Optical Coherence Tomography (OCT) and Multiple Sclerosis (MS) (abstract)

The Optic Neuritis Treatment Trial (ONTT) was a landmark study in the field of neuro-ophthalmology. This study provided a large-scale systematic view into the course and clinical characteristics of acute demyelinating optic neuritis (ON). ON may be the first clinical demyelinating event in up to 20% of patients with multiple sclerosis (MS) and the overall cumulative probability of developing clinically-definite MS, defined as a second clinical event, was 50% by 15 years after the onset of acute ON. Presence of magnetic resonance imaging (MRI)-detected brain lesions and oligoclonal bands were found to be associated with an increased risk of developing clinically definite MS (CDMS), defined by a second clinical demyelinating event.

OPTICAL COHERENCE TOMOGRAPHY (OCT) AND MULTIPLE SCLEROSIS (MS) Steven L. Galetta MD NYU Langone Medical Center NYU School of Medicine New York, NY LEARNING OBJECTIVES: KEYWORDS 1. Discuss the utility of OCT in the differential diagnosis of optic neuritis 1. Optic Neuritis (ON) 2. Discuss the time course of RNFL and Ganglion Cell layer loss after optic neuritis 3. Discuss the utility of OCT in the management of multiple sclerosis 2. MS-Associated Optic Neuritis (MSON) 3. Optical Coherence Tomography (OCT) 4. Retinal Nerve Fiber Layer (RNFL) 5. Total Macular Volume (TMV) 6. Ganglion Cell/Inner Plexiform Layer (GCL+IPL) CME QUESTIONS: 1. For every line of low contrast acuity loss, approximately how much RNFL is lost in microns? a. 5 b. 10 c. 15 d. 20 e. 25 2. After about of optic neuritis, the majority of the loss of the retinal ganglion cell layer occurs a. b. c. d. e. After 6 weeks of the onset of the visual loss After 3 months of the onset of the visual loss After 6 months of the onset of the visual loss After 1 year of the onset of the visual loss. Very quickly, within weeks of the visual loss 3. The loss of RNFL in patients that are labeled as having benign multiple sclerosis a. Is equal to controls b. Similar to those with a clinically isolated syndrome c. Similar to those with relapsing remitting multiple sclerosis d. Similar to those with secondary progressive multiple sclerosis 7. Microcystic Macular Edema (MMO) BACKGROUND The Optic Neuritis Treatment Trial (ONTT)1-5 was a landmark study in the field of neuro-ophthalmology. This study provided a large-scale systematic view into the course and clinical characteristics of acute demyelinating optic neuritis (ON). ON may be the first clinical demyelinating event in up to 20% of patients with multiple sclerosis (MS)6 and the overall cumulative probability of developing clinicallydefinite MS, defined as a second clinical event, was 50% by 15 years after the onset of acute ON.7 Presence of magnetic resonance imaging (MRI)-detected brain lesions and oligoclonal bands7, 8 were found to be associated with an increased risk of developing clinically definite MS (CDMS), defined by a second clinical demyelinating event. Patients with one or more MRI lesions at baseline had a 56% risk of CDMS at 10 years and a 72% risk at 15 years.7,9 While visual recovery from ON as a first demyelinating event and in the setting of established MS is said to be good,5,10 studies of vision in MS have shown that patients will have continued deficits that are not well captured by high-contrast visual acuity (VA) alone. Visual symptoms in MS may result from a variety of pathological processes, including inflammation, demyelination, and axonal degeneration in the afferent visual pathways.11,12 Subclinical optic neuropathy and involvement of the optic chiasm or post-chiasmal regions of the visual pathway have been reported.13-15 Significant progress has been made in understanding the additional ways to assess qualitative and quantitative visual function in patients with MS. Tests of low-contrast vision, particularly low-contrast letter acuity (LCLA), have emerged as methods that demonstrate the greatest capacity to capture visual impairment in patients with MS.16-19 Vision2017 Annual Meeting Syllabus | 239 specific quality of life (QOL), measured by 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and the 10-Item Neuro-Ophthalmic Supplement has been shown to be reduced among patients with worse visual function by low-contrast letter acuity and with structural changes of RNFL and GCL+IPL thinning by OCT.20-22 These measurements from an ongoing collaborative study23 of visual structure, function and QOL in MS are presented in Table 1. OPTICAL COHERENCE TOMOGRAPHY (OCT) IN MS Optical coherence tomography (OCT) is a non-invasive technique that is close to a tissue level in vivo optical biopsy of the retina. During the past decade, OCT has become increasingly recognized as a highly sensitive method for imaging the retina and optic disc. Imaging of the RNFL, both in the peripapillary region (pRNFL) and in the macula (mRNFL), represents a unique opportunity in the central nervous system to image axons without myelin sheaths (retinal ganglion cell axons are not myelinated until they traverse behind the lamina cribosa). Measures of ganglion cell layer/inner plexiform layer (GCL+IPL) thickness and total macular volume (TMV) also reflect neuronal loss in the anterior visual pathway. In 2006, Costello et al.29 reported that the majority of patients (approximately 75%) with acute ON, 94% of whom had a clinically isolated syndrome, will sustain 10-40 μm thinning of the pRNFL within a period of 3 to 6 months following the acute event. Importantly, pRNFL thinning to the level of 75-80 μm in that study was found to be a "threshold level" below which there were more severe decrements in visual function, as measured by automated perimetry mean deviation. To provide perspective on these measurements, normal pRNFL thickness by TD OCT is approximately 105 μm, with an estimated physiological loss due to aging of only about 0.017% per year from age 18 years onward (approximately 10-20 μm loss over 60 years).30 Pro et al.31 demonstrated mild, relative thickening of the pRNFL in 8 patients with clinical retrobulbar optic neuritis (no visible optic disc swelling on ophthalmoscopy). Even though these OCT findings were subtle, and were within the range of the normal (100.7 μm in affected eye versus 92.9 μm in unaffected eye), the authors pointed out that these represented true change, as the unaffected eye remained stable over follow up. There was subsequent RNFL thinning in these affected eyes below the expected value for disease-free control eyes.31 The RNFL thinning was seen as early as 2-4 months following the acute ON. OCT was thus able to identify very mild, and in some cases clinically undetectable, optic disc edema in eyes with acute ON. These findings represent one way in which OCT has helped to refine the clinical profile of acute ON and of visual pathway structure in MS even in the absence of ON. OCT IN PATIENTS WITH MS AND ON As OCT imaging has advanced to provide retinal detail that is nearly histologic in its level of detail, autopsy studies have likewise have shown that up to 94%-99% of MS patients have detectable optic nerve lesions.24, 25 The earliest application of OCT technology to the study of ON in patients with MS was reported by Parisi et al. in 1999,26 utilizing a first-generation OCT technology. In those patients with MS-associated ON (MSON), pRNFL thickness was reduced by an average of 46 % in eyes with an ON history, compared to disease-free control eyes. Even fellow eyes had RNFL thickness reductions of 28%. In 2005, Trip et al.27 reported further findings using time-domain (TD-) OCT. This study revealed a 33% reduction in pRNFL thickness in eyes with a history of ON and incomplete recovery. Unaffected eyes in this study had a 27% reduction in pRNFL thickness compared to controls. Eyes with a history of ON had macular volume reductions of 11%. These first reports of OCT were thus able to show both axonal loss and retinal ganglion cell loss. OCT CHANGES IN THE SUBACUTE PHASE AND RECOVERY FROM ON The time course of RNFL axonal loss following acute ON may be important for determining the "window of opportunity" for potential intervention with therapies that could protect and repair the nervous system. Reductions in pRNFL thickness in affected eyes, usually by 10-40 μm, are maximal after acute ON within 3-6 months. This pattern of rapid RNFL thinning suggests that significant axonal degeneration follows immediately after the primary demyelinating event.29, 32 There is stabilization of RNFL thickness within 7-12 months from the beginning of the disease.32 However, we now recognize that thinning of the GCL-IPL layer begins within weeks of the onset of acute ON and may precede the thinning of the RNFL narrowing the window of therapeutic window of neuro-repair.93 In 2010, Petzold et al.28 performed a meta-analysis of available published reports on OCT in patients with MS and found pRNFL thinning by an average of 20.38 μm (95% CI 17.91-22.86, n=2063, p<0.0001) in MS eyes with a history of acute ON, and by an average of 7.08 μm (5.52-8.65, n=3154, p<0.0001) in MS eyes without an ON history compared to disease-free controls. Peripapillary RNFL thickness also was found to correlate with visual and neurological functioning. Henderson et al.32 performed comprehensive qualitative and quantitative visual assessments in a study of 23 patients with acute clinically isolated unilateral ON. The mean time to 90% of maximum loss from baseline in pRNFL thickness for affected eyes was 2.38 months. Ninety-nine percent of the degree of pRNFL loss occurred by an average of 4.75 months. The time of first detectable pRNFL thinning compared to the baseline fellow eye value was 1.64 months (95% CI, 0.96-2.32; p<0.05). Eyes with poor recovery had a significantly greater decline of 240 | North American Neuro-Ophthalmology Society RNFL from baseline to 3 months (p=0.002). Macular volumes also declined significantly at the time of last follow-up. We have now learned that GCL/IPL thinning occurs way before pRNFL thinning and in a matter of weeks after the onset of visual loss. OCT IN MS SUBTYPES Costello et al.33 demonstrated that patterns of OCT RNFL thinning may be able to distinguish MS disease subtypes. For ON eyes among the different MS subtypes, differences among groups were noted in the overall and temporal RNFL regions. Patients with CIS had the highest overall RNFL thickness values (mean 87.8 μm), while patients with secondary progressive MS (SPMS) had the greatest degree of thinning compared to control reference values (mean RNFL thickness 70.8 μm). For MS non-ON eyes, RNFL thickness was reduced in patients with primary progressive MS (PPMS, average 94.3 μm p=0.04), relapsing remitting MS (RRMS, average 99.6 μm, p=0.02), and SPMS (average 84.7 μm, p<0.0001) relative to eyes of patients with CIS (average RNFL thickness 105.7 μm). RNFL thickness may thus represent an important structural marker of disease progression. In a study by Pulicken et al.,34 progressive MS patients showed more marked decreases in RNFL and macular volume than relapsing-remitting MS. However, even patients with "benign MS" may have pRNFL axonal loss that is as marked as that of typical RRMS and have reduced vision and QOL. While overall neurologic impairment may be mild in such cases, visual dysfunction may account for a substantial degree of disability in benign MS.35 RNFL THICKNESS IN ASYMPTOMATIC FELLOW EYES IN ON Thinning of RNFL has been observed not only in the eyes with a history of ON, but also in the asymptomatic fellow eyes of MS patients, as well as in MS patients without a clinical history of ON. The average pRNFL thickness was found to be between 91.08 and 109.3 μm in the fellow eye in patients with MSON.27, 31, 34, 36-48 In MS patients with no history suggestive of ON, the average RNFL thickness was between 93.9 and 110.9 μm.34, 48-51 These findings emphasize the common occurrence of subclinical anterior visual pathway axonal loss in patients with MS even in eyes without history of ON. RNFL THINNING AND VISUAL LOSS One of the most important findings that has resulted from the use of OCT MS studies is the association of RNFL thinning to visual loss, as measured by low-contrast letter acuity.23 In 2006, Fisher et al.39 conducted a cross-sectional study that compared RNFL thickness among MS eyes with a history of ON (MS ON eyes), MS eyes without a history of ON (MS non-ON eyes), and disease-free control eyes. These investigators found that RNFL thickness was reduced significantly among MS eyes as a group overall (92 μm) vs. controls (105 μm , p<0.001, generalized estimating equation models, accounting for age and within-patient, inter-eye correlations) and particularly reduced in MS ON eyes (85 mm, p<0.001). Furthermore, lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 μm. These findings supported the validity of low-contrast visual assessment and suggested a potential role for OCT in trials that may examine neuroprotective and other disease-modifying therapies. Several other investigations have demonstrated correlations between RNFL thinning and visual loss.52-54 Costello et al.55 found that RNFL thickness after an episode of isolated ON cannot be used to predict the risk of MS. RELATION OF RNFL THICKNESS TO VISUAL EVOKED POTENTIAL (VEP) AND MRI FINDINGS Several recent studies have highlighted the structure function-correlations provided by neuroimaging (MRI) and electrophysiological testing (visual evoked potentials).56-59 In a retrospective study, visual evoked potential (VEP) latency was found to be sensitive for detecting demyelination,60 while RNFL thickness reflects more structural aspects of optic nerve damage following acute ON. As might be expected, OCT RNFL thickness correlated well with VEP amplitude, but not with the latency.42 In another study, retinal ganglion cell (RGC) axonal loss was associated with retinal dysfunction in eyes of MS patients without a history of ON and evidence of post-chiasmal involvement of the visual pathway.61 In a study that compared 112 partners of patients with MS to a control group of 93 volunteers, abnormal VEP latency in 5 of the partners and one clinically definite case of MS was found. Studies of OCT among partners of people with MS may provide further context for this finding.62 In terms of brain MRI studies, RNFL thickness has been shown to reflect the volumes of brain white and gray matter as well as the normalized volumes of whole brain and white matter.52,63 The correlations between RNFL thickness and MRI measurements of brain atrophy were more significant in the subset of patients with no clinical history of ON than in those who had an ON history in either eye. Studies also suggest that RNFL thickness measurements could be considered a marker for brain atrophy in MS.39 The relation of RNFL thicknesses and brain parenchymal fraction (BPF), measured using highresolution MRI was also recently shown to reflect the likely global nature of axonal and neuronal loss in MS.48 A correlation between RNFL thickness, volume of T1 and T2 lesions, gray matter atrophy, MTR and diffusion tensor 2017 Annual Meeting Syllabus | 241 imaging measures (DTI) measurements in MS patients with or without a history of ON was also reported.38 These MRI parameters also correlated with low-contrast letter acuity measurements, consistent with prior studies suggesting that both posterior and anterior visual pathway disease contribute to visual function in MS.64 Interestingly, in MS patients with optic radiation lesions, a correlation was found between the volume of the lesion and RNFL thickness (p<0.001).65 ROLE FOR OCT IN MONITORING MS THERAPY ADVERSE EVENTS AND EFFICACY Fingolimod, an oral sphingosine-1-phosphate receptor modulator approved for treatment of MS, has been shown in clinical trials to cause macular edema in 0.3-1.2% of patients, with uveitis and other ocular pathology elevating risk.66 Patients present with blurred vision, decreased visual acuity or eye pain. Macular edema resolves in most cases when fingolimod treatment is discontinued.66,67 OCT studies of patients on fingolimod have shown elevations in macular volume consistent with diffuse macular edema; some of these patients were symptomatic, presenting with metamorphopsia and blurred vision.68 Ophthalmologic evaluations, including OCT scans of the macula, are recommended before initiating treatment. Follow-up at 3-4-month intervals is also recommended. Though not common, cases of retinopathy associated with interferon-beta 1a treatment in MS have been reported.69-72 This retinopathy was characterized by clinical/OCT findings of retinal hemorrhages or cotton wool spots at the posterior fundus and improved with discontinuation of medication. In a prospective study of 94 MS patients and 50 healthy subjects followed over 3 years, the authors evaluated whether treatment with interferon 1a, interferon 1b or glatiramer acetate was associated with reduced degrees of RNFL thinning. Progressive RNFL thinning was detected in both the treated and untreated groups, but untreated patients had lower mean RNFL thicknesses. Otherwise, no differences in the treatment groups were noted.73 Another study showed that the peripapillary RNFL, ganglion cell layer thicknesses, and macular volumes measured by OCT were all reduced among patients with or without disease modifying therapy when compared with controls. The abnormal findings were more prominent for MS eyes with an ON history.74 Using various databases and registries, we hope to define meaningful OCT changes in order to help guide therapeutic decisions and to potentially develop criteria to diagnose an asymptomatic optic nerve lesion. 242 | North American Neuro-Ophthalmology Society MICROCYSTIC INNER NUCLEAR LAYER ABNORMALITIES Microcystic changes in the inner nuclear layer (MMO, microcystic macular oedema) are characterized by retinal microcysts in the inner nuclear layer and are easily identified perifoveally on macular spectral-domain OCT. These findings are typically not identifiable by direct ophthalmoscopy, and may be associated with reductions in VA. In many cases, a perifoveal hyporeflective crescent shape can be seen on confocal infrared laser fundus imaging directly correlating with the area of microcysts observed on OCT. It has been hypothesized that inner nuclear layer microcysts associated with various forms of optic neuropathy could be either a sign of inflammation,75,76 autoantibodies against AQP4 and KIR4.1, microglial activation, blood-retina barrier breakdown or retrograde or anterograde trans-synaptic degeneration changes secondary to neurodegeneration.77,78 Microcystic changes in the inner nuclear layers in eyes of patients with MS were first described by Gelfand et al.75 These findings were seen in association with increased disease severity (4.7% of patients), with higher prevalence in patients with a history of ON.75 Further evaluation of MMO found that patients with neuromyelitis optica (NMO), who are known to have a high incidence of ON, had a higher prevalence of MMO (2026%).79,80 Microcystic inner nuclear layer abnormalities are not specific to MS and ON and have been found associated with other optic neuropathies, including hereditary optic neuropathy.81-91 SEGMENTATION AND NEWER TRENDS Segmentation of the macular retinal layers is now possible for use in the clinical and research setting. Thinning of the ganglion cell layer has been demonstrated to be greatest among patients with decrements in vision-specific QOL and among those with the highest degrees of visual loss.92 In a study by Gabilondo et al., retinal changes by OCT in ON were evaluated using the latest segmentation techniques. Changes in ganglion cell layer thickness within the first month were predictive of visual impairment by 6 months.93 These studies, and others, have confirmed an important role for neuronal loss as measured by ganglion cell layer thickness in determining visual disability in MS. In the recent clinical trial of opicinimab in acute optic neuritis, most RGCL/ IPL thinning occurred before the first administration of the drug or within weeks of the onset of the visual loss.95 The implications are that any therapeutic agent is likely going to need to be administered within two weeks and maybe sooner from the onset of the visual loss. OCT angiography is a newer technique that demonstrates the optic nerve blood flow, which may be reflective of the metabolic demand. This is hypothesized to be a sensitive measure of axonal loss. Wang and colleagues showed that eyes of patients with MS and ON had lower flow indices as compared to controls and MS eyes without an ON history. In addition, the flow index was abnormal in a greater proportion of eyes with a history of ON than was the peripapillary RNFL.94 One caution in interpreting these findings might be the very high threshold (thickness below 5th percentile) for categorizing an RNFL thickness measurement as abnormal. CONCLUSIONS OCT has provided a basis for correlating structural aspects of anterior visual pathway axonal and neuronal loss with visual function in ON as well as in MS. It is now known that patients with MS have thinning of the retinal nerve fiber layer (RNFL, axons) and ganglion cell/inner plexiform layer (GCL+IPL, neurons) even in the absence of a history of acute ON. Such patients have clinically meaningful worsening of vision and quality of life (QOL). Furthermore, OCT is useful in patients with MS for distinguishing retinal disease from ON, and for monitoring patients for macular edema associated with use of fingolimod. OCT is a powerful tool that may be used to assess neuro-repair and neuroprotective mechanisms in both acute and chronic optic nerve injury. We are now on the verge of using OCT in MS to make therapeutic decisions as we better understand the values that translate into meaningful clinical change. ACKNOWLEDGMENTS Syllabus modified from: Rachel C. Nolan, BA; Kannan Narayana, MD; Laura J. Balcer, MD, MSCE; Steven L. Galetta, MD. In: Grzybowski A and Barboni P, editors. 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Mean reference values from recent investigations of vision, QOL, and OCT in MS Disease-Free Controls All MS MS, No History of ON MS, History of ON 59 ± 6 (n=52 eyes) 53 ± 10 (n=559 eyes) 55 ± 7 (n=301 eyes) 52 ± 12 (n=252 eyes) 62 ± 4 (n=26 pts) 58 ± 7 (n=273 pts) 59 ± 6 (n=147 pts) 57 ± 8 (n=123 pts) 35 ± 6 (n=52 eyes) 25 ± 12 (n=550 eyes) 27 ± 11 (n=296 eyes) 23 ± 13 (n=248 eyes) 44 ± 4 (n=26 pts) 34 ± 11 (n=273 pts) 36 ± 9 (n=147 pts) 32 ± 112 (n=123 pts) 21 ± 9 (n=52 eyes) 13 ± 11 (n=550 eyes) 15 ± 11 (n=296 eyes) 11 ± 11 (n=248 eyes) 32 ± 5 (n=26 pts) 23 ± 11 (n=271 pts) 25 ± 11 (n=146 pts) 21 ± 12 (n=122 pts) NEI-VFQ-25 composite score, best score=100 98 ± 2 (n=27 pts) 85 ± 15 (n=264 pts) 88 ± 14 (n=142 pts) 82 ± 15 (n=119 pts) 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, best score=100 97 ± 5 (n=28 pts) 78 ± 18 (n=256 pts) 83 ± 16 (n=137 pts) 73 ± 18 (n=117 pts) Peripapillary RNFL thickness, µm 104.5 ± 10.7 (n=219 eyes) 92.5 ± 16.7 (n=1,058 eyes) 95.6 ± 14.5 (n=730 eyes) 85.7 ± 19.0 (n=328 eyes) Total macular volume, mm3 6.84 ± 0.36 (n=219 eyes) 6.54 ± 0.51 (n=1,058 eyes) 6.63 ± 0.48 (n=730 eyes) 6.36 ± 0.53 (n=328 eyes) Peripapillary RNFL thickness, µm 93.0 ± 9.0 (n=48 eyes) 83.1 ± 12.9 (n=529 eyes) 86.4 ± 10.9 (n=287 eyes) 79.1 ± 14.1 (n=236 eyes) Ganglion cell + inner plexiform layer (GCL+IPL), µm 88.9 ± 6.9 (n=61 eyes) 84.1 ± 8.4 (n=239 eyes) 87.0 ± 6.6 (n=150 eyes) 79.7 ± 9.2 (n=87 eyes) Macular Thickness, µm 10.1 ± 0.4 (n=50 eyes) 9.8 ± 0.6 (n=509 eyes) 9.9 ± 0.5 (n=282 eyes) 9.7 ± 0.6 (n=221 eyes) High-contrast visual acuity (VA), ETDRS, number of letters correct Binocular testing Low-contrast letter acuity (2.5%), number of letters correct Binocular testing Low-contrast letter acuity (1.25%), number of letters correct Binocular testing Time-domain (TD) OCT Spectral-domain (SD) OCT Abbreviations: MS = multiple sclerosis; ETDRS = Early Treatment Diabetic Retinopathy Study; QOL = quality of life ; NEI-VFQ-25 = 25-Item National Eye Institute Visual Functioning Questionnaire; TD = time-domain (OCT-3 platform); SD = spectral-domain (Cirrus platform); OCT = optical coherence tomography; RNFL = retinal nerve fiber layer. 246 | North American Neuro-Ophthalmology Society