History Of Unilateral Optic Neuritis Research Articles

Application of the International Interocular Difference Thresholds into Practice: Localising the Patient Experience

ABSTRACT Demyelinating diseases of the central nervous system (CNS) often have neuro-ophthalmological manifestations, and retinal examination can be helpful in making the diagnosis. The latest iteration of optical coherence tomography (OCT)-based criteria for optic neuritis in multiple sclerosis has been developed in the research realm, but its application to clinical practice, and to the more uncommon demyelinating diseases requires further study. The ability to use OCT data to distinguish between various CNS demyelinating disorders could provide additional paraclinical tools to accurately diagnose patients. Furthermore, neuro-ophthalmological testing can define the extent of inflammatory damage in the CNS, independent of patient-reported history. New referrals for OCT at a tertiary multiple sclerosis and neuro-immunology referral centre (n = 167) were analysed retrospectively for the self-reporting of optic neuritis, serological test results, and diagnosis. Only approximately 30% of patients with a clinical history of unilateral optic neuritis solely had a unilateral optic neuropathy, nearly 40% of those subjects actually having evidence of bilateral optic neuropathies. Roughly 30% of patients reporting a history of bilateral optic neuritis did not have any evidence of structural disease, with 20% of these patients having a separate, intervenable diagnosis noted on macular scans. OCT is a useful adjunct diagnostic tool in the evaluation of demyelinating disease and has the ability to aid in a more accurate diagnosis for patients. Application of the international interocular difference thresholds to a clinical patient population generally reproduces the original results, emphasising their appropriateness. The analysis distinguishing the demyelinating diseases needs to be replicated in a blinded, multi-centre setting.

Posterior segment spectral domain oct in the differential diagnosis of bilateral temporal optic neuropathy and its correlation with visual acuity.

To identify the underlying etiologies and to evaluate the differential diagnostic value of posterior segment spectral domain OCT measurements and their correlation with best-corrected visual acuity (BCVA) in a group of patients with OCT documented bilateral optic neuropathy limited to the temporal quadrants. Retrospective study. We included 61 patients: 35 presented with presumed "classic" acquired mitochondrial optic neuropathy (MON) (18 nutritional, 11 toxic, 6 mixed toxic-nutritional) and 2 with suspected hereditary MON. Nine patients were identified as 'MON mimickers' (especially multiple sclerosis), and 4 were found to have a mixed mechanism, while 11 remained undiagnosed. Across all etiologies, the strongest positive relationship between BCVA and tested OCT parameters was with macular GCL (ganglion cell layer) and GCIPL (combined ganglion cell and inner plexiform layer) volumes rather than peripapillary retinal nerve fiber layer (RNFL) thicknesses (all statistically significant). There was an inverse relationship between BCVA and inner nuclear layer (INL) volumes, with significant differences for BCVA and all tested OCT parameters between eyes with and without INL microcystoid lesions. OCT (absolute values and intereye differences) was not helpful in distinguishing between presumed acquired mitochondrial disease and patients with multiple sclerosis without optic neuritis. However, significantly greater intereye differences in global RNFL and inner plexiform layer and GCIPL volumes were found in patients with a previous history of unilateral optic neuritis. The strongest positive relationship with BCVA was found for macular GCL and GCIPL volumes. OCT could not differentiate between acquired mitochondrial disease and multiple sclerosis without optic neuritis.

The Role of Optical Coherence Tomography Criteria and Machine Learning in Multiple Sclerosis and Optic Neuritis Diagnosis.

Recent studies have suggested that intereye differences (IEDs) in peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell + inner plexiform (GCIPL) thickness by spectral domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral optic neuritis (ON). However, this requires further validation. Machine learning classification may be useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests, such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and for unilateral ON history. Participants were from 11 sites within the International Multiple Sclerosis Visual System consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining OCT and visual measures was compared individual measurements to determine the best model to distinguish PwMS from controls. These methods were also used to distinguish those with a history of ON among PwMS. Receiver operating characteristic (ROC) curve analysis was performed on a training data set (2/3 of cohort) and then applied to a testing data set (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether machine learning models improved diagnostic capability of OCT. Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs controls. This composite score performed best, with area under the curve (AUC) = 0.89 (95% CI 0.85-0.93), sensitivity = 81%, and specificity = 80%. The composite score ROC curve performed better than any of the individual measures from the model (p < 0.0001). GCIPL IED remained the best single discriminator of unilateral ON history among PwMS (AUC = 0.77, 95% CI 0.71-0.83, sensitivity = 68%, specificity = 77%). SVM analysis performed comparably with standard logistic regression models. A composite score combining visual structure and function improved the capacity of SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with a history of unilateral ON. SVM performed as well as standard statistical models for these classifications. This study provides Class III evidence that SD-OCT accurately distinguishes multiple sclerosis from normal controls as compared with clinical criteria.

Long-term Effect of Permanent Demyelination on Axonal Survival in Multiple Sclerosis.

Background and ObjectivesTo investigate the long-term effect of permanent demyelination on axonal attrition by examining an association between intereye asymmetry of the multifocal visual evoked potential (mfVEP) latency delay and subsequent thinning of retinal ganglion cell axons in patients with a long-standing history of unilateral optic neuritis (ON).MethodsOnly patients with a significant degree of chronic demyelination (intereye latency asymmetry >5 ms) were included in this study. The level of optic nerve demyelination was estimated at baseline by the latency delay of mfVEP, while the degree of axonal loss was assessed by thinning of the retinal nerve fiber layer (RNFL) thickness between baseline and follow-up visits. Low-contrast visual acuity (LCVA) was also evaluated at baseline and follow-up. Patients were examined twice with an average interval of 6.1 ± 1.4 years.ResultsFrom 85 examined patients with multiple sclerosis, 28 satisfied inclusion criteria. Latency of the mfVEP was delayed, and RNFL thickness was reduced in ON eyes compared with fellow eyes at both visits. There was significant correlation between latency asymmetry and baseline or follow-up intereye RNFL thickness asymmetry. Intereye asymmetry of LCVA at baseline correlated with baseline latency asymmetry of mfVEP and baseline asymmetry of RNFL thickness. Latency of the mfVEP in ON eyes improved slightly during the follow-up period, whereas latency of the fellow eye remained stable. By contrast, RNFL thickness significantly declined in both ON and fellow eyes during the follow-up period. The rate of RNFL thinning in ON eyes, however, was more than 2 times faster compared with the fellow eyes (p < 0.001). Furthermore, baseline latency asymmetry significantly correlated with the rate of RNFL thinning in ON eyes during the follow-up (p < 0.001), explaining almost half of the variability of temporal RNFL progression. For each millisecond of latency delay (i.e., ∼0.5 mm of demyelination along the optic nerve), temporal RNFL thickness was annually reduced by 0.05%.DiscussionOur study provides clear in vivo evidence that chronic demyelination significantly accelerates axonal loss. However, because this process is slow and its effect is mild, long-term monitoring is required to establish and confidently measure the neurodegenerative consequences of demyelination.

Agreement of different OCT scan directions for individual retinal-layer thickness measurements in multiple sclerosis subjects with prior unilateral optic neuritis

The similarities between horizontal and vertical Optical Coherence Tomography (OCT) scans for the individual retinal layer thickness measurements in the macula was evaluated. Two volumetric scans (B-scans oriented horizontally and vertically) were performed in 64 multiple sclerosis subjects with history of unilateral optic neuritis and 64 healthy controls. The agreement between the thickness measurements with horizontal and vertical OCT scans was evaluated in 3 groups of eyes: healthy controls, eyes with history of optic neuritis and the fellow eyes. The mean difference in individual layer thickness between the scans was smaller than the instrument’s axial resolution in all 3 groups. The limit of agreement (LoA) varied among the different layers and sectors analyzed and this trend was similar in all the groups. For the inner retinal layers (retinal nerve fiber layer to inner nuclear layer), the inner macular sectors had a larger LoA compared to the corresponding outer sectors. In the outer plexiform and nuclear layers, the central and inner sectors (except inner temporal) had LoA larger than the other sectors and layers. The larger LoA seen for different layers and sectors suggests that the scan direction must be same for the follow-up OCT measurements and in clinical studies.

Retinal Oxygen Metabolism and Haemodynamics in Patients With Multiple Sclerosis and History of Optic Neuritis.

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 μl O2/min), higher in MS-ON (2.1 ± 0.5 μl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 μl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 μl/min) compared to MS-ON (38.3 ± 4.6 μl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 μl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation.Clinical Trial Registration: ClinicalTrials.gov registry, NCT03401879.

Abnormal Dynamic Pupillometry Relates to Neurologic Disability and Retinal Axonal Loss in Patients With Multiple Sclerosis.

PurposeTo assess alterations in quantitative dynamic pupil responses to light in relation to neurologic disability and retinal axonal loss in patients with multiple sclerosis (MS).MethodsTwenty-five patients with relapsing-remitting MS and 25 healthy subjects were included in this cross-sectional study. Pupillary responses were measured with an infrared dynamic pupillometry unit, and peripapillary retinal nerve fiber layer (RNFL) thickness was measured with spectral-domain optical coherence tomography. Neurologic disability was assessed by the Expanded Disability Status Scale (EDSS). Patients with a history of optic neuritis (ON) within 6 months were excluded. Only the right eyes were assessed, except in 11 patients with a history of unilateral ON in whom both eyes were further analyzed to evaluate the effect of previous ON.ResultsThe initial pupil diameter (P = 0.003) and pupil contraction amplitude (P = 0.027) were lower in patients with MS compared with healthy controls. Initial pupil diameter correlated with EDSS score (ρ = −0.458; P = 0.021), and RNFL correlated with contraction latency (ρ = −0.524; P = 0.007). There were no significant differences in any of the pupil parameters between eyes with and without a history of ON, and between the ON and fellow eyes of the 11 patients with previous unilateral ON.ConclusionsDynamic pupillometry reveals significant alterations in pupillary light reflex responses associated with neurologic disability and retinal axonal loss, independent of previous ON.Translational RelevanceDynamic pupillometry is a simple, noninvasive tool that may be useful in detecting autonomic dysfunction in patients with MS.

Optical Coherence Tomography and Optical Coherence Tomography Angiography Findings After Optic Neuritis in Multiple Sclerosis.

Background: In people with multiple sclerosis (MS), optic neuritis (ON) results in inner retinal layer thinning, and reduced density of the retinal microvasculature.Objective: To compare inter-eye differences (IEDs) in macular optical coherence tomography (OCT) and OCT angiography (OCTA) measures in MS patients with a history of unilateral ON (MS ON) vs. MS patients with no history of ON (MS non-ON), and to assess how these measures correlate with visual function outcomes after ON.Methods: In this cross-sectional study, people with MS underwent OCT and OCTA. Superficial vascular plexus (SVP) density of each eye was quantified using a deep neural network. IEDs were calculated with respect to the ON eye in MS ON patients, and with respect to the right eye in MS non-ON patients. Statistical analyses used mixed-effect regression models accounting for intra-subject correlations.Results: We included 43 MS ON patients (with 92 discrete OCT/OCTA visits) and 14 MS non-ON patients (with 24 OCT/OCTA visits). Across the cohorts, mean IED in SVP density was −2.69% (SD 3.23) in MS ON patients, as compared to 0.17% (SD 2.39) in MS non-ON patients (p = 0.002). When the MS ON patients were further stratified according to time from ON and compared to MS non-ON patients with multiple cross-sectional analyses, we identified that IED in SVP density was significantly increased in MS ON patients at 1–3 years (p = < 0.001) and >3 years post-ON (p < 0.001), but not at <3 months (p = 0.21) or 3–12 months post-ON (p = 0.07), while IED in ganglion cell + inner plexiform layer (GCIPL) thickness was significantly increased in MS ON patients at all time points post-ON (p ≦ 0.01 for all). IED in SVP density and IED in GCIPL thickness demonstrated significant relationships with IEDs in 100% contrast, 2.5% contrast, and 1.25% contrast letter acuity in MS ON patients (p < 0.001 for all).Conclusions: Our findings suggest that increased IED in SVP density can be detected after ON in MS using OCTA, and detectable changes in SVP density after ON may occur after changes in GCIPL thickness. IED in SVP density and IED in GCIPL thickness correlate well with visual function outcomes in MS ON patients.

Interocular Difference in Retinal Nerve Fiber Layer Thickness Predicts Optic Neuritis in Pediatric-Onset Multiple Sclerosis.

Optical coherence tomography (OCT) is capable of quantifying retinal damage. Defining the extent of anterior visual pathway injury is important in multiple sclerosis (MS) as a way to document evidence of prior disease, including subclinical injury, and setting a baseline for patients early in the course of disease. Retinal nerve fiber layer (RNFL) thickness is typically classified as low if values fall outside of a predefined range for a healthy population. In adults, an interocular difference (IOD) in RNFL thickness greater than 5 μm identified a history of unilateral optic neuritis (ON). Through our PERCEPTION (PEdiatric Research Collaboration ExPloring Tests in Ocular Neuroimmunology) study, we explored whether RNFL IOD informs on remote ON in a multicenter pediatric-onset MS (POMS) cohort. POMS (defined using consensus criteria and first attack <18 years) patients were recruited from 4 academic centers. A clinical history of ON (>6 months prior to an OCT scan) was confirmed by medical record review. RNFL thickness was measured on Spectralis machines (Heidelberg, Germany). Using a cohort of healthy controls from our centers tested on the same machines, RNFL thickness <86 μm (<2 SDs below the mean) was defined as abnormal. Based on previously published findings in adults, an RNFL IOD >5 μm was defined as abnormal. The proportions of POMS participants with RNFL thinning (<86 μm) and abnormal IOD (>5 μm) were calculated. Logistic regression was used to determine whether IOD was associated with remote ON. A total of 157 participants with POMS (mean age 15.2 years, SD 3.2; 67 [43%] with remote ON) were enrolled. RNFL thinning occurred in 45 of 90 (50%) ON eyes and 24 of 224 (11%) non-ON eyes. An IOD >5 μm was associated with a history of remote ON (P < 0.001). An IOD >5 μm occurred in 62 participants, 40 (65%) with remote ON. Among 33 participants with remote ON but normal RNFL values (≥86 μm in both eyes), 14 (42%) were confirmed to have ON by IOD criteria (>5 μm). In POMS, the diagnostic yield of OCT in confirming remote ON is enhanced by considering RNFL IOD, especially for those patients with RNFL thickness for each eye in the normal range. An IOD >5 μm in patients with previous visual symptoms suggests a history of remote ON.

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis.

ObjectiveTo examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons.MethodsProgressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve.ResultsAlthough both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination.ConclusionsAlthough the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS.

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

Longitudinal study of visual function in patients with relapsing-remitting multiple sclerosis with and without a history of optic neuritis

IntroductionThe contrast sensitivity test determines the quality of visual function in patients with multiple sclerosis (MS). The purpose of this study is to analyse changes in visual function in patients with relapsing-remitting MS with and without a history of optic neuritis (ON). MethodsWe conducted a longitudinal study including 61 patients classified into 3 groups as follows: (a) disease-free patients (control group); (b) patients with MS and no history of ON; and (c) patients with MS and a history of unilateral ON. All patients underwent baseline and 6-year follow-up ophthalmologic examinations, which included visual acuity and monocular and binocular Pelli-Robson contrast sensitivity tests. ResultsMonocular contrast sensitivity was significantly lower in MS patients with and without a history of ON than in controls both at baseline (P=.00 and P=.01, respectively) and at 6 years (P=.01 and P=.02). Patients with MS and no history of ON remained stable throughout follow-up whereas those with a history of ON displayed a significant loss of contrast sensitivity (P=.01). Visual acuity and binocular contrast sensitivity at baseline and at 6 years was significantly lower in the group of patients with a history of ON than in the control group (P=.003 and P=.002 vs P=.006 and P=.005) and the group with no history of ON (P=.04 and P=.038 vs P=.008 and P=.01). However, no significant differences were found in follow-up results (P=.1 and P=.5). ConclusionsMonocular Pelli-Robson contrast sensitivity test may be used to detect changes in visual function in patients with ON.

Pathophysiological basis of low contrast visual acuity loss in multiple sclerosis.

ObjectiveThere is currently an urgent need for reliable clinical biomarkers of remyelination to be used in Phase 2 and Phase 3 clinical trials. Low contrast visual acuity (LCVA) has been suggested as a functional measure of the integrity of the visual pathway. Therefore, the aim of this study was to elucidate the potential contribution of axonal loss and demyelination to LCVA loss in MS patients.MethodIn this study, 50 consecutive relapsing remitting MS patients with a previous history of unilateral optic neuritis were enrolled. Using the linear regression model, we assessed the relative contribution of multifocal Visual Evoked Potentials (mfVEP) latency and Retinal Nerve Fiber Layer (RNFL) thickness to LCVA deficit.ResultsIntereye asymmetry of mfVEP latency and RNFL thickness correlated significantly with intereye asymmetry of LCVA (P < 0.001). A linear regression model demonstrated increased predictive power of LCVA when mfVEP latency and RNFL thinning were combined (reaching R 2 = 0.67) and confirmed a higher predictive value of RNFL thinning compared to mfVEP latency delay for both contrast levels. However, elimination of subjects with severe axonal loss dramatically increased the relative contribution of mfVEP latency, with contribution of RNFL thickness losing significance for both 1.25% and 2.5% LCVA.InterpretationWhile retinal ganglion cell axonal loss is a superior predictor of LCVA, the degree of demyelination contributes significantly to worsening of LCVA, particularly when patients with severe axonal loss are excluded. These results support the feasibility of using LCVA as a functional biomarker in remyelination therapy trials, providing appropriate patient's selection criteria are implemented.

A novel method of inducing endogenous pupil oscillations to detect patients with unilateral optic neuritis

PurposeTo use and test a new method of inducing endogenously generated pupillary oscillations (POs) in patients with unilateral optic neuritis (ON), to describe a signal analysis approach quantifying pupil activity and to evaluate the extent to which POs permit to discriminate patients from control participants.MethodPupil size was recorded with an eye-tracker and converted in real time to modulate the luminance of a stimulus (a 20° disk) presented in front of participants. With this biofeedback setting, an increasing pupil size transforms into a high luminance, entraining a pupil constriction that in turn decreases the stimulus luminance, and so on, resulting in endogenously generated POs. POs were recorded for 30 seconds in the affected eye, in the fellow eye and in binocular conditions with 22 patients having a history of unilateral ON within a period of 5 years, and with 22 control participants. Different signal analysis methods were used to quantify the power and frequency of POs.ResultsOn average, pupil size oscillated at around 1 Hz. The amplitude of POs appears not to be a reliable marker of ON. In contrast, the frequency of POs was significantly lower, and was more variable over time, in the patients’ affected eye, as compared to their fellow eye and to the binocular condition. No such differences were found in control participants. Receiver operating characteristic analyses based on the frequency and the variability of POs to classify patients and control participants gave an area under the curve of 0.82, a sensitivity of 82% (95%CI: 60%-95%) and a specificity of 77% (95%CI: 55%-92%).ConclusionsThe new method used to induce POs allowed characterizing the visual afferent pathway defect in ON patients with encouraging accuracy. The method was fast, easy to use, only requiring that participants look ahead, and allows testing many stimulus parameters (e.g. color, stimulus location, size, etc).

Estudio longitudinal de la función visual en pacientes con esclerosis múltiple remitente-recurrente con y sin antecedentes de neuritis óptica

IntroductionThe contrast sensitivity test determines the quality of visual function in patients with multiple sclerosis (MS). The purpose of this study is to analyse changes in visual function in patients with relapsing-remitting MS with and without a history of optic neuritis (ON). MethodsWe conducted a longitudinal study including 61 patients classified into 3 groups as follows: a) disease-free patients (control group); b) patients with MS and no history of ON; and c) patients with MS and a history of unilateral ON. All patients underwent baseline and 6-year follow-up ophthalmologic examinations, which included visual acuity and monocular and binocular Pelli-Robson contrast sensitivity tests. ResultsMonocular contrast sensitivity was significantly lower in MS patients with and without a history of ON than in controls both at baseline (P=.00 and P=.01, respectively) and at 6 years (P=.01 and P=.02). Patients with MS and no history of ON remained stable throughout follow-up whereas those with a history of ON displayed a significant loss of contrast sensitivity (P=.01). Visual acuity and binocular contrast sensitivity at baseline and at 6 years was significantly lower in the group of patients with a history of ON than in the control group (P=.003 and P=.002 vs P=.006 and P=.005) and the group with no history of ON (P=.04 and P=.038 vs P=.008 and P=.01). However, no significant differences were found in follow-up results (P=.1 and P=.5). ConclusionsMonocular Pelli-Robson contrast sensitivity test may be used to detect changes in visual function in patients with ON.

Spectral-Domain Optical Coherence Tomography of Retinal Nerve Fiber Layer Thickness in NMO Patients

Neuromyelitis optica (NMO) is a demyelinating syndrome of the central nervous system. NMO might be underdiagnosed at early stages when patients have not yet developed the full spectrum of disease. The aim of this study was to analyze the retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT) and to compare RNFL measurements between NMO patients, patients with relapsing-remitting multiple sclerosis (RRMS), and healthy controls to determine whether differences in RNFL thickness could be an early diagnostic marker for NMO. In a cross-sectional study, eyes of 25 NMO patients, 25 RRMS patients, and 50 healthy controls underwent RNFL measurements by OCT. Clinical parameters were collected by history and chart review. Pairwise Wilcoxon rank sum tests with Holm correction were used to compare means of RNFL thickness among 6 groups (NMO, RRMS, and healthy control) of patients [without or with 1 or more episode of optic neuritis (ON)]. The association between RNFL thickness and patient characteristics for NMO group was examined via linear mixed-effects models (adjusting for within-patient intereye correlations and history of ON, where appropriate). Based on the pairwise Wilcoxon rank sum tests with Holm correction, significant differences were found between NMO with 1 episode of ON and non-ON eyes (mean RNFL 63.7 vs 97.0 µm, P < 0.0001), multiple sclerosis (MS) non-ON eyes, and controls (RNFL 93.2 vs 98.4 µm, P = 0.03). No significant differences were found between NMO and MS with 1 attack of ON eyes (RNFL 63.7 vs 73.9 µm, P = 0.46), NMO non-ON eyes and healthy controls (RNFL 97.0 vs 98.4 µm, P = 0.56), and NMO non-ON and MS non-ON (RNFL 97.0 vs 93.2 µm, P = 0.56). For NMO group, RNFL thickness was associated with a history of ON (P < 0.001) but not with disability or disease duration when adjusting for the history of ON (P > 0.1). RNFL in NMO is not different enough to distinguish NMO ON from MS ON eyes, but the intereye difference in RFNL with a history of unilateral ON may be a better diagnostic marker for NMO.

Assessment of Multiple Sclerosis Patients with a Known History of Unilateral Optic Neuritis Shows Optic Nerve Head Component Loss in the Fellow Unaffected Eye (S58.004)

Objective: To assess whether optic nerve head component testing can reveal sub-clinical damage not detected by optical coherence tomography and visual acuity testing in otherwise healthy MS eyes. Background Optical coherence tomography has long been used to determine thinning of the retinal nerve fiber layer, and its corresponding relationship to vision loss; in particular, abnormalities of low contrast letter acuity or sensitivity. A modification in the stimulus characteristics of multifocal electroretinography generates the optic nerve head component potential; a physiologic signature that signifies the integrity of ganglion cell axonal transmission and the transformation of membrane to saltatory conduction as these axons traverse the lamina cribrosa and acquires oligodendrocyte derived myelin. Design/Methods: Patients with multiple sclerosis were recruited to participate in the study. Subjects underwent retinal nerve fiber layer testing by optical coherence tomography (Spectralis), GDx, high and low contrast visual acuity, and blue optic nerve head component testing. The optic nerve head component testing was performed using the Veris FMS3 stimulator with a Grass amplifier and Burrian-Allan bipolar corneal electrode. Infra-red fundus and optic nerve head monitoring were performed throughout the 9 minute recording to ensure fixation and proper nerve head placement. Results: Preliminary data shows a large number of multiple sclerosis patients who have normal visual acuity, visual fields, oct and fundus exams exhibit a higher number of lost optic nerve component waveforms when compared to patients without multiple sclerosis and/or patients with no known history of ophthalmic or neurologic disease. Conclusions: Testing the optic nerve head component can detect damage to previously considered healthy eyes. This method could be used to assess previous damage for upcoming trials of neuro-protective and neuro-regenerative drugs. Supported by: DADS Foundation, Viragh Family Foundation. Disclosure: Dr. Conger has nothing to disclose. Dr. Conger has nothing to disclose. Dr. Frohman has received personal compensation for activities with Biogen Idec and Teva Pharmaceuticals. Dr. Beh has nothing to disclose. Dr. Greenberg has received personal compensation for activities with DioGenix, Greater Good Foundation, Biogen Idec, Serono, Inc., Sanofi-Aventis Pharmaceuticals, Inc., the Multiple Sclerosis Association of America and Teva Neuroscience as a consultant and/or speaker. Dr. Greenberg holds stock and/or stock options in Diogeix. Dr. Greenberg has received research support from Guthy-Jackson Charitable Foundation, Amplimmune, Inc. and the Accelerated Cure Project. Dr. Balcer has received personal compensation for activities with Biogen Idec, Vaccinex and Bayer as a consultant and has received honoraria from Biogen Idec and Novartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Frohman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Acorda Therapeutics, Novartis, Astellas, and Abbott Laboratories, Inc.

Deriving Clinically Useful Visual Evoked Potential Measurements from 120 Sector Multi-Focal Visual Evoked Potential Sequences (P07.259)

Objective: To characterize a high precision and clinically useful paradigm for multifocal, digitally generated, visual evoked potential responses. Background Conventional visual evoked potential techniques are performed with sophisticated, multi-focal stimulators, coupled with digital amplifiers that generate a heterogeneity of cortical responses, with wide variability when compared to the traditional black and white CRT stimulators. While contemporary stimulators represent a technical refinement capable of yielding multi-focal data, with high spatial resolution using m-sequence patterns, no paradigm has been validated to produce a physiologic signature commensurate with the p-100 metric. Design/Methods: Patients with a history of unilateral optic neuritis, along with a control group of healthy patients with no known ophthalmic or neurologic disease, were scanned using the Veris FMS3 Stimulator with a Grass Digital Amplifier. Patients were tested using a 7 minute 120 sector m-sequence multi-focal visual evoked potential test. A standard template was used for each patient. Each electrode was monitored for impedance. The Veris Scientific software was used to formulate an analysis paradigm that would yield valid and reproducible signatures reflecting visual cortical responses. Various combinations of analysis patterns were tested. Results: ROC curves were utilized to assess sensitivity and specificity of data. By dividing the central 20 degrees into three rings, and deriving a single wave form for each of the corresponding geometries, a simulated and reproducible metric was derived, the application of which was confirmed as a highly sensitive and specific discriminator for differentiating normal vs abnormal cortical responses. Conclusions: While multi-focal VEP techniques have impressive spatial resolution, and appear to have utility for confirming pathophysiologic evidence for unilateral visual system dysfunction, the results are not yet comparable to the conventional gold standard p-100 metric. Our proposed technique was effective in segregating geometric ring ratios into a single codified waveform metric, from which normative values can be established. Supported by: DADS Foundation, VIRAGH Family Foundation. Disclosure: Dr. Conger has nothing to disclose. Dr. Conger has nothing to disclose. Dr. Frohman has received personal compensation for activities with Biogen Idec and Teva Pharmaceuticals. Dr. Balcer has received personal compensation for activities with Biogen Idec, Vaccinex and Bayer as a consultant and has received honoraria from Biogen Idec and Novartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Beh has nothing to disclose. Dr. Greenberg has received personal compensation for activities with DioGenix, Greater Good Foundation, Biogen Idec, Serono, Inc., Sanofi-Aventis Pharmaceuticals, Inc., the Multiple Sclerosis Association of America and Teva Neuroscience as a consultant and/or speaker. Dr. Greenberg holds stock and/or stock options in Diogeix. Dr. Greenberg has received research support from Guthy-Jackson Charitable Foundation, Amplimmune, Inc. and the Accelerated Cure Project. Dr. Frohman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Acorda Therapeutics, Novartis, Astellas, and Abbott Laboratories, Inc.

Toward a practical protocol for human optic nerve DTI with EPI geometric distortion correction

To develop a practical protocol for diffusion tensor imaging (DTI) of the human optic nerve with echo planar imaging (EPI) geometric distortion correction. A conventional DTI protocol was modified to acquire images with fat and cerebrospinal fluid (CSF) suppression and field inhomogeneity maps of contiguous coronal slices covering the whole brain. The technique was applied to healthy volunteers and multiple sclerosis patients with and without a history of unilateral optic neuritis. DTI measures and optic nerve tractography before and after geometric distortion correction were compared. Diffusion measures from left and right or from affected and unaffected eyes in different subject cohorts were reported. The image geometry after correction closely resembled reference anatomical images. Optic nerve tractography became feasible after distortion correction. The diffusion measures from the healthy volunteers were in good agreement with the literature. Statistically significant differences were found in the fractional anisotropy and orthogonal eigenvalues between affected and unaffected eyes in optic neuritis patients with poor recovery. The diffusion measures before and after geometric distortion correction were not significantly different. For cohorts without optic neuritis, the difference between diffusion measures from left and right eyes was not statistically significant. The proposed technique could provide a practical DTI protocol to study the human optic nerve.

Relationship of optic nerve and brain conventional and non-conventional MRI measures and retinal nerve fiber layer thickness, as assessed by OCT and GDx: A pilot study

Background Measurement of retinal nerve fiber layer (RNFL) thickness in multiple sclerosis (MS) is gaining increasing attention. Objectives To explore the relationship between RNFL thickness as measured by optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx), and conventional and non-conventional optic nerve and brain MRI measures. Methods Twelve relapsing–remitting (RR) MS patients (12 affected and 12 unaffected eyes) and 4 age- and sex-matched normal controls (NC) (8 unaffected eyes) were enrolled. Four MS patients had a history of bilateral optic neuritis (ON), four had a history of unilateral ON, and 4 had no history of ON. Optic nerve MRI measurements included the length of T2 lesions, measurement of optic nerve atrophy, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) measures. Optic nerve atrophy was measured by a novel method with high reproducibility. Brain MRI measurements included T1 and T2 lesion volumes (LVs) and their relative MTRs, and tissue class specific atrophy, MTR and DTI measures. Measures of RNFL were evaluated with OCT and GDx. We also evaluated both high and low contrast letter acuities (LCLA) in order to determine the relationship between vision, MRI metrics, and retinal structural architecture. Results LCLA, RNFL-OCT and optic nerve radius measures showed more robust differences between NC and MS patients, and between MS patients with affected and unaffected eyes. T2-LV and T1-LV, as well as gray matter atrophy, DTI and MTR measures were related to LCLA and RNFL thickness. Unique additive variance regression models showed that both brain and optic nerve MRI measures independently accounted for about 50% of the variance in LCLA and RNFL thickness. In reverse models, about 20% of the additional independent variance was explained by optic nerve or brain MRI metrics. Conclusions Measurement of RNFL thickness and radius of the optic nerve should be preferred to the other optic nerve MRI measures in clinical studies. Whole brain lesion and GM measures are predictive of impaired visual function with corresponding structural concomitants.