Faculty Bibliography

Background: The retinal microcirculation has been studied in various diseases including multiple sclerosis (MS). However, inter-eye correlations and potential differences of the retinal blood flow velocity (BFV) remain largely unstudied, but may be important in guiding eye selection, as well as the design and interpretation of studies assessing or utilizing retinal BFV.
Objective(s): The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls (HCs). Since prior studies raise the possibility of reduced BFV in MS eyes, a secondary aim was to compare retinal BFVs between MS eyes, grouped based on optic neuritis (ON) history, and HC eyes.
Method(s): Macular arteriole and venule BFVs were determined using a retinal function imager (RFI) in both eyes of 20 HCs. One eye from a total of 38 MS patients comprising 13 eyes with ON (MSON) and 25 eyes without ON (MSNON) history were similarly imaged with RFI.
Result(s): OD (right) and OS (left) BFVs were not significantly different in arterioles (OD: 3.95 +/- 0.59 mm/s; OS: 4.08 +/- 0.60 mm/s, P = 0.10) or venules (OD: 3.11 +/- 0.46 mm/s; OS: 3.23 +/- 0.52 mm/s, P = 0.06) in HCs. Very strong inter-eye correlations were also found between arteriolar (r = 0.84, P < 0.001) and venular (r = 0.87, P < 0.001) BFVs in HCs. Arteriolar (3.48 +/- 0.88 mm/s) and venular (2.75 +/- 0.53 mm/s) BFVs in MSNON eyes were significantly lower than in HC eyes (P = 0.009 and P = 0.005 respectively). Similarly, arteriolar (3.59 +/- 0.69 mm/s) and venular (2.80 +/- 0.45 mm/s) BFVs in MSON eyes were also significantly lower than in HC eyes (P = 0.046 and P = 0.048 respectively). Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other (P = 0.42 and P = 0.48 respectively).
Conclusion(s): Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated. Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes. Moreover, this seems to be the case in both MS eyes with and without a history of ON, raising the possibility of global blood flow alterations in MS. Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes

Background: Optical coherence tomography (OCT) studies have shown that retinal nerve fiber layer (RNFL) and ganglion cell + inner plexiform layer (GCIP) thinning are accelerated in multiple sclerosis (MS). Increased inner nuclear layer (INL) thickness has been associated with inflammatory disease activity, but decreased thicknesses of the INL and outer nuclear layer (ONL) have also been identified in a subset of patients with more severe disability. INL atrophy has also been found post-mortem in MS eyes, more frequently in progressive MS (PMS). These data suggest that there exist differences in retinal pathology at various stages of the disease, however these have been incompletely characterized, as the vast majority of OCT studies comparing retinal measures between MS subtypes have been cross-sectional, with small numbers of PMS eyes.
Objective(s): To assess the effects of age and MS subtype on longitudinal changes in retinal layer thicknesses.
Method(s): A cohort of MS patients and healthy controls (HC), followed with serial spectral-domain OCT, was evaluated. Retinal layer thicknesses were derived utilizing a validated, automated segmentation algorithm. Statistical analyses were performed with mixed-effects linear regression models.
Result(s): Data from 364 MS (178 relapsing-remitting MS [RRMS], 186 PMS) and 66 HC participants were analyzed. Median follow-up duration was 3.6 years. Higher age was associated with slower rates of RNFL atrophy in MS (p<0.001), but not in HC. Rates of GCIP atrophy did not differ across age in MS, but in HC higher age was associated with accelerated rates of GCIP atrophy (p=0.006). The proportion of RNFL and GCIP atrophy in MS attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. PMS was independently associated with accelerated RNFL and GCIP atrophy compared to RRMS (RNFL: p=0.002; GCIP: p=0.001). Higher age was associated with accelerated INL and ONL atrophy and this relationship was similar in MS and HC. INL and ONL atrophy rates were faster in PMS compared to HC (INL: p=0.03; ONL: p=0.04) and RRMS (INL: p=0.008; ONL: p=0.01), but did not differ between RRMS and HC.
Conclusion(s): PMS is independently associated with accelerated retinal layer atrophy, and INL and ONL atrophy may be novel biomarkers of neurodegeneration in PMS. The effects of normal aging on retinal layer thicknesses should be considered when designing clinical trials incorporating OCT measures as outcomes

Background: Myopia's axial elongation of the eye causes an irregularly shaped retina. Cross-sectional studies show that increasing diopters and axial lengths in myopia correlate negatively with Optical Coherence Tomography (OCT) derived measures of Retinal Nerve Fiber Layer (RNFL) thickness. This has largely precluded including OCT data from high myopia individuals in Multiple Sclerosis (MS) and other studies. OCT is a promising marker of neurodegeneration in MS. However, the impact of high myopia in longitudinal studies remains to be investigated.
Objective(s): To assess the impact of high myopia on rates of change in OCT retinal layer thicknesses in MS patients and healthy controls (HC).
Method(s): A 1:2 age and sex matching scheme was used in the MS [13 high myopia (MSHM): 26 non myopia (MSNM)] and HC [7 high myopia (HCHM): 14 non myopia (HCNM)] cohorts. OCT thickness measures of the peripapillary RNFL (pRNFL), ganglion cell+inner plexiform layer (GCIP), and other retinal layers were determined using a validated segmentation algorithm. Mixed effects linear regression was used in statistical analyses.
Result(s): Baseline MSHM eyes had lower GCIP (-4.01 mum, p = 0.06) and pRNFL thicknesses (-8.15 mum, p = 0.04), as compared to MSNM eyes. HC GCIP and pRNFL thicknesses were lower in HCHM than HCNM eyes (-4.15 mum, p = 0.01 and -0.84 mum, p = 0.83 respectively). Despite cross-sectional differences in retinal layer thicknesses in eyes stratified by myopia, longitudinal (median duration of follow-up= 4.6, 6.9, 4.0, 5.1 years in MSHM, MSNM, HCHM, and HCNM respectively) rates of retinal layer change did not differ between participants with and without high myopia. In the MS cohort, rates of thinning were significant in both groups but there was no difference between rates of GCIP and pRNFL thinning among MSHM and MSNM (DELTA0.07 mum/y, p = 0.71 and DELTA0.12 mum/y, p = 0.52 respectively) eyes. Similarly, no difference in rates of GCIP and pRNFL change was found between HCHM and HCNM (DELTA0.06 mum/y, p = 0.49 and DELTA0.21 mum/y, p = 0.22 respectively) eyes. Similar results were observed for the inner and outer nuclear layers in MS and HCs.
Conclusion(s): Although cross-sectional retinal thickness measures may vary due to myopia, longitudinal rates of retinal change appear unaffected. Therefore, despite longstanding opinion, our findings suggest high myopia may not confound longitudinal OCT analyses. Future research is needed to verify and validate our preliminary findings in larger, longitudinal studies

BACKGROUND:STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS:Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS:The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS:These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov, NCT01485003 , registered 5 December 2011.

OBJECTIVE:The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation. Measures of rapid automatic naming (RAN) have been used for over 50 years to capture aspects of vision and cognition. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. We examined MULES performance in youth, collegiate and professional athletes at pre-season baseline and at the sidelines following concussion. METHODS:Our study teams administered the MULES to youth, collegiate and professional athletes during pre-season baseline testing. Sideline post-concussion time scores were compared to pre-season baseline scores among athletes with concussion to determine degrees and directions of change. RESULTS:Among 681 athletes (age 17 ± 4 years, range 6-37, 38% female), average test times at baseline were 41.2 ± 11.2 s. The group included 280 youth, 357 collegiate and 44 professional athletes; the most common sports were ice hockey (23%), soccer (17%) and football (11%). Age was a predictor of MULES test times, with longer times noted for younger participants (P < .001, linear regression). Consistent with other timed performance measures, significant learning effects were noted for the MULES during baseline testing with trial 1 test times (mean 49.2 ± 13.1 s) exceeding those for trial 2 (mean 41.3 ± 11.2 s, P < .0001, paired t-test). Among 17 athletes with concussion during the sports seasons captured to date (age 18 ± 3 years), all showed increases (worsening) of MULES time scores from pre-season baseline (median increase 11.2 s, range 0.6-164.2, P = .0003, Wilcoxon signed-rank test). The Symptom Severity Score from the SCAT5 Symptom Evaluation likewise worsened from pre-season baseline following injury among participants with concussion (P = .002). CONCLUSIONS:Concussed athletes demonstrate worsening performance on the MULES test compared to their baseline time scores. This test samples a wide network of brain pathways and complements other vision-based measures for sideline concussion assessment. The MULES test demonstrates capacity to identify athletes with sports-related concussion.

BACKGROUND:Optical coherence tomography (OCT) measurements of ganglion cell + inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses are associated with visual function (VF) and disability in multiple sclerosis (MS). However, the value of measuring Bruch membrane opening-minimum rim width (BMO-MRW) thickness in MS remains unclear. METHODS:Sixty-eight patients with MS and 22 healthy controls (HCs) underwent spectral domain OCT, 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA), and Expanded Disability Status Scale (EDSS) testing. Mixed-effects linear regression models, accounting for within-subject, intereye correlations, were used to assess relationships. RESULTS:The MS cohort exhibited significantly lower BMO-MRW (P = 0.01), pRNFL at 3.7-, 4.1-, and 4.7-mm diameters surrounding the optic disc (P < 0.001 for all), and GCIPL (P < 0.001) thicknesses than HCs. BMO-MRW thickness was associated with 100%-VA (P < 0.001, R = 0.08), 2.5%-LA (P < 0.001; R = 0.13), and 1.25%-LA (P = 0.002; R = 0.11). All measured pRNFL thicknesses were associated with high- and low-contrast VF (all: P < 0.001). GCIPL thickness was more strongly associated with 100%-VA (P < 0.001; R = 0.23), 2.5%-LA (P < 0.001; R = 0.27), and 1.25%-LA (P < 0.001; R = 0.21) than the other OCT measures assessed. All OCT measures were significantly, but weakly, associated with EDSS scores. CONCLUSIONS:BMO-MRW and pRNFL thicknesses are reduced and associated with VF and disability in MS, but GCIPL thickness is a stronger marker of visual impairment. Our findings corroborate the utility of OCT in providing valuable information regarding the MS disease process.

OBJECTIVE:To determine the optimal thresholds for inter-eye differences in retinal nerve fiber and ganglion cell+inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. BACKGROUND:Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions. METHODS:In this multi-center international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis. RESULTS:Among patients (n=1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer inter-eye difference threshold of 5 microns and ganglion cell+inner plexiform layer threshold of 4 microns for identifying unilateral optic neuritis (n=477). Greater inter-eye differences in acuities were associated with greater inter-eye retinal layer thickness differences (p≤0.001). INTERPRETATION/CONCLUSIONS:Inter-eye differences of 5 microns for retinal nerve fiber layer and 4 microns for macular ganglion cell+inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful to establish the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting.

Objective/UNASSIGNED:Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later. Methods/UNASSIGNED: = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status. Results/UNASSIGNED:= 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models. Interpretation/UNASSIGNED:Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.

PURPOSE OF REVIEW/OBJECTIVE:To review emerging vision-based assessments in the evaluation of concussion. RECENT FINDINGS/RESULTS:Involvement of the visual pathways is common following concussion, the mildest form of traumatic brain injury. The visual system contains widely distributed networks that are prone to neurophysiologic changes after a concussion, resulting in visual symptoms and ocular motor dysfunction. Vision-based testing is increasingly used to improve detection and assess head injury. Several rapid automatized naming (RAN) tasks, such as the King-Devick test and the Mobile Universal Lexicon Evaluation System, show capacity to identify athletes with concussion. Video-oculography (VOG) has gained widespread use in eye-tracking and gaze-tracking studies of head trauma from which objective data have shown increased saccadic latencies, saccadic dysmetria, errors in predictive target tracking, and changes in vergence in concussed individuals. SUMMARY/CONCLUSIONS:RAN tasks demonstrate promise as rapid screening tools for concussion. Further investigation will involve assessment of the role for age, characterization of learning effects over repeated measurements, and identification of optimal thresholds for clinically significant performance decrements. Various RAN tasks are likely to be functionally distinct, engaging different neural networks according to the demands of each task. Measures of saccades, smooth pursuit eye-movements, the vestibulo-ocular reflex and, more recently, disparity vergence are candidate vision-based markers for concussion. Work to adopt these assessments to the sideline or clinical environments is ongoing.