 2.38 months. Baseline RNFL thickness did not differentiate patients destined for poor visual recovery from those with good visual outcome. Those subjects with poor final visual outcome showed a significantly greater decrease from baseline RNFL to 3-month value, but only 5 subjects had poor recovery. At 12 months, RNFL thickness significantly correlated with logarithm of the minimum angle of deviation visual acuity, visual field mean deviation, and impaired color perception. Although these and other studies (10,15) have suggested a potential “window of opportunity” for intervention with a neuroprotective agent, sample sizes have been relatively small, and only 1 group (11) studied patients using a prospective rather than cross-sectional design. The fact remains that to date, no such neuroprotective agent exists, and even if one emerges, it will need to pass multiple hurdles before becoming widely available for clinical practice.
Few studies have explored the potential role of OCT in predicting conversion to MS in patients presenting with ON as a clinically isolated syndrome (CIS). Dr. Costello et al (16) retrospectively compared RNFL thickness in ON eyes vs non-ON eyes between groups of patients who developed MS and those who did not 2 years after an ON CIS. Temporal quadrant RNFL values were lower in the non-ON eyes of MS patients, but this difference was not statistically significant. These investigators concluded that RNFL thickness did not reliably identify patients at a higher risk for developing MS. Another group (17) studied 56 consecutive patients with CIS (18 with ON, 38 with non-ON CIS) and 32 controls subjects. Global and quadrantic RNFL values, as well as macular volume measurements, were obtained in all subjects. Their results showed that patients who developed clinically definite MS (n = 13) or those meeting the McDonald criteria (n = 23) did not have more severe RNFL atrophy or more macular volume loss. They also found no association between RNFL thickness and dissemination in space by Barkhof criteria or revised McDonald criteria at initial MRI, gadolinium enhancement at initial MRI, or development of MS at 6 months. They concluded that OCT measurements (both RNFL and macular volume) did not predict conversion to MS at 6 months.
NMO is an immune-mediated inflammatory disorder associated with preferential involvement of the optic nerve and spinal cord, and can present as demyelinating ON. There is good evidence that NMO is a distinct disease from MS, with poorer visual and neurologic outcomes and lack of response to conventional MS therapy (18). The ON associated with NMO is typically bilateral rather than unilateral, but is in many ways indistinguishable from MS-related ON. RNFL measurements could potentially serve as a biomarker to distinguish between NMO and MS, perhaps early enough to influence therapy. Several studies have found lower RNFL and macular volume measurements in patients with NMO vs MS. In a study of 47 patients with MS and 22 subjects with NMO, NMO-related ON eyes had lower RNFL values compared with MS (19). However, there was considerable overlap of OCT measures at each level of visual function, limiting the diagnostic utility of the test in an individual patient. In addition, subjects were not screened for other ophthalmic conditions known to alter RNFL, such as glaucoma and high myopia. Finally, the authors did not report what they considered an acceptable level for signal strength on OCT. Ratchford et al (7) measured RNFL thickness in 26 patients with NMO, 378 patients with transverse myelitis, 378 patients with relapsing-remitting MS, and 77 controls. The authors found significant thinning of RNFL in NMO-ON eyes relative to relapsing-remitting MS-ON eyes and control eyes and argued that substantial RNFL thickness after an episode of ON should raise suspicion for NMO. However, standard high-contrast visual acuity measurements were also significantly worse in NMO-ON eyes relative to the other groups, and there was no significant difference among groups in RNFL thickness in non-ON eyes. A recent study (20) compared the results of automated perimetry in patients with NMO-related ON and MS-related ON and found that visual field mean deviation was significantly greater in the NMO-ON eyes than in the MS-ON eyes. Therefore, OCT in this setting may simply be another marker of incomplete visual recovery after ON, and it is unclear whether OCT measurements add any further prognostic information regarding the future development of NMO.
Finally, the changes in RNFL are not tissue specific. The thinning reflects loss of axons (and ganglion cell neurons) secondary to acquired, pregeniculate lesions in the visual pathway, although recently a purely pregeniculate origin has been challenged (21). Patients with lesions in the optic radiations had reduced overall RNFL compared with controls, indicating that decreased RNFL in some MS patients may reflect transsynaptic degeneration from postgeniculate axonal loss, accentuated, in some, by episodes of ON causing anterior visual pathway damage (22).
Although most of the thickness of RNFL using OCT is presumed to be from axons, other components, including blood vessels and glial elements, influence the measured thickness (23). A study of 4 eyes with no light perception vision (from different causes of optic neuropathy) and severe optic atrophy showed persistent RNFL thickness of approximately 40–45 μm, illustrating the contribution of other retinal elements (24). Chauhan and Marshall (25) performed progressive ablation of inner retinal tissue in cadaver eyes using excimer laser, with sequential measurement of RNFL thickness using OCT. They found a persistent signal of approximately 36 μm even after destruction of the entire RNFL. These studies suggest that there may be a “floor effect,” in which clinically meaningful data cannot be obtained at RNFL thickness measurements of <40 μm (Fig. 4).
Studies documenting changes in OCT measurements over time suggest that there is considerable variability in measurements among (and within) patients, making it difficult to apply population statistics in cross-sectional studies to the individual patient. Similarly, since progression of disease (optic neuropathy and MS) is highly variable, it can be challenging to detect clinically meaningful (as opposed to statistically significant) change in RNFL thickness with longitudinal monitoring of disease activity. For example, what change in RNFL would be enough to warrant a change in therapy in a patient with MS?
RNFL thickness and macular volume measurements are currently used as a secondary outcome in many ongoing and planned future MS clinical treatment trials. This should provide higher quality longitudinal data about the utility of OCT in monitoring disease. Even so, the issues with test-retest reliability, heterogeneity, and variability in the clinical course of MS among patients and inherent limitations in the technology (floor effect, effect of other ocular disease on measurements) will remain. Further innovations in OCT technology may offer higher levels of resolution and better test-retest variability, but various OCT technologies are not quantitatively comparable to one another. Each new iteration disrupts previous collections of the longitudinal data, which might best inform daily practice. The effect of postgeniculate lesions on RNFL thickness and macular volume might indicate that the measurements obtained with OCT are a mixture of anterior and posterior visual pathway disease, and it may be difficult or impossible to dissect out the “pure” anterior visual pathway axons and ganglion cell neurons. OCT remains a powerful tool, which can complement or augment the metrics currently used to monitor the progression in MS, such as neuroimaging, tests of visual function, and electrophysiologic studies, and will likely be included as an outcome measure in all future clinical trials. Future large-scale, longitudinal studies may provide data, which can more easily be transferred into clinical practice and patient care. More detailed analytic techniques, such as segmentation of the ganglion cell layer within the central macula, may provide more precise and meaningful structure-function relationships (2). However, I suspect that the use of OCT measurements in MS (and NMO) will remain limited to large-scale clinical trials and clinical research for the foreseeable future.
Rebuttal: Fiona Costello, MD, FRCP
I agree with many of the excellent points made by my colleague, Dr Van Stavern regarding the limitations of OCT in the routine management of ON and MS patients. Most OCT publications in MS patients have reported the findings from small, observational studies; and there is a paucity of long-term data. Caution must be exercised in interpreting what incremental changes in retinal architecture may mean in terms of global brain injury in MS. The severity of anterior visual pathway involvement may vary with the age, stage, and subtype of MS; and the extent of RNFL thinning may not be commensurate with other metrics of disease activity for this reason (26). As Dr Van Stavern has indicated, statistical significance is not synonymous with clinical relevance when it comes to determining the amount of RNFL thinning that is meaningful in the management of any given patient. Suffice to say, like any technology, OCT has inherent limitations. These limitations need to be fully understood, lest OCT become an imaging tool that is initially oversold, only to ultimately underdeliver in the area of patient care.
I would also echo the concerns raised by Dr Van Stavern regarding our ability to accurately track MS-related disease activity with OCT in “all comers” because the estimated yearly thinning of the overall RNFL (2 μm) has been below the detection limit of time-domain OCT technologies. This challenge will remain in the Fourier or spectral-domain OCT (SD-OCT) era because the longitudinal monitoring of RNFL is technically challenging (6). While promising methods are on the horizon, there remains uncertainty regarding the optimal approach to obtain and analyze longitudinal OCT data in MS (6). Going forward, the goal will be to define the amount of RNFL change measured by SD-OCT that represents pathology related to MS and to distinguish this “signal” from the “noise” of the technology (27).
I believe the most robust evidence for the use of OCT is in the ON “relapse” model of MS in which there is a clear time of onset, and potential interventions can be tested within a defined time “window” with objectively measurable end points. Even in this context, the effects of potential biases including age of onset of ON, disease duration, history of disease-modifying therapy use, acute management with high-dose corticosteroids (or lack thereof), gender, and MS subtype on RNFL thickness and macular measurements remain unknown. As OCT is implemented in ongoing randomized controlled trials of MS patients, many of the issues that have hampered previous observational studies will be addressed because the randomization process will help equalize the effects of potential confounders.
Returning to the original question and with due respect to the valid concerns raised by my colleague, I would argue that the question could be rephrased as follows: “Should OCT be used to complement our existing arsenal of tools in the management of patients with multiple sclerosis?” I believe that OCT findings should not be interpreted in the absence of validated ophthalmic and/or neurological end points and should not be viewed as a putative “stand-alone” marker of disease activity in MS. As anyone who has ever depended upon GPS (Global Positioning System) can attest, there are obvious pitfalls to reliance on a tool without knowledge of its potential shortcomings. This is equally true for OCT as it is for the MRI. The latter is largely held as the gold-standard surrogate marker of disease activity in MS but is at best, “gold plated.” There is an established dissociation between MRI-measured lesion burden and corresponding deficits on the neurologic examination in MS patients, which is commonly referred to as the “clinical-radiological paradox” (28). While more than 95% of MS patients have MRI manifestations of focal or confluent abnormalities in the white matter of the CNS, the presence of such MRI lesions does not alone confirm the diagnosis of MS (29). Similar neuroimaging lesions can appear in people without clinical signs of disease, and many individuals older than 50 years have nonspecific white matter cerebral lesions, which need to be interpreted with caution (26). Despite these issues, few would suggest that the MRI does not have a role in the management of MS patients. Its utility comes from understanding the context of its use, and balancing the information it provides against its inherent limitations.
To answer Dr Van Stavern's salient question of “What change in RFNL would be enough to warrant a change in therapy in a patient with MS?” my response would be that this decision should be based not upon a single OCT measurement but rather a careful consideration of several factors, including the patient's clinical course, existing comorbidities, knowledge of his/her disease and indications for therapy, recent MRI findings, history and tolerance of disease-modifying therapies, previous response to high-dose corticosteroids, potential contraindications to disease-modifying therapies, lifestyle factors, and, if appropriate, RNFL measurements. While it is true that we do not have established neuroprotective agents in MS, we must avoid the tendency to become somewhat nihilistic in our approach to the long-term management of MS. Instead, we must explore new technologies that might help us better understand the mechanisms and manifestations of disease activity. By doing so, we may be in a more proactive position to objectively measure the purported benefits of current, emerging, and future therapies for our patients.
Finally, OCT is not an esoteric, inaccessible ocular imaging device utilized only in obscure research laboratories, but rather a tool commonly used in clinical ophthalmic practice. Neuro-ophthalmologists need to understand it. I would recommend that our colleagues approach the question posed with a balanced attitude of skeptical curiosity and open-mindedness and determine for themselves how OCT may aid them in the care of their patients.
Rebuttal: Gregory P. Van Stavern, MD
Dr Costello presents a cogent argument for the routine use of OCT in ON and MS. I agree that OCT has enormous potential as a noninvasive method of analyzing and tracking axonal and neuronal loss in MS. However, there remain limits to our ability to infer clinically meaningful information from OCT in a way that informs daily clinical decision making. This test, as with all other testing techniques, must be integrated into the entire clinical picture and combined with other data to make the best decision for a particular patient on a particular day. This actually touches on an important point regarding the use of any paraclinical test, that of clinical expertise and interpretation. The utility of any diagnostic test relies not just on issues such as test–retest reliability, sensitivity, and specificity but on the skill and expertise of the clinician interpreting the test and placing the result into the entire clinical framework (26). Clinicians who utilize a diagnostic procedure frequently and have a high level of expertise in performing and interpreting the test may be better able to integrate the results of that test into patient care. Dr Costello is one of the foremost authorities on the use of OCT in clinical practice and MS, and she is also an expert neuro-ophthalmologist. She also practices in a large, well-respected MS center. Possibly, this combination of factors provides a more favorable environment for using OCT in daily practice.
I also agree that newer OCT modalities, such as high-resolution macular OCT and segmentation analysis, might provide the clinicians better data regarding disease status in their MS patients. However, issues regarding heterogeneity of disease and reproducibility may still hinder routine use, and these newer techniques have yet to be validated. At this time, I do not believe that OCT has a role in the day-to-day management of ON or MS.
Conclusion: Andrew G. Lee, MD and Valérie Biousse, MD
We have witnessed multiple applications of OCT over the past decade. High-quality studies have demonstrated that OCT has enormous potential as a noninvasive method of analyzing and tracking axonal and neuronal loss in ON and even in MS patients without a history of ON. In the right hands, OCT measurements are reliable and reproducible; for the right patient, OCT provides valuable information. Each new study is a step toward a better understanding of how to use this technology to guide us in managing our patients efficiently and better outcome for clinical trials. As emphasized in this debate, it is certainly a mistake to think that OCT can replace measurement of visual function or other clinical markers of disease activity or could be a “stand-alone” test. However, it is probably equally invalid to reject OCT as an ancillary test in patients with ON and MS at this time. We predict that the incorporation of OCT findings into validated ophthalmic and neurological evaluations will likely become routine for neuro-ophthalmologists much in the same way that this has already occurred for automated visual field testing and for MRI in patients with ON and MS.
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